ramipril and tamsulosin
 

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ED Pills

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tamsulosin


Generic Name: tamsulosin (tam soo LOE sin)
Brand Names: Flomax

What is tamsulosin?

Tamsulosin is in a group of drugs called alpha-adrenergic (AL-fa ad-ren-ER-jik) blockers. Tamsulosin relaxes the muscles in the prostate and bladder neck, making it easier to urinate.

Tamsulosin is used to improve urination in men with benign prostatic hyperplasia (enlarged prostate).

Tamsulosin may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about tamsulosin? You should not use this medication if you are allergic to tamsulosin. Do not take tamsulosin with other similar medicines such as alfuzosin (Uroxatral), doxazosin (Cardura), prazosin (Minipress), silodosin (Rapaflo), or terazosin (Hytrin). Tamsulosin may cause dizziness or fainting, especially when you first start taking it or when you start taking it again. Be careful if you drive or do anything that requires you to be alert. Avoid standing for long periods of time or becoming overheated during exercise and in hot weather. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. If you stop taking tamsulosin for any reason, call your doctor before you start taking it again. You may need a dose adjustment.

Tamsulosin can affect your pupils during cataract surgery. Tell your eye surgeon ahead of time that you are using this medication. Do not stop using tamsulosin before surgery unless your surgeon tells you to.

There are many other drugs that can interact with tamsulosin. Tell your doctor about all medications you use. What should I discuss with my healthcare provider before taking tamsulosin? You should not use this medication if you are allergic to tamsulosin. Do not take tamsulosin with other similar medicines such as alfuzosin (Uroxatral), doxazosin (Cardura), prazosin (Minipress), silodosin (Rapaflo), or terazosin (Hytrin).

If you have a history of prostate cancer, you may need a dose adjustment or special tests to safely take this tamsulosin.

Tamsulosin can affect your pupils during cataract surgery. Tell your eye surgeon ahead of time that you are using this medication. Do not stop using tamsulosin before surgery unless your surgeon tells you to.

Although this medication is not for use in women, tamsulosin is not expected to harm an unborn baby. If you are a woman using this medication, tell your doctor if you are pregnant or breast-feeding. Tamsulosin is not for use in children. How should I take tamsulosin?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results.

Tamsulosin is usually taken once a day, approximately 30 minutes after a meal. Try to take this medication at the same time each day. Do not crush, chew, or open a tamsulosin capsule. Swallow it whole. Tamsulosin lowers blood pressure and may cause dizziness or fainting, especially when you first start taking it, or when you start taking it again. Call your doctor if you have severe dizziness or feel like you might pass out.

You may feel very dizzy when you first wake up. Be careful when standing or sitting up from a lying position.

If you stop taking tamsulosin for any reason, call your doctor before you start taking it again. You may need a dose adjustment.

Your blood pressure and prostate will need to be checked often. Visit your doctor regularly.

Some things can cause your blood pressure to get too low. This includes vomiting, diarrhea, heavy sweating, heart disease, dialysis, a low-salt diet, or taking diuretics (water pills). Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.

Store at room temperature away from moisture and heat.

See also: Tamsulosin dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

If you miss your doses for several days in a row, contact your doctor before restarting the medication. You may need a lower dose.

What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include extreme dizziness or fainting.

What should I avoid while taking tamsulosin? Tamsulosin may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

To prevent dizziness, avoid standing for long periods of time or becoming overheated during exercise and in hot weather.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall. Drinking alcohol can increase certain side effects of tamsulosin. Tamsulosin side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop using tamsulosin and call your doctor at once if you have any of these serious side effects:

feeling like you might pass out;

chest pain;

fever, chills, body aches, or flu symptoms; or

penis erection that is painful or lasts 4 hours or longer.

Less serious side effects may include:

mild dizziness;

weakness, drowsiness;

headache;

nausea, diarrhea;

back pain;

blurred vision;

dental problems;

sleep problems (insomnia);

abnormal ejaculation, decreased sex drive; or

runny nose, sore throat, cough.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Tamsulosin Dosing Information

Usual Adult Dose for Benign Prostatic Hyperplasia:

0.4 mg orally once daily one-half hour following the same meal each day

What other drugs will affect tamsulosin?

Tell your doctor about all other medications you use, especially:

cimetidine (Tagamet);

conivaptan (Vaprisol);

cyclosporine (Gengraf, Neoral, Sandimmune);

imatinib (Gleevec);

isoniazid (for treating tuberculosis);

methimazole (Tapazole);

pioglitazone (Actos);

ropinirole (Requip);

ticlopidine (Ticlid);

warfarin (Coumadin);

an antibiotic such as clarithromycin (Biaxin), dalfopristin/quinupristin (Synercid), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin), metronidazole (Flagyl, Protostat), telithromycin (Ketek), or terbinafine (Lamisil);

an antidepressant such as citalopram (Celexa), clomipramine (Anafranil), desipramine (Norpramin), duloxetine (Cymbalta), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), imipramine (Tofranil), nefazodone, paroxetine (Paxil), sertraline (Zoloft), or tranylcypromine (Parnate);

antifungal medication such as clotrimazole (Mycelex Troche), itraconazole (Sporanox), ketoconazole (Extina, Ketozole, Nizoral, Xolegal), or voriconazole (Vfend);

anti-malaria medication such as chloroquine (Arelan) or pyrimethamine (Daraprim), or quinine (Qualaquin);

erectile dysfunction medicine such as sildenafil (Viagra), tadalafil (Cialis), or vardenafil (Levitra);

heart or blood pressure medication such as diltiazem (Cartia, Cardizem), felodipine (Plendil), nicardipine (Cardene), nifedipine (Nifedical, Procardia), verapamil (Calan, Covera, Isoptin, Verelan), and others;

a heart rhythm medication such as amiodarone (Cordarone, Pacerone) or quinidine (Quin-G);

HIV/AIDS medicine such as atazanavir (Reyataz), delavirdine (Rescriptor), fosamprenavir (Lexiva), indinavir (Crixivan), nelfinavir (Viracept), saquinavir (Invirase), or ritonavir (Norvir); or

medicine to treat psychiatric disorders, such as aripiprazole (Abilify), chlorpromazine (Thorazine), clozapine (Clozaril, FazaClo), fluphenazine (Permitil, Prolixin), haloperidol (Haldol), perphenazine (Trilafon), or thioridazine (Mellaril).

This list is not complete and there are many other drugs that can interact with tamsulosin. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you. More tamsulosin resources Tamsulosin Side Effects (in more detail)Tamsulosin DosageTamsulosin Use in Pregnancy & BreastfeedingDrug ImagesTamsulosin Drug InteractionsTamsulosin Support Group65 Reviews for Tamsulosin - Add your own review/rating tamsulosin Advanced Consumer (Micromedex) - Includes Dosage Information Tamsulosin MedFacts Consumer Leaflet (Wolters Kluwer) Tamsulosin Prescribing Information (FDA) Flomax Prescribing Information (FDA) Flomax Monograph (AHFS DI) Flomax Consumer Overview Compare tamsulosin with other medications Benign Prostatic HyperplasiaOveractive BladderUrinary Tract Stones Where can I get more information? Your pharmacist can provide more information about tamsulosin.

See also: tamsulosin side effects (in more detail)


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Ramipril 1.25mg, 2.5mg, 5mg & 10mg Capsules


Ramipril 1.25mg, 2.5mg, 5mg and 10mg Capsules

Read all of this leaflet carefully before you start taking this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or pharmacist. This medicine has been prescribed for you. Do not pass it on to others. It may harm them even if their symptoms are the same as yours. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. Your doctor may have given you this medicine before from another company. It may have looked slightly different. However, either brand will have the same effect In this leaflet: 1. What ramipril is and what it is used for. 2. Before you take ramipril. 3. How to take ramipril. 4. Possible side effects. 5. How to store ramipril. 6. Further Information. What Ramipril Is And What It Is Used For

The name of your medicine is Ramipril 1.25mg, 2.5mg, 5mg or 10mg Capsules (called ramipril throughout this leaflet). It belongs to a group of medicines called ACE inhibitors (Angiotensin Converting Enzyme Inhibitors).

Ramipril works by:

Decreasing your body’s production of substances that could raise your blood pressure Making your blood vessels relax and widen Making it easier for your heart to pump blood around your body.

Ramipril can be used:

To treat high blood pressure (hypertension) To reduce the risk of you having a heart attack or stroke To reduce the risk or delay the worsening of kidney problems (whether or not you have diabetes) To treat your heart when it cannot pump enough blood to the rest of your body (heart failure) As treatment following heart attack (myocardial infarction) complicated with heart failure. Before You Take Ramipril Do not take ramipril: If you are allergic (hypersensitive) to ramipril, any other ACE inhibitor medicine or any of the other ingredients of ramipril capsules (see Section 6).
Signs of an allergic reaction may include a rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue. If you have ever had a serious allergic reaction called “angioedema”. The signs include itching, hives (urticaria), red marks on the hands, feet and throat, swelling of the throat and tongue, swelling around the eyes and lips, difficulty breathing and swallowing. If you are having dialysis or any other type of blood filtration. Depending on the machine that is used, ramipril may not be suitable for you If you have kidney problems where the blood supply to your kidney is reduced (renal artery stenosis) During the last 6 months of pregnancy (see section below on “Pregnancy and breast-feeding”) If your blood pressure is abnormally low or unstable. Your doctor will need to make this assessment.

Do not take ramipril if any of the above apply to you. If you are not sure, talk to your doctor before taking ramipril.

Take special care with ramipril

Check with your doctor or pharmacist before taking your medicine :

If you have heart, liver or kidney problems If you have lost a lot of body salts or fluids (through being sick (vomiting), having diarrhoea, sweating more than usual, being on a low salt diet, taking diuretics (water tablets) for a long time or having had dialysis) If you are going to have treatment to reduce your allergy to bee or wasp stings (desensitisation) If you are going to receive an anaesthetic. This may be given for an operation or any dental work. You may need to stop your ramipril treatment one day beforehand; ask your doctor for advice If you have high amounts of potassium in your blood (shown in blood test results) If you have a collagen vascular disease such as scleroderma or systemic lupus erythematosus You must tell your doctor if you think that you are (or might become) pregnant. Ramipril is not recommended in the first 3 months of pregnancy and may cause serious harm to your baby after 3 months of pregnancy, see section “Pregnancy and breast-feeding”. Children

Ramipril is not recommended for use in children and adolescents below 18 years of age because there is no information available in this population.

If any of the above apply to you (or you are not sure), talk to your doctor before taking ramipril.

Taking ramipril with other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription (including herbal medicines). This is because ramipril can affect the way some other medicines work. Also some medicines can affect the way ramipril works.

Please tell your doctor if you are taking any of the following medicines. They can make ramipril work less well:

Medicines used to relieve pain and inflammation (e.g. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as ibuprofen or indometacin and aspirin) Medicines used for the treatment of low blood pressure, shock, cardiac failure, asthma or allergies such as ephedrine, noradrenaline or adrenaline. Your doctor will need to check your blood pressure.

Please tell your doctor if you are taking any of the following medicines. They can increase the chance of getting side effects if you take them with ramipril:

Medicines used to relieve pain and inflammation (e.g. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as ibuprofen or indometacin and aspirin) Medicines for cancer (chemotherapy) Medicines to stop the rejection of organs after a transplant such as ciclosporin Diuretics (water tablets) such as furosemide Medicines which can increase the amount of potassium in your blood such as spironolactone, triamterene, amiloride, potassium salts and heparin (for thinning blood) Steroid medicines for inflammation such as prednisolone Allopurinol (used to lower the uric acid in your blood) Procainamide (for heart rhythm problems).

Please tell your doctor if you are taking any of the following medicines. They may be affected by ramipril:

Medicines for diabetes such as oral glucose lowering medicines and insulin. Ramipril may lower your blood sugar. Check your blood sugar closely while taking ramipril Lithium (for mental health problems). Ramipril may increase the amount of lithium in your blood. Your lithium levels will need to be closely checked by your doctor.

If any of the above apply to you (or you are not sure), talk to your doctor before taking ramipril.

Taking ramipril with food and alcohol Drinking alcohol with ramipril may make you feel dizzy or light-headed. If you are concerned about how much you can drink while you are taking ramipril, discuss this with your doctor as medicines used to reduce blood pressure and alcohol can have additive effects. Ramipril may be taken with or without food. Pregnancy and breast-feeding

You must tell your doctor if you think that you are (or might become) pregnant
You should not take ramipril in the first 12 weeks of pregnancy, and you must not take them at all after the 13th week as their use during pregnancy may possibly be harmful to the baby.

If you become pregnant while on ramipril, tell your doctor immediately. A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy.

You should not take ramipril if you are breast-feeding. Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

You may feel dizzy, while taking ramipril. This is more likely to happen when you start taking ramipril or start taking a higher dose. If this happens, do not drive or use any tools or machines.

How To Take Ramipril

Always take ramipril exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Taking this medicine Take this medicine by mouth at the same time of the day each day. Swallow the capsules whole with liquid. Do not crush or chew the capsules. How much to take

Treatment of high blood pressure

The usual starting dose is 1.25mg or 2.5mg once daily. Your doctor will adjust the amount you take until your blood pressure is controlled. The maximum dose is 10 mg once daily. If you are already taking diuretics (water tablets), your doctor may stop or reduce the amount of the diuretic you take before beginning treatment with ramipril.

To reduce the risk of you having a heart attack or stroke

The usual starting dose is 2.5 mg once daily. Your doctor may then decide to increase the amount you take. The usual dose is 10 mg once daily.

Treatment to reduce or delay the worsening of kidney problems

You may be started on a dose of 1.25 mg or 2.5 mg once daily. Your doctor will adjust the amount you are taking. The usual dose is 5 mg or 10 mg once daily.

Treatment of heart failure

The usual starting dose is 1.25 mg once daily. Your doctor will adjust the amount you take. The maximum dose is 10 mg daily. Two administrations per day are preferable.

Treatment after you have had a heart attack

The usual starting dose is 1.25 mg once daily to 2.5 mg twice daily. Your doctor will adjust the amount you take. The usual dose is 10 mg daily. Two administrations per day are preferable.

Elderly

Your doctor will reduce the initial dose and adjust your treatment more slowly.

If you take more ramipril than you should

Tell a doctor or go to the nearest hospital casualty department straight away. Do not drive to the hospital, get somebody else to take you or call for an ambulance. Take the medicine pack with you. This is so the doctor knows what you have taken.

If you forget to take ramipril If you miss a dose, take your normal dose when it is next due. Do not take a double dose to make up for a forgotten capsule.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Possible Side Effects

Like all medicines, ramipril can cause side effects, although not everybody gets them.

Stop taking ramipril and see a doctor straight away, if you notice any of the following serious side effects - you may need urgent medical treatment: Swelling of the face, lips or throat which make it difficult to swallow or breathe, as well as itching and rashes. This could be a sign of a severe allergic reaction to ramipril capsules Severe skin reactions including rash, ulcers in your mouth, worsening of a pre-existing skin disease, reddening, blistering or detachment of skin (such as Stevens-Johnson syndrome, toxic epidermal necrolysis or erythema multiform). Tell your doctor immediately if you experience: Faster heart rate, uneven or forceful heartbeat (palpitations), chest pain, tightness in your chest or more serious problems including heart attack and stroke Shortness of breath or a cough. These could be signs of lung problems Bruising more easily, bleeding for longer than normal, any sign of bleeding (e.g. bleeding from the gums), purple spots, blotching on the skin or getting infections more easily than usual, sore throat and fever, feeling tired, faint, dizzy or having pale skin. These can be signs of blood or bone marrow problems Severe stomach pain which may reach through to your back. This could be a sign of pancreatitis (inflammation of the pancreas). Fever, chills, tiredness, loss of appetite, stomach pain, feeling sick, yellowing of your skin or eyes (jaundice). These can be signs of liver problems such as hepatitis (inflammation of the liver) or liver damage. Other side effects include:

Please tell your doctor if any of the following gets serious or lasts longer than a few days.

Common (affects less than 1 in 10 people)

Headache or feeling tired Feeling dizzy. This is more likely to happen when you start taking ramipril or start taking a higher dose Fainting, hypotension (abnormally low blood pressure), especially when you stand or sit up quickly Dry tickly cough, inflammation of your sinuses (sinusitis) or bronchitis, shortness of breath Stomach or gut pain, diarrhoea, indigestion, feeling or being sick Skin rash with or without raised area Chest pain Cramps or pain in your muscles Blood tests showing more potassium than usual in your blood.

Uncommon (affects less than 1 in 100 people)

Balance problems (vertigo) Itching and unusual skin sensations such as numbness, tingling, pricking, burning or creeping on your skin (paraesthesia) Loss of or change in the way things taste Sleep problems Feeling depressed, anxious, more nervous than usual or restless Blocked nose, difficulty breathing or worsening of asthma A swelling in your gut called “intestinal angioedema” presenting with symptoms like abdominal pain, vomiting and diarrhoea Heartburn, constipation or dry mouth Passing more water (urine) than usual over the day Sweating more than usual Loss or decrease of appetite (anorexia) Increased or irregular heartbeat Swollen arms and legs. This may be a sign of your body holding onto more water than usual Flushing Blurred vision Pain in your joints Fever Sexual inability in men, reduced sexual desire in men or women An increased number of certain white blood cells (eosinophilia) found during a blood test Blood tests showing changes in the way your liver, pancreas or kidneys are working.

Rare (affects less than 1 in 1,000 people)

Feeling shaky or confused Red and swollen tongue Severe flaking or peeling of the skin, itchy, lumpy rash Nail problems (e.g. loosening or separation of a nail from its bed) Skin rash or bruising Blotches on your skin and cold extremities Red, itchy, swollen or watery eyes Disturbed hearing and ringing in your ears Feeling weak Blood tests showing a decrease in the number of red blood cells, white blood cells or platelets or in the amount of haemoglobin.

Very rare (affects less than 1 in 10,000 people)

Being more sensitive to the sun than usual. Other side effects reported:

Please tell your doctor if any of the following gets serious or lasts longer than a few days.

Difficulty concentrating Swollen mouth Blood tests showing too few blood cells in your blood Blood tests showing less sodium than usual in your blood Fingers and toes changing colour when you are cold and then tingling or feeling painful when you warm up (Raynaud’s phenomenon) Breast enlargement in men Slowed or impaired reactions Burning sensation Change in the way things smell Hair loss.

If you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How To Store Ramipril Keep out of the reach and sight of children. Do not use Ramipril Capsules after the expiry date which is stated on the label of the carton. Store below 25°C. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. Further Information What Ramipril Capsules contain. The active substance is ramipril. The other ingredients are pregelatinised starch and gelatin. The 1.25mg capsules also contain titanium dioxide (E171) and yellow ferric oxide (E172). The 2.5mg capsules also contain erythrosine (E127), titanium dioxide (E171) and yellow ferric oxide (E172). The 5mg capsules also contain erythrosine (E127), patent blue (E131) and titanium dioxide (E171). The 10mg capsules also contain erythrosine (E127), indigo carmine (E132), titanium dioxide (E171) and black ferric oxide (E172). What Ramipril Capsules look like and contents of the pack Ramipril 1.25mg Capsules are yellow and white hard capsules. Ramipril 2.5mg Capsules are orange and white hard capsules. Ramipril 5mg Capsules are scarlet and white hard capsules. Ramipril 10mg Capsules are blue and white hard capsules.

All strengths are supplied in blister (calendar) packs of 28 capsules.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Aventis Pharma Ltd 50 Kings Hill Avenue Kings Hill West Malling ME19 4AH UK

Manufacturer

Sanofi Winthrop Industrie 6 Boulevard de L’Europe F-21800 Qu?tigny France

This leaflet does not contain all the information about your medicine. If you have any questions or are not sure about anything, ask your doctor or pharmacist.

This leaflet was last revised in April 2009


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Ramipril 1.25mg, 2.5mg, 5mg & 10mg Tablets


RAMIPRIL 1.25MG, 2.5MG, 5MG AND 10MG TABLETS

Read all of this leaflet carefully before you start taking this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or pharmacist. This medicine has been prescribed for you. Do not pass it on to others. It may harm them even if their symptoms are the same as yours. If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. Your doctor may have given you this medicine before from another company. It may have looked slightly different. However, either brand will have the same effect. In this leaflet: 1. What ramipril is and what it is used for. 2. Before you take ramipril. 3. How to take ramipril. 4. Possible side effects. 5. How to store ramipril. 6. Further Information. What Ramipril Is And What It Is Used For

The name of your medicine is Ramipril 1.25mg, 2.5mg, 5mg or 10mg Tablets (called ramipril throughout this leaflet). It belongs to a group of medicines called ACE inhibitors (Angiotensin Converting Enzyme Inhibitors).

Ramipril works by:

Decreasing your body’s production of substances that could raise your blood pressure Making your blood vessels relax and widen Making it easier for your heart to pump blood around your body.

Ramipril can be used:

To treat high blood pressure (hypertension) To reduce the risk of you having a heart attack or stroke To reduce the risk or delay the worsening of kidney problems (whether or not you have diabetes) To treat your heart when it cannot pump enough blood to the rest of your body (heart failure) As treatment following heart attack (myocardial infarction) complicated with heart failure. Before You Take Ramipril Do not take and tell your doctor before taking this medicine if: If you are allergic (hypersensitive) to ramipril, any other ACE inhibitor medicine or any of the other ingredients of ramipril tablets (see Section 6).
Signs of an allergic reaction may include a rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue. If you have ever had a serious allergic reaction called “angioedema” . The signs include itching, hives (utricaria) red marks on the hands, feet and throat, swelling of the throat and tongue, swelling around the eyes and lips, difficulty breathing and swallowing. If you are having dialysis or any other type of blood filtration. Depending on the machine that is used, ramipril may not be suitable for you If you have kidney problems where the blood supply to your kidney is reduced (renal artery stenosis) During the last 6 months of pregnancy (see section below on “Pregnancy and breast-feeding”) If your blood pressure is abnormally low or unstable. Your doctor will need to make this assessment.

Do not take ramipril if any of the above apply to you. If you are not sure, talk to your doctor before taking ramipril.

Take special care with ramipril

Check with your doctor or pharmacist before taking your medicine:

If you have heart, liver or kidney problems If you have lost a lot of body salts or fluids (through being sick (vomiting), having diarrhoea, sweating more than usual, being on a low salt diet, taking diuretics (water tablets) for a long time or having had dialysis) If you are going to have treatment to reduce your allergy to bee or wasp stings (desensitization) If you are going to receive an anaesthetic. This may be given for an operation or any dental work. You may need to stop your ramipril treatment one day beforehand; ask your doctor for advice If you have high amounts of potassium in your blood (shown in blood test results) If you have a collagen vascular disease such as scleroderma or systemic lupus erythematosus You must tell your doctor if you think that you are (or might become) pregnant. Ramipril is not recommended in the first 3 months of pregnancy and may cause serious harm to your baby after 3 months of pregnancy, see section “Pregnancy and breast-feeding”.

Children

Ramipril is not recommended for use in children and adolescents below 18 years of age because there is no information available in this population.

If any of the above apply to you (or you are not sure),talk to your doctor before taking ramipril.

Taking ramipril with other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription (including herbal medicines). This is because ramipril can affect the way some other medicines work. Also some medicines can affect the way ramipril works.

Please tell your doctor if you are taking any of the following medicines. They can make ramipril work less well:

Medicines used to relieve pain and inflammation (e.g. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as ibuprofen or indometacin and aspirin) Medicines used for the treatment of low blood pressure, shock, cardiac failure, asthma or allergies such as ephedrine, noradrenaline or adrenaline. Your doctor will need to check your blood pressure.

Please tell your doctor if you are taking any of the following medicines. They can increase the chance of getting side effects if you take them with ramipril:

Medicines used to relieve pain and inflammation (e.g. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as ibuprofen or indometacin and aspirin) Medicines for cancer (chemotherapy) Medicines to stop the rejection of organs after a transplant such as ciclosporin Diuretics (water tablets) such as furosemide Medicines which can increase the amount of potassium in your blood such as spironolactone, triamterene, amiloride, potassium salts and heparin (for thinning blood) Steroid medicines for inflammation such as prednisolone Allopurinol (used to lower the uric acid in your blood) Procainamide (for heart rhythm problems).

Please tell your doctor if you are taking any of the following medicines. They may be affected by ramipril:

Medicines for diabetes such as oral glucose lowering medicines and insulin. Ramipril may lower your blood sugar. Check your blood sugar closely while taking ramipril. Lithium (for mental health problems). Ramipril may increase the amount of lithium in your blood. Your lithium levels will need to be closely checked by your doctor.

If any of the above apply to you (or you are not sure), talk to your doctor before taking ramipril.

Taking ramipril with food and alcohol Drinking alcohol with ramipril may make you feel dizzy or light-headed. If you are concerned about how much you can drink while you are taking ramipril, discuss this with your doctor as medicines used to reduce blood pressure and alcohol can have additive effects. Ramipril may be taken with or without food. Pregnancy and breast-feeding

You must tell your doctor if you think that you are (or might become) pregnant

You should not take ramipril in the first 12 weeks of pregnancy, and you must not take them at all after the 13th week as their use during pregnancy may possibly be harmful to the baby.

If you become pregnant while on ramipril, tell your doctor immediately. A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy.

You should not take ramipril if you are breast-feeding.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

You may feel dizzy, while taking ramipril. This is more likely to happen when you start taking ramipril or start taking a higher dose. If this happens, do not drive or use any tools or machines.

How To Take Ramipril

Always take ramipril exactly as your doctor has told you.

You should check with your doctor or pharmacist if you are not sure.

Taking this medicine Take this medicine by mouth at the same time of the day. Swallow the tablets whole with liquid. Do not crush or chew the tablets. How much to take

Treatment of high blood pressure

The usual starting dose is 1.25mg or 2.5mg once daily. Your doctor will adjust the amount you take until your blood pressure is controlled. The maximum dose is 10 mg once daily. If you are already taking diuretics (water tablets), your doctor may stop or reduce the amount of the diuretic you take before beginning treatment with ramipril.

To reduce the risk of you having a heart attack or stroke

The usual starting dose is 2.5 mg once daily. Your doctor may then decide to increase the amount you take. The usual dose is 10 mg once daily.

Treatment to reduce or delay the worsening of kidney problems

You may be started on a dose of 1.25 mg or 2.5 mg once daily. Your doctor will adjust the amount you are taking. The usual dose is 5 mg or 10 mg once daily.

Treatment of heart failure

The usual starting dose is 1.25 mg once daily. Your doctor will adjust the amount you take. The maximum dose is 10 mg daily. Two administrations per day are preferable.

Treatment after you have had a heart attack

The usual starting dose is 1.25 mg once daily to 2.5 mg twice daily. Your doctor will adjust the amount you take. The usual dose is 10 mg daily. Two administrations per day are preferable.

Elderly

Your doctor will reduce the initial dose and adjust your treatment more slowly.

If you take more ramipril than you should

Tell a doctor or go to the nearest hospital casualty department straight away. Do not drive to the hospital, get somebody else to take you or call for an ambulance. Take the medicine pack with you. This is so the doctor knows what you have taken.

If you forget to take ramipril If you miss a dose, take your normal dose when it is next due. Do not take a double dose to make up for a forgotten tablet.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Possible Side Effects

Like all medicines, ramipril can cause side effects, although not everybody gets them.

Stop taking ramipril and see a doctor straight away, if you notice any of the following serious side effects - you may need urgent medical treatment: Swelling of the face, lips or throat which make it difficult to swallow or breathe, as well as itching and rashes. This could be a sign of a severe allergic reaction to ramipril tablets. Severe skin reactions including rash, ulcers in your mouth, worsening of a pre-existing skin disease, reddening, blistering or detachment of skin (such as Stevens-Johnson syndrome, toxic epidermal necrolysis or erythema multiform). Tell your doctor immediately if you experience: Faster heart rate, uneven or forceful heartbeat (palpitations), chest pain, tightness in your chest or more serious problems including heart attack and stroke Shortness of breath or a cough. These could be signs of lung problems Bruising more easily, bleeding for longer than normal, any sign of bleeding (e.g. bleeding from the gums), purple spots, blotching on the skin or getting infections more easily than usual, sore throat and fever, feeling tired, faint, dizzy or having pale skin. These can be signs of blood or bone marrow problems Severe stomach pain which may reach through to your back. This could be a sign of pancreatitis (inflammation of the pancreas). Fever, chills, tiredness, loss of appetite, stomach pain, feeling sick, yellowing of your skin or eyes (jaundice). These can be signs of liver problems such as hepatitis (inflammation of the liver) or liver damage. Other side effects include:

Please tell your doctor if any of the following gets serious or lasts longer than a few days.

Common (affects less than 1 in 10 people)

Headache or feeling tired Feeling dizzy. This is more likely to happen when you start taking ramipril or start taking a higher dose Fainting, hypotension (abnormally low blood pressure), especially when you stand or sit up quickly Dry tickly cough, inflammation of your sinuses (sinusitis) or bronchitis, shortness of breath Stomach or gut pain, diarrhoea, indigestion, feeling or being sick Skin rash with or without raised area Chest pain Cramps or pain in your muscles Blood tests showing more potassium than usual in your blood.

Uncommon (affects less than 1 in 100 people)

Balance problems (vertigo) Itching and unusual skin sensations such as numbness, tingling, pricking, burning or creeping on your skin (paraesthesia) Loss or change in the way things taste Sleep problems Feeling depressed, anxious, more nervous than usual or restless Blocked nose, difficulty breathing or worsening of asthma A swelling in your gut called “intestinal angioedema” presenting with symptoms like abdominal pain, vomiting and diarrhoea Heartburn, constipation or dry mouth Passing more water (urine) than usual over the day Sweating more than usual Loss or decrease of appetite (anorexia) Increased or irregular heartbeat Swollen arms and legs. This may be a sign of your body holding onto more water than usual Flushing Blurred vision Pain in your joints Fever Sexual inability in men, reduced sexual desire in men or women An increased number of certain white blood cells (eosinophilia) found during a blood test Blood tests showing changes in the way your liver, pancreas or kidneys are working.

Rare (affects less than 1 in 1,000 people)

Feeling shaky or confused Red and swollen tongue Severe flaking or peeling of the skin, itchy, lumpy rash Nail problems (e.g. loosening or separation of a nail from its bed) Skin rash or bruising Blotches on your skin and cold extremities Red, itchy, swollen or watery eyes Disturbed hearing and ringing in your ears Feeling weak Blood tests showing a decrease in the number of red blood cells, white blood cells or platelets or in the amount of haemoglobin.

Very rare (affects less than 1 in 10,000 people)

Being more sensitive to the sun than usual. Other side effects reported:

Please tell your doctor if any of the following gets serious or lasts longer than a few days.

Difficulty concentrating Swollen mouth Blood tests showing too few blood cells in your blood Blood tests showing less sodium than usual in your blood Fingers and toes changing colour when you are cold and then tingling or feeling painful when you warm up (Raynaud's phenomenon) Breast enlargement in men Slowed or impaired reactions Burning sensation Change in the way things smell Hair loss.

If you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How To Store Ramipril Keep out of the reach and sight of children. Do not use Ramipril Tablets after the expiry date which is stated on the carton and blister packs. The expiry date refers to the last day of that month Store below 25°C. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. Further Information What Ramipril Tablets contain. The active substance is ramipril. Tablets: The other ingredients are methylhydroxypropylcellulose, pregelatinised maize starch, microcrystalline cellulose, sodium stearyl fumarate, E172 (in the 2.5 and 5mg) What Ramipril Tablets look like and contents of the pack Ramipril 1.25mg Tablets are white to almost white oblong tablets with score-line. The upper face is marked with 1.25 and a logo and the lower face is marked with HMN and 1.25. Ramipril 2.5mg Tablets are yellowish to yellow oblong tablets with a score-line. The upper face is marked with 2.5 and a logo and the lower face is marked with HMR and 2.5. Ramipril 5mg Tablets are pale red oblong tablets with a score-line. The upper face is marked with 5 and a logo and the lower face is marked with HMP and 5. Ramipril 10mg Tablets are white to almost white oblong tablets with a score-line. The upper face is marked with HMO/HMO and the lower face is unmarked.

All strengths are supplied in PVC aluminium blisters in packs of 28 or 30 tablets. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Aventis Pharma Ltd 50 Kings Hill Avenue Kings Hill West Malling ME19 4AH UK

Manufacturer

Sanofi-Aventis S.p.A. SS 17 Km 22 Scoppito (AQ) Italy

This leaflet does not contain all the information about your medicine. If you have any questions or are not sure about anything, ask your doctor or pharmacist.

This leaflet was last revised in (03/2009)

‘Winthrop’ is a registered trade mark


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Flomax


Generic Name: tamsulosin (Oral route)

tam-SOO-loe-sin hye-droe-KLOR-ide

Commonly used brand name(s)

In the U.S.

Flomax

Available Dosage Forms:

Capsule

Therapeutic Class: Benign Prostatic Hypertrophy Agent

Pharmacologic Class: Tamsulosin

Uses For Flomax

Tamsulosin is used to treat men who have symptoms of an enlarged prostate gland, which is also known as benign enlargement of the prostate (benign prostatic hyperplasia or BPH). Benign enlargement of the prostate is a problem that can occur in men as they get older. The prostate gland is located below the bladder. As the prostate gland enlarges, certain muscles in the gland may become tight and get in the way of the tube that drains urine from the bladder. This can cause problems in urinating, such as a need to urinate often, a weak stream when urinating, or a feeling of not being able to empty the bladder completely.

Tamsulosin helps relax the muscles in the prostate and the opening of the bladder. This may help increase the flow of urine or decrease the symptoms. However, tamsulosin will not shrink the prostate. The prostate may continue to get larger. This may cause the symptoms to become worse over time. Therefore, even though tamsulosin may lessen the problems caused by enlarged prostate now, surgery still may be needed in the future.

This medicine is available only with your doctor's prescription.

Before Using Flomax

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Tamsulosin is not indicated for use in the pediatric population.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of tamsulosin in the elderly.

Pregnancy Pregnancy Category Explanation All Trimesters B Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus. Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Atazanavir Clarithromycin Indinavir Itraconazole Ketoconazole Nefazodone Nelfinavir Ritonavir Saquinavir Tadalafil Telithromycin

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Acebutolol Alprenolol Atenolol Betaxolol Bevantolol Bisoprolol Bucindolol Carteolol Carvedilol Celiprolol Cimetidine Dilevalol Esmolol Labetalol Levobunolol Mepindolol Metipranolol Metoprolol Nadolol Nebivolol Oxprenolol Paroxetine Penbutolol Pindolol Propranolol Sildenafil Sotalol Talinolol Tertatolol Timolol Vardenafil Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

Allergy to sulfa drugs (e.g., sulfamethoxazole, sulfasalazine, sulfasoxazole, Azulfidine®, Bactrim®, or Septra®)—Increased allergic reaction risk in patients with this condition. Kidney disease or Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body. Low blood pressure—Use with caution. May make this conditions worse. Proper Use of Flomax

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine comes with a patient information insert. Read and follow the instructions in the insert carefully. Ask your doctor if you have any questions.

Take the capsule approximately 30 minutes after the same meal each day. Swallow the capsule whole. Do not crush, chew, or open it.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For oral dosage form (capsules): For benign prostatic hyperplasia: Adults—At first, 0.4 milligram (mg) once a day. Your doctor may increase your dose if needed. Children—Use is not recommended. Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Flomax

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly and to check for unwanted effects.

Women and children should not use this medicine.

Dizziness, lightheadedness, or fainting may occur after you take this medicine, especially when you get up from a lying or sitting position. Getting up slowly may help lessen this problem. If you feel dizzy, lie down so you do not faint. Then sit for a few moments before standing to prevent the dizziness from returning.

Because tamsulosin may cause some people to become dizzy or feel faint, make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

This medication may rarely cause a severe allergic reaction (swelling of face, tongue, or throat; difficulty breathing; and blistering of the skin. Check with your doctor immediately if this occurs.

You should seek medical attention right away if you experience a prolonged erection while using this medicine. This is an extremely rare unwanted effect that must be treated right away to prevent permanent erectile damage (impotence).

If you plan to have cataract surgery, tell your eye doctor (ophthalmologist) that you are taking this medicine or that you used this medicine in the past 9 months. A serious eye problem called Intraoperative Floppy Iris Syndrome (IFIS) has occurred in some patients who were taking this medicine or who had recently taken this medicine when they had cataract surgery.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Flomax Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common Cough or hoarseness fever or chills lower back or side pain painful or difficult urination Less common Chest pain Rare Dizziness or lightheadedness dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position fainting feeling of constant movement of self or surroundings painful or prolonged erection of the penis sensation of spinning Incidence not known Blistering, peeling, or loosening of the skin blurred vision confusion diarrhea difficult or labored breathing fast, pounding, or irregular heartbeat or pulse itching joint or muscle pain large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs red skin lesions, often with a purple center red, irritated eyes shortness of breath or troubled breathing sore throat sores, ulcers, or white spots in the mouth or on the lips sweating tightness of the chest or wheezing unusual tiredness or weakness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common Abnormal ejaculation back pain body aches or pain congestion headache lack or loss of strength sneezing stuffy or runny nose tender, swollen glands in the neck trouble with swallowing voice changes Less common Decreased interest in sexual intercourse decreased sexual drive or performance drowsiness inability to have or keep an erection increased cough loss in sexual ability, desire, drive, or performance nausea pain or tenderness around the eyes and cheekbones sleepiness or unusual drowsiness sleeplessness tooth disorder trouble with sleeping unable to sleep Incidence not known Constipation hives or welts redness of the skin skin rash vomiting

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Flomax side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Flomax resources Flomax Side Effects (in more detail) Flomax Dosage Flomax Use in Pregnancy & Breastfeeding Drug Images Flomax Drug Interactions Flomax Support Group 53 Reviews for Flomax - Add your own review/rating Flomax Prescribing Information (FDA) Flomax Consumer Overview Flomax Monograph (AHFS DI) Flomax MedFacts Consumer Leaflet (Wolters Kluwer) Tamsulosin Prescribing Information (FDA) Compare Flomax with other medications Benign Prostatic Hyperplasia Overactive Bladder Urinary Tract Stones
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Ramipril 1.25 mg Capsules (Winthrop Pharmaceuticals UK Ltd)


1. Name Of The Medicinal Product

Ramipril 1.25 mg Capsules

2. Qualitative And Quantitative Composition

1.25 mg ramipril.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Yellow opaque/white opaque hard gelatin capsules.

4. Clinical Particulars 4.1 Therapeutic Indications - Treatment of hypertension.

- Cardiovascular prevention: reduction of cardiovascular morbidity and mortality in patients with:

    o manifest atherothrombotic cardiovascular disease (history of coronary heart disease or stroke, or peripheral vascular disease) or

o diabetes with at least one cardiovascular risk factor (see section 5.1).

- Treatment of renal disease:     o Incipient glomerular diabetic nephropathy as defined by the presence of microalbuminuria,

o Manifest glomerular diabetic nephropathy as defined by macroproteinuria in patients with at least one cardiovascular risk factor (see section 5.1),

o Manifest glomerular non diabetic nephropathy as defined by macroproteinuria

- Treatment of symptomatic heart failure.

- Secondary prevention after acute myocardial infarction: reduction of mortality from the acute phase of myocardial infarction in patients with clinical signs of heart failure when started > 48 hours following acute myocardial infarction.

4.2 Posology And Method Of Administration

Oral use.

It is recommended that ramipril capsules are taken each day at the same time of the day.

Ramipril capsules can be taken before, with or after meals, because food intake does not modify its bioavailability (see section 5.2).

Ramipril capsules should be swallowed with liquid. They must not be chewed or crushed.

Adults

Diuretic-Treated patients

Hypotension may occur following initiation of therapy with ramipril; this is more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume and/or salt depleted.

If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with ramipril (see section 4.4).

In hypertensive patients in whom the diuretic is not discontinued, therapy with ramipril should be initiated with a 1.25 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of ramipril should be adjusted according to blood pressure target.

Hypertension

The dose should be individualised according to the patient profile (see section 4.4) and blood pressure control.

Ramipril may be used in monotherapy or in combination with other classes of antihypertensive medicinal products.

Starting dose

Ramipril should be started gradually with an initial recommended dose of 2.5 mg daily.

Patients with a strongly activated renin-angiotensin-aldosterone system may experience an excessive drop in blood pressure following the initial dose. A starting dose of 1.25 mg is recommended in such patients and the initiation of treatment should take place under medical supervision (see section 4.4).

Titration and maintenance dose

The dose can be doubled at interval of two to four weeks to progressively achieve target blood pressure; the maximum permitted dose of ramipril is 10 mg daily. Usually the dose is administered once daily.

Cardiovascular prevention

Starting dose

The recommended initial dose is 2.5 mg of ramipril once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose should be gradually increased. It is recommended to double the dose after one or two weeks of treatment and - after another two to three weeks - to increase it up to the target maintenance dose of 10 mg ramipril once daily.

See also posology on diuretic treated patients above.

Treatment of renal disease

In patients with diabetes and microalbuminuria:

Starting dose:

The recommended initial dose is 1.25 mg of ramipril once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

In patients with diabetes and at least one cardiovascular risk

Starting dose:

The recommended initial dose is 2.5 mg of ramipril once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the daily dose to 5 mg ramipril after one or two weeks and then to 10 mg ramipril after a further two or three weeks is recommended. The target daily dose is 10 mg.

In patients with non- diabetic nephropathy as defined by macroproteinuria

Starting dose:

The recommended initial dose is 1.25 mg of ramipril once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

Symptomatic heart failure

Starting dose

In patients stabilized on diuretic therapy, the recommended initial dose is 1.25 mg daily.

Titration and maintenance dose

Ramipril should be titrated by doubling the dose every one to two weeks up to a maximum daily dose of 10 mg. Two administrations per day are preferable.

Secondary prevention after acute myocardial infarction and with heart failure

Starting dose

After 48 hours, following myocardial infarction in a clinically and haemodynamically stable patient, the starting dose is 2.5 mg twice daily for three days. If the initial 2.5 mg dose is not tolerated a dose of 1.25 mg twice a day should be given for two days before increasing to 2.5 mg and 5 mg twice a day. If the dose cannot be increased to 2.5 mg twice a day the treatment should be withdrawn.

See also posology on diuretic treated patients above.

Titration and maintenance dose

The daily dose is subsequently increased by doubling the dose at intervals of one to three days up to the target maintenance dose of 5 mg twice daily.

The maintenance dose is divided in 2 administrations per day where possible.

If the dose cannot be increased to 2.5 mg twice a day treatment should be withdrawn. Sufficient experience is still lacking in the treatment of patients with severe (NYHA IV) heart failure immediately after myocardial infarction. Should the decision be taken to treat these patients, it is recommended that therapy be started at 1.25 mg once daily and that particular caution be exercised in any dose increase.

Special populations

Patients with renal impairment

Daily dose in patients with renal impairment should be based on creatinine clearance (see section 5.2):

- if creatinine clearance is

- if creatinine clearance is between 30-60 ml/min, it is not necessary to adjust the initial dose (2.5 mg/day); the maximal daily dose is 5 mg;

- if creatinine clearance is between 10-30 ml/min, the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg;

- in haemodialysed hypertensive patients: ramipril is slightly dialysable; the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg; the medicinal product should be administered a few hours after haemodialysis is performed.

Patients with hepatic impairment (see section 5.2)

In patients with hepatic impairment, treatment with ramipril must be initiated only under close medical supervision and the maximum daily dose is 2.5 mg ramipril.

Elderly

Initial doses should be lower and subsequent dose titration should be more gradual because of a greater chance of undesirable effects especially in very old and frail patients. A reduced initial dose of 1.25 mg ramipril should be considered.

Paediatric population

Ramipril is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy.

4.3 Contraindications

- Hypersensitivity to the active substance, any of the excipients or any other ACE(Angiotensin Converting Enzyme) inhibitors (see section 6.1).

- History of angioedema (hereditary, idiopathic or due to previous angioedema with ACE inhibitors or AIIRAs).

- Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5)

- Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney

- 2nd and 3rd trimester of pregnancy (see sections 4.4 and 4.6)

- Ramipril must not be used in patients with hypotensive or haemodynamically unstable states.

4.4 Special Warnings And Precautions For Use

Special populations

Pregnancy: ACE inhibitors such as ramipril, or Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued ACE inhibitor/ AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors/ AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

o Patients at particular risk of hypotension

- Patients with strongly activated renin-angiotensin-aldosterone system

Patients with strongly activated renin-angiotensin-aldosterone system are at risk of an acute pronounced fall in blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor or a concomitant diuretic is given for the first time or at first dose increase.

Significant activation of renin-angiotensin-aldosterone system is to be anticipated and medical supervision including blood pressure monitoring is necessary, for example in:

• patients with severe hypertension.

• patients with decompensated congestive heart failure

• patients with haemodynamically relevant leftventricular inflow or outflow impediment (e.g.stenosis of the aortic or mitral valve ).

• patients with unilateral renal artery stenosis with a second functional kidney

• patients in whom fluid or salt depletion exists or may develop (including patients with diuretics)

• patients with liver cirrhosis and/or ascites

• patients undergoing major surgery or during anaesthesia with agents that produce hypotension.

Generally, it is recommended to correct dehydration, hypovolaemia or salt depletion before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed up against the risk of volume overload).

- Transient or persistent heart failure post MI

- Patients at risk of cardiac or cerebral ischemia in case of acute hypotension

The initial phase of treatment requires special medical supervision.

o Elderly patients

See section 4.2.

Surgery

It is recommended that treatment with angiotensin converting enzyme inhibitors such as ramipril should be discontinued where possible one day before surgery.

Monitoring of renal function

Renal function should be assessed before and during treatment and dosage adjusted especially in the initial weeks of treatment. Particularly careful monitoring is required in patients with renal impairment (see section 4.2). There is a risk of impairment of renal function, particularly in patients with congestive heart failure or after a renal transplant.

Angioedema

Angioedema has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8).

In case of angioedema, ramipril must be discontinued.

Emergency therapy should be instituted promptly. Patient should be kept under observation for at least 12 to 24 hours and discharged after complete resolution of the symptoms.

Intestinal angioedema has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8). These patients presented with abdominal pain (with or without nausea or vomiting).

Anaphylactic reactions during desensitization

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased under ACE inhibition. A temporary discontinuation of ramipril should be considered prior to desensitization.

Hyperkalaemia

Hyperkalaemia has been observed in some patients treated with ACE inhibitors including ramipril. Patients at risk for development of hyperkalaemia include those with renal insufficiency, age (> 70 years), uncontrolled diabetes mellitus, or those using potassium salts, potassium retaining diuretics and other plasma potassium increasing active substances, or conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been rarely seen and bone marrow depression has also been reported. It is recommended to monitor the white blood cell count to permit detection of a possible leucopoenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease (e.g. lupus erythematosus or scleroderma), and all those treated with other medicinal products that can cause changes in the blood picture (see sections 4.5 and 4.8).

Ethnic differences

ACE inhibitors cause higher rate of angioedema in black patients than in non black patients.

As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black people than in non black patients, possibly because of a higher prevalence of hypertension with low renin level in the black hypertensive population.

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Contra-indicated combinations

Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Precautions for use

Potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances (including Angiotensin II antagonists, trimethoprim, tacrolimus, ciclosporin): Hyperkalaemia may occur, therefore close monitoring of serum potassium is required.

Antihypertensive agents (e.g. diuretics) and other substances that may decrease blood pressure (e.g. nitrates, tricyclic antidepressants, anaesthetics, acute alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): Potentiation of the risk of hypotension is to be anticipated (see section 4.2 for diuretics)

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of ramipril: Blood pressure monitoring is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count: Increased likelihood of haematological reactions (see section 4.4).

Lithium Salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased.. Lithium levels must be monitored.

Antidiabetic agents including insulin: Hypoglycaemic reactions may occur. Blood glucose monitoring is recommended.

Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: Reduction of the antihypertensive effect of ramipril is to be anticipated. Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function and to an increase in kalaemia.

4.6 Pregnancy And Lactation

Ramipril is not recommended during the first trimester of pregnancy (see section 4.4) and contraindicated during the second and third trimesters of pregnancy (see section 4.3).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

ACE inhibitor/ Angiotensin II Receptor Antagonist (AIIRA) therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also 5.3 'Preclinical safety data'). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Newborns whose mothers have taken ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia (see also sections 4.3 and 4.4).

Because insufficient information is available regarding the use of ramipril during breastfeeding (see section 5.2), ramipril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects On Ability To Drive And Use Machines

Some adverse effects (e.g. symptoms of a reduction in blood pressure such as dizziness) may impair the patient's ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance (e.g. operating a vehicle or machinery).

This can happen especially at the start of treatment, or when changing over from other preparations. After the first dose or subsequent increases in dose it is not advisable to drive or operate machinery for several hours.

4.8 Undesirable Effects

The safety profile of ramipril includes persistent dry cough and reactions due to hypotension. Serious adverse reactions include angioedema, hyperkalaemia, renal or hepatic impairment, pancreatitis, severe skin reactions and neutropenia/agranulocytosis.

Adverse reactions frequency is defined using the following convention:

Very common (

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

 

Common

Uncommon

Rare

Very rare

Not known

Cardiac disorders

 

 

Myocardial ischaemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, oedema peripheral

 

 

 

 

 

 

Blood and lymphatic system disorders

 

 

 

Eosinophilia

White blood cell count decreased (including neutropenia or agranulocytosis), red blood cell count decreased, haemoglobin decreased, platelet count decreased

 

 

Bone marrow failure, pancytopenia, haemolytic anaemia

Nervous system disorders

 

Headache, dizziness

Vertigo, paraesthesia, ageusia, dysgeusia,

Tremor, balance disorder

 

 

Cerebral ischaemia including ischaemic stroke and transient ischaemic attack, psychomotor skills impaired, burning sensation, parosmia

Eye disorders

 

 

 

Visual disturbance including blurred vision

Conjunctivitis

 

 

 

 

Ear and labyrinth disorders

 

 

 

 

Hearing impaired, tinnitus

 

 

 

 

Respiratory, thoracic and mediastinal disorders

 

Non-productive tickling cough, bronchitis, sinusitis, dyspnoea

Bronchospasm including asthma aggravated, nasal congestion

 

 

 

 

 

 

Gastrointestinal disorders

 

 

Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting

Pancreatitis (cases of fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, abdominal pain upper including gastritis, constipation, dry mouth

Glossitis

 

 

Aphtous stomatitis

Renal and urinary disorders

 

 

 

Renal impairment including renal failure acute, urine output increased, worsening of a pre-existing proteinuria, blood urea increased, blood creatinine increased

 

 

 

 

 

 

 

Skin and subcutaneous tissue disorders

 

Rash in particular maculo-papular

Angioedema; very exceptionally, the airway obstruction resulting from angioedema may have a fatal outcome; pruritus, hyperhidrosis

Exfoliative dermatitis, urticaria, onycholysis,

Photosensitivity reaction

Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema, alopecia

Musculoskeletal and connective tissue disorders

 

Muscle spasms, myalgia

Arthralgia

 

 

 

 

 

 

Metabolism and nutrition disorders

 

Blood potassium increased

Anorexia, decreased appetite,

 

 

 

 

Blood sodium decreased

Vascular disorders

 

Hypotension, orthostatic blood pressure decreased, syncope

Flushing

Vascular stenosis, hypoperfusion, vasculitis

 

 

Raynaud's phenomenon

General disorders and administration site conditions

 

Chest pain, fatigue

Pyrexia

Asthenia

 

 

 

 

Immune system disorders

 

 

 

 

 

 

 

 

 

Anaphylactic or anaphylactoid reactions, antinuclear antibody increased

Hepatobiliary disorders

 

 

Hepatic enzymes and/or bilirubin conjugated increased,

Jaundice cholestatic, hepatocellular damage

 

 

Acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional).

Reproductive system and breast disorders

 

 

Transient erectile impotence, libido decreased

 

 

 

 

 

Gynaecomastia

Psychiatric disorders

 

 

Depressed mood, anxiety, nervousness, restlessness, sleep disorder including somnolence

 

Confusional state

 

 

Disturbance in attention

4.9 Overdose

Symptoms associated with overdosage of ACE inhibitors may include excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure. The patient should be closely monitored and the treatment should be symptomatic and supportive. Suggested measures include primary detoxification (gastric lavage, administration of adsorbents) and measures to restore haemodynamic stability, including, administration of alpha 1 adrenergic agonists or angiotensin II (angiotensinamide) administration. Ramiprilat, the active metabolite of ramipril is poorly removed from the general circulation by haemodialysis.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: ACE Inhibitors, plain, ATC code C09AA05.

Mechanism of action

Ramiprilat, the active metabolite of the prodrug ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In plasma and tissue this enzyme catalyses the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduced angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilatation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The average response to ACE inhibitor monotherapy was lower in black (Afro-Caribbean) hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.

Pharmacodynamic effects

Antihypertensive properties:

Administration of ramipril causes a marked reduction in peripheral arterial resistance. Generally, there are no major changes in renal plasma flow and glomerular filtration rate. Administration of ramipril to patients with hypertension leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate.

In most patients the onset of the antihypertensive effect of a single dose becomes apparent 1 to 2 hours after oral administration. The peak effect of a single dose is usually reached 3 to 6 hours after oral administration. The antihypertensive effect of a single dose usually lasts for 24 hours.

The maximum antihypertensive effect of continued treatment with ramipril is generally apparent after 3 to 4 weeks. It has been shown that the antihypertensive effect is sustained under long term therapy lasting 2 years.

Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in blood pressure.

Heart failure:

In addition to conventional therapy with diuretics and optional cardiac glycosides, ramipril has been shown to be effective in patients with functional classes II-IV of the New-York Heart Association. The drug had beneficial effects on cardiac haemodynamics (decreased left and right ventricular filling pressures, reduced total peripheral vascular resistance, increased cardiac output and improved cardiac index). It also reduced neuroendocrine activation.

Clinical efficacy and safety

Cardiovascular prevention/Nephroprotection;

A preventive placebo-controlled study (the HOPE-study), was carried out in which ramipril was added to standard therapy in more than 9,200 patients. Patients with increased risk of cardiovascular disease following either atherothrombotic cardiovascular disease (history of coronary heart disease, stroke or peripheral vascular disease) or diabetes mellitus with at least one additional risk factor (documented microalbuminuria, hypertension, elevated total cholesterol level, low high-density lipoprotein cholesterol level or cigarette smoking) were included in the study.

The study showed that ramipril statistically significantly decreases the incidence of myocardial infarction, death from cardiovascular causes and stroke, alone and combined (primary combined events).

The HOPE Study: Main Results;

 

 

Ramipril

Placebo

relative risk

(95% confidence interval)

p-value

 

 

%

%

 

 

 

 

All patients

n=4,645

N=4,652

 

 

Primary combined events

14.0

17.8

0.78 (0.70-0.86)

<0.001

Myocardial infarction

9.9

12.3

0.80 (0.70-0.90)

<0.001

Death from cardiovascular causes

6.1

8.1

0.74 (0.64-0.87)

<0.001

Stroke

3.4

4.9

0.68 (0.56-0.84)

<0.001

 

 

 

 

 

 

 

 

 

 

Secondary endpoints

 

 

 

 

Death from any cause

10.4

12.2

0.84 (0.75-0.95)


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Ramipril 10mg Tablets


1. Name Of The Medicinal Product

Ramipril 10mg Tablets

2. Qualitative And Quantitative Composition

10 mg ramipril.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet

White to almost white, oblong tablets with a score-line.

Upper stamp: HMO/HMO

Lower stamp: anonymous

4. Clinical Particulars 4.1 Therapeutic Indications

- Treatment of hypertension.

- Cardiovascular prevention: reduction of cardiovascular morbidity and mortality in patients with:

o manifest atherothrombotic cardiovascular disease (history of coronary heart disease or stroke, or peripheral vascular disease) or

o diabetes with at least one cardiovascular risk factor (see section 5.1).

- Treatment of renal disease:

o Incipient glomerular diabetic nephropathy as defined by the presence of microalbuminuria,

o Manifest glomerular diabetic nephropathy as defined by macroproteinuria in patients with at least one cardiovascular risk factor (see section 5.1),

o Manifest glomerular non diabetic nephropathy as defined by macroproteinuria

- Treatment of symptomatic heart failure.

- Secondary prevention after acute myocardial infarction: reduction of mortality from the acute phase of myocardial infarction in patients with clinical signs of heart failure when started> 48 hours following acute myocardial infarction.

4.2 Posology And Method Of Administration

Oral use.

It is recommended that RAMIPRIL is taken each day at the same time of the day.

RAMIPRIL can be taken before, with or after meals, because food intake does not modify its bioavailability (see section 5.2).

RAMIPRIL has to be swallowed with liquid. It must not be chewed or crushed.

Adults

Diuretic-Treated patients

Hypotension may occur following initiation of therapy with RAMIPRIL; this is more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume and/or salt depleted.

If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with RAMIPRIL (see section 4.4).

In hypertensive patients in whom the diuretic is not discontinued, therapy with RAMIPRIL should be initiated with a 1.25 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of RAMIPRIL should be adjusted according to blood pressure target.

Hypertension

The dose should be individualised according to the patient profile (see section 4.4) and blood pressure control.

RAMIPRIL may be used in monotherapy or in combination with other classes of antihypertensive medicinal products.

Starting dose

RAMIPRIL should be started gradually with an initial recommended dose of 2.5 mg daily.

Patients with a strongly activated renin-angiotensin-aldosterone system may experience an excessive drop in blood pressure following the initial dose. A starting dose of 1.25 mg is recommended in such patients and the initiation of treatment should take place under medical supervision (see section 4.4).

Titration and maintenance dose

The dose can be doubled at interval of two to four weeks to progressively achieve target blood

pressure; the maximum permitted dose of RAMIPRIL is 10 mg daily. Usually the dose is administered once daily.

Cardiovascular prevention

Starting dose

The recommended initial dose is 2.5 mg of RAMIPRIL once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose should be gradually increased. It is recommended to double the dose after one or two weeks of treatment and - after another two to three weeks - to increase it up to the target maintenance dose of 10 mg RAMIPRIL once daily.

See also posology on diuretic treated patients above.

Treatment of renal disease

In patients with diabetes and microalbuminuria:

Starting dose:

The recommended initial dose is 1.25 mg of RAMIPRIL once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

In patients with diabetes and at least one cardiovascular risk

Starting dose:

The recommended initial dose is 2.5 mg of RAMIPRIL once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the daily dose to 5 mg RAMIPRIL after one or two weeks and then to 10 mg RAMIPRIL after a further two or three weeks is recommended. The target daily dose is 10 mg.

In patients with non- diabetic nephropathy as defined by macroproteinuria

Starting dose:

The recommended initial dose is 1.25 mg of RAMIPRIL once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

Symptomatic heart failure

Starting dose

In patients stabilized on diuretic therapy, the recommended initial dose is 1.25 mg daily.

Titration and maintenance dose

RAMIPRIL should be titrated by doubling the dose every one to two weeks up to a maximum daily dose of 10 mg. Two administrations per day are preferable.

Secondary prevention after acute myocardial infarction and with heart failure

Starting dose

After 48 hours, following myocardial infarction in a clinically and haemodynamically stable patient, the starting dose is 2.5 mg twice daily for three days. If the initial 2.5 mg dose is not tolerated a dose of 1.25 mg twice a day should be given for two days before increasing to 2.5 mg and 5 mg twice a day. If the dose cannot be increased to 2.5 mg twice a day the treatment should be withdrawn.

See also posology on diuretic treated patients above.

Titration and maintenance dose

The daily dose is subsequently increased by doubling the dose at intervals of one to three days up to the target maintenance dose of 5 mg twice daily.

The maintenance dose is divided in 2 administrations per day where possible.

If the dose cannot be increased to 2.5 mg twice a day treatment should be withdrawn. Sufficient experience is still lacking in the treatment of patients with severe (NYHA IV) heart failure immediately after myocardial infarction. Should the decision be taken to treat these patients, it is recommended that therapy be started at 1.25 mg once daily and that particular caution be exercised in any dose increase.

Special populations

Patients with renal impairment

Daily dose in patients with renal impairment should be based on creatinine clearance (see section 5.2):

- if creatinine clearance is

- if creatinine clearance is between 30-60 ml/min, it is not necessary to adjust the initial dose (2.5 mg/day); the maximal daily dose is 5 mg;

- if creatinine clearance is between 10-30 ml/min, the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg;

- in haemodialysed hypertensive patients: ramipril is slightly dialysable; the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg; the medicinal product should be administered few hours after haemodialysis is performed.

Patients with hepatic impairment (see section 5.2)

In patients with hepatic impairment, treatment with RAMIPRIL must be initiated only under close medical supervision and the maximum daily dose is 2.5 mg RAMIPRIL.

Elderly

Initial doses should be lower and subsequent dose titration should be more gradual because of greater chance of undesirable effects especially in very old and frail patients. A reduced initial dose of 1.25 mg ramipril should be considered.

Paediatric population

RAMIPRIL is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy.

4.3 Contraindications

- Hypersensitivity to the active substance, to any of the excipients or any other ACE (Angiotensin Converting Enzyme) inhibitors (see section 6.1)

- History of angioedema (hereditary, idiopathic or due to previous angioedema with ACE inhibitors or AIIRAs)

- Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5)

- Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney

- 2nd and 3rd trimester of pregnancy (see sections 4.4 and 4.6)

- Ramipril must not be used in patients with hypotensive or haemodynamically unstable states.

4.4 Special Warnings And Precautions For Use

Special populations

Pregnancy: ACE inhibitors such as ramipril, or Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued ACE inhibitor/ AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors/ AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Patients at particular risk of hypotension

Patients with strongly activated renin-angiotensin-aldosterone system:

Patients with strongly activated renin-angiotensin-aldosterone system are at risk of an acute pronounced fall in blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor or a concomitant diuretic is given for the first time or at first dose increase.

Significant activation of renin-angiotensin-aldosterone system is to be anticipated and medical supervision including blood pressure monitoring is necessary, for example in:

- patients with severe hypertension

- patients with decompensated congestive heart failure

- patients with haemodynamically relevant left ventricular inflow or outflow impediment (e.g. stenosis of the aortic or mitral valve)

- patients with unilateral renal artery stenosis with a second functional kidney

- patients in whom fluid or salt depletion exists or may develop (including patients with diuretics)

- patients with liver cirrhosis and/or ascites

- patients undergoing major surgery or during anaesthesia with agents that produce hypotension.

Generally, it is recommended to correct dehydration, hypovolaemia or salt depletion before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed out against the risk of volume overload).

Transient or persistent heart failure post MI

Patients at risk of cardiac or cerebral ischemia in case of acute hypotension

The initial phase of treatment requires special medical supervision.

Elderly patients

See section 4.2.

Surgery

It is recommended that treatment with angiotensin converting enzyme inhibitors such as ramipril should be discontinued where possible one day before surgery.

Monitoring of renal function

Renal function should be assessed before and during treatment and dosage adjusted especially in the initial weeks of treatment. Particularly careful monitoring is required in patients with renal impairment (see section 4.2). There is a risk of impairment of renal function, particularly in patients with congestive heart failure or after a renal transplant.

Angioedema

Angioedema has been reported in patients treated with ACE inhibitors including ramipril (see

section 4.8).

In case of angioedema, RAMIPRIL must be discontinued.

Emergency therapy should be instituted promptly. Patient should be kept under observation for at least 12 to 24 hours and discharged after complete resolution of the symptoms.

Intestinal angioedema has been reported in patients treated with ACE inhibitors including RAMIPRIL (see section 4.8). These patients presented with abdominal pain (with or without nausea or vomiting).

Anaphylactic reactions during desensitization

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased under ACE inhibition. A temporary discontinuation of RAMIPRIL should be considered prior to desensitization.

Hyperkalaemia

Hyperkalaemia has been observed in some patients treated with ACE inhibitors including RAMIPRIL. Patients at risk for development of hyperkalaemia include those with renal insufficiency, age (> 70 years), uncontrolled diabetes mellitus, or those using potassium salts, potassium retaining diuretics and other plasma potassium increasing active substances, or conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been rarely seen and bone marrow depression has also been reported. It is recommended to monitor the white blood cell count to permit detection of a possible leucopoenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease (e.g. lupus erythematosus or scleroderma), and all those treated with other medicinal products that can cause changes in the blood picture (see sections 4.5 and 4.8).

Ethnic differences

ACE inhibitors cause higher rate of angioedema in black patients than in non black patients.

As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black people than in non black patients, possibly because of a higher prevalence of hypertension with low renin level in the black hypertensive population.

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Contra-indicated combinations

Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Precautions for use

Potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances (including Angiotensin II antagonists, trimethoprim, tacrolimus, ciclosporin): Hyperkalaemia may occur, therefore close monitoring of serum potassium is required.

Antihypertensive agents (e.g. diuretics) and other substances that may decrease blood pressure (e.g.nitrates, tricyclic antidepressants, anaesthetics, acute alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): Potentiation of the risk of hypotension is to be anticipated (see section 4.2 for diuretics)

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of RAMIPRIL: Blood pressure monitoring is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count: Increased likelihood of haematological reactions (see section 4.4).

Lithium salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased. Lithium level must be monitored.

Antidiabetic agents including insulin: Hypoglycaemic reactions may occur. Blood glucose monitoring is recommended.

Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: Reduction of the antihypertensive effect of RAMIPRIL is to be anticipated. Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function and to an increase in kalaemia.

4.6 Pregnancy And Lactation

RAMIPRIL is not recommended during the first trimester of pregnancy (see section 4.4) and contraindicated during the second and third trimesters of pregnancy (see section 4.3).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. ACE inhibitor/ Angiotensin II Receptor Antagonist (AIIRA) therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also 5.3 'Preclinical safety data'). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Newborns whose mothers have taken ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia (see also sections 4.3 and 4.4).

Because insufficient information is available regarding the use of ramipril during breastfeeding (see section 5.2), ramipril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects On Ability To Drive And Use Machines

Some adverse effects (e.g. symptoms of a reduction in blood pressure such as dizziness) may impair the patient's ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance (e.g. operating a vehicle or machinery).

This can happen especially at the start of treatment, or when changing over from other preparations. After the first dose or subsequent increases in dose it is not advisable to drive or operate machinery for several hours.

4.8 Undesirable Effects

The safety profile of ramipril includes persistent dry cough and reactions due to hypotension. Serious adverse reactions include angioedema, hyperkalaemia, renal or hepatic impairment, pancreatitis, severe skin reactions and neutropenia/agranulocytosis.

Adverse reactions frequency is defined using the following convention:

Very common (

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

 

Common

Uncommon

Rare

Very rare

Not known

Cardiac disorders

 

 

Myocardial ischaemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, oedema peripheral

 

 

 

 

 

 

Blood and lymphatic system disorders

 

 

 

Eosinophilia

White blood cell count decreased (including neutropenia or agranulocytosis), red blood cell count decreased, haemoglobin decreased, platelet count decreased

 

 

Bone marrow failure, pancytopenia, haemolytic anaemia

Nervous system disorders

 

Headache, dizziness

Vertigo, paraesthesia, ageusia, dysgeusia,

Tremor, balance disorder

 

 

Cerebral ischaemia including ischaemic stroke and transient ischaemic attack, psychomotor skills impaired, burning sensation, parosmia

Eye disorders

 

 

 

Visual disturbance including blurred vision

Conjunctivitis

 

 

 

 

Ear and labyrinth disorders

 

 

 

 

Hearing impaired, tinnitus

 

 

 

 

Respiratory, thoracic and mediastinal disorders

 

Non-productive tickling cough, bronchitis, sinusitis, dyspnoea

Bronchospasm including asthma aggravated, nasal congestion

 

 

 

 

 

 

Gastrointestinal disorders

 

 

Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting

Pancreatitis (cases of fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, abdominal pain upper including gastritis, constipation, dry mouth

Glossitis

 

 

Aphtous stomatitis

Renal and urinary disorders

 

 

 

Renal impairment including renal failure acute, urine output increased, worsening of a pre-existing proteinuria, blood urea increased, blood creatinine increased

 

 

 

 

 

 

 

Skin and subcutaneous tissue disorders

 

Rash in particular maculo-papular

Angioedema; very exceptionally, the airway obstruction resulting from angioedema may have a fatal outcome; pruritus, hyperhidrosis

Exfoliative dermatitis, urticaria, onycholysis,

Photosensitivity reaction

Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema, alopecia

Musculoskeletal and connective tissue disorders

 

Muscle spasms, myalgia

Arthralgia

 

 

 

 

 

 

Metabolism and nutrition disorders

 

Blood potassium increased

Anorexia, decreased appetite,

 

 

 

 

Blood sodium decreased

Vascular disorders

 

Hypotension, orthostatic blood pressure decreased, syncope

Flushing

Vascular stenosis, hypoperfusion, vasculitis

 

 

Raynaud's phenomenon

General disorders and administration site conditions

 

Chest pain, fatigue

Pyrexia

Asthenia

 

 

 

 

Immune system disorders

 

 

 

 

 

 

 

 

 

Anaphylactic or anaphylactoid reactions, antinuclear antibody increased

Hepatobiliary disorders

 

 

Hepatic enzymes and/or bilirubin conjugated increased,

Jaundice cholestatic, hepatocellular damage

 

 

Acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional).

Reproductive system and breast disorders

 

 

Transient erectile impotence, libido decreased

 

 

 

 

 

Gynaecomastia

Psychiatric disorders

 

 

Depressed mood, anxiety, nervousness, restlessness, sleep disorder including somnolence

 

Confusional state

 

 

Disturbance in attention

4.9 Overdose

Symptoms associated with overdosage of ACE inhibitors may include excessive peripheral

vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure. The patient should be closely monitored and the treatment should be symptomatic and supportive. Suggested measures include primary detoxification (gastric lavage, administration of adsorbents) and measures to restore haemodynamic stability, including, administration of alpha 1 adrenergic agonists or angiotensin II (angiotensinamide) administration. Ramiprilat, the active metabolite of ramipril is poorly removed from the general circulation by haemodialysis.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: ACE Inhibitors, plain, ATC code C09AA05.

Mechanism of action

Ramiprilat, the active metabolite of the prodrug ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In plasma and tissue this enzyme catalyses the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduced angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilatation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The average response to ACE inhibitor monotherapy was lower in black (Afro-Caribbean) hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.

Pharmacodynamic effects

Antihypertensive properties:

Administration of ramipril causes a marked reduction in peripheral arterial resistance. Generally, there are no major changes in renal plasma flow and glomerular filtration rate. Administration of ramipril to patients with hypertension leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate.

In most patients the onset of the antihypertensive effect of a single dose becomes apparent 1 to 2 hours after oral administration. The peak effect of a single dose is usually reached 3 to 6 hours after oral administration. The antihypertensive effect of a single dose usually lasts for 24 hours.

The maximum antihypertensive effect of continued treatment with ramipril is generally apparent after 3 to 4 weeks. It has been shown that the antihypertensive effect is sustained under long term therapy lasting 2 years.

Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in blood pressure.

Heart failure:

In addition to conventional therapy with diuretics and optional cardiac glycosides, ramipril has been shown to be effective in patients with functional classes II-IV of the New-York Heart Association. The drug had beneficial effects on cardiac haemodynamics (decreased left and right ventricular filling pressures, reduced total peripheral vascular resistance, increased cardiac output and improved cardiac index). It also reduced neuroendocrine activation.

Clinical efficacy and safety

Cardiovascular prevention/Nephroprotection;

A preventive placebo-controlled study (the HOPE-study), was carried out in which ramipril was added to standard therapy in more than 9,200 patients. Patients with increased risk of cardiovascular disease following either atherothrombotic cardiovascular disease (history of coronary heart disease, stroke or peripheral vascular disease) or diabetes mellitus with at least one additional risk factor (documented microalbuminuria, hypertension, elevated total cholesterol level, low high-density lipoprotein cholesterol level or cigarette smoking) were included in the study.

The study showed that ramipril statistically significantly decreases the incidence of myocardial infarction, death from cardiovascular causes and stroke, alone and combined (primary combined events).

The HOPE Study: Main Results;

 

 

Ramipril

Placebo

relative risk

(95% confidence interval)

p-value

 

 

%

%

 

 

 

 

All patients

n=4,645

N=4,652

 

 

Primary combined events

14.0

17.8

0.78 (0.70-0.86)

<0.001

Myocardial infarction

9.9

12.3

0.80 (0.70-0.90)

<0.001

Death from cardiovascular causes

6.1

8.1

0.74 (0.64-0.87)

<0.001

Stroke

3.4

4.9

0.68 (0.56-0.84)

<0.001

 

 

 

 

 

 

 

 

 

 

Secondary endpoints

 

 

 

 

Death from any cause

10.4

12.2

0.84 (0.75-0.95)

0.005

Need for Revascularisation

16.0

18.3

0.85 (0.77-0.94)

0.002

Hospitalisation for unstable angina

12.1

12.3

0.98 (0.87-1.10)

NS

Hospitalisation for heart failure


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Tarka


Generic Name: trandolapril and verapamil (tran DOL a pril and ver AP a mil)
Brand Names: Tarka

What is Tarka (trandolapril and verapamil)?

Trandolapril is an ACE inhibitor. ACE stands for angiotensin converting enzyme.

Verapamil is a calcium channel blocker. It works by relaxing the muscles of your heart and blood vessels.

The combination of trandolapril and verapamil is used to treat high blood pressure (hypertension).

Trandolapril and verapamil may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Tarka (trandolapril and verapamil)? Do not use trandolapril and verapamil if you are pregnant. It could harm the unborn baby. Stop using this medication and tell your doctor right away if you become pregnant. You should not use this medicine if you have certain serious heart problems, or if you are allergic to trandolapril (Mavik) or similar medicines such as benazepril (Lotensin), captopril (Capoten), fosinopril (Monopril), enalapril (Vasotec), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), or ramipril (Altace).

There are many other drugs that can interact with trandolapril and verapamil. Tell your doctor about all medications you use.

Keep using this medicine as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.

Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting. What should I discuss with my healthcare provider before taking Tarka (trandolapril and verapamil)? You should not use this medicine if you are allergic to trandolapril (Mavik) or verapamil (Calan, Covera, Isoptin, Verelan), or if you have:

certain serious heart conditions, especially "sick sinus syndrome" or "AV block" (unless you have a pacemaker);

a heart rhythm disorder;

low blood pressure; or

if you are allergic to any other ACE inhibitor, such as benazepril (Lotensin), captopril (Capoten), fosinopril (Monopril), enalapril (Vasotec), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), or ramipril (Altace).

To make sure you can safely take trandolapril and verapamil, tell your doctor if you have any of these other conditions:

kidney disease (or if you are on dialysis);

liver disease;

congestive heart failure;

diabetes;

a nerve-muscle disease such as muscular dystrophy; or

a connective tissue disease such as Marfan syndrome, Sjogren's syndrome, lupus, scleroderma, or rheumatoid arthritis.

FDA pregnancy category D. Do not use trandolapril and verapamil if you are pregnant. Stop using this medication and tell your doctor right away if you become pregnant. Trandolapril and verapamil can cause injury or death to the unborn baby if you take the medicine during your second or third trimester. Use effective birth control while taking trandolapril and verapamil. Trandolapril and verapamil can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using trandolapril and verapamil. How should I take Tarka (trandolapril and verapamil)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results.

Trandolapril and verapamil works best if you take it with food.

Your blood pressure will need to be checked often. Visit your doctor regularly.

Conditions that may cause very low blood pressure include: vomiting, diarrhea, heavy sweating, heart disease, dialysis, a low salt diet, or taking diuretics (water pills). Follow your doctor's instructions about the type and amount of liquids you should drink while taking trandolapril and verapamil. Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting. If you need surgery, tell the surgeon ahead of time that you are using trandolapril and verapamil.

Keep using this medicine as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.

Store at room temperature away from moisture and heat. What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include slow heart rate, weak pulse, muscle weakness, tingly feeling, seizure (convulsions), feeling light-headed, or fainting.

What should I avoid while taking Tarka (trandolapril and verapamil)?

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Do not use salt substitutes or potassium supplements while taking trandolapril and verapamil, unless your doctor has told you to. Tarka (trandolapril and verapamil) side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; severe stomach pain; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects:

urinating less than usual or not at all;

swelling, weight gain, feeling short of breath;

feeling like you might pass out;

anxiety, sweating, pale skin, severe shortness of breath, wheezing, gasping for breath, cough with foamy mucus;

chest pain, fast, slow, or uneven heart rate; or

fever, upper stomach pain, and jaundice (yellowing of the skin or eyes).

Less serious side effects may include:

cough;

headache;

runny or stuffy nose, sore throat;

constipation, diarrhea;

dizziness;

back pain;

joint pain; or

nausea.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Tarka (trandolapril and verapamil)?

Many drugs can interact with trandolapril and verapamil. Below is just a partial list. Tell your doctor if you are using:

buspirone (BuSpar);

colchicine (Colcrys);

cyclosporine (Neoral, Sandimmune, Gengraf);

dexamethasone (Cortastat, Dexasone, Solurex, DexPak);

digoxin (digitalis, Lanoxin);

gold injections (to treat arthritis);

lithium (Lithobid, Eskalith);

phenobarbital (Solfoton) or other barbiturates;

insulin or oral diabetes medication;

sirolimus (Rapamune) or tacrolimus (Prograf);

St. John's wort;

theophylline (Elixophyllin, Respbid, Theo-Dur, and others);

an antibiotic such as clarithromycin (Biaxin), erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin, Pediazole), rifampin (Rifadin, Rifater, Rifamate) and others;

antifungal medication such as itraconazole (Sporanox), ketoconazole (Nizoral), miconazole (Oravig), or voriconazole (Vfend);

aspirin or other NSAIDs (non-steroidal anti-inflammatory drugs) such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others;

a beta-blocker such as atenolol (Tenormin), carvedilol (Coreg), metoprolol (Lopressor, Toprol), propranolol (Inderal, InnoPran), and others;

a diuretic (water pill);

drugs to treat high blood pressure or a prostate disorder, such as alfuzosin (Uroxatral), doxazosin (Cardura), prazosin (Minipress), terazosin (Hytrin), tamsulosin (Flomax);

cholesterol-lowering drugs such as atorvastatin (Lipitor, Caduet), lovastatin (Mevacor, Altoprev, Advicor), or simvastatin (Zocor, Simcor, Vytorin, Juvisync);

heart rhythm or blood pressure medication such as disopyramide (Norpace), flecainide (Tambocor), nicardipine (Cardene) or quinidine (Quin-G);

HIV or AIDS medication; or

seizure medication such as carbamazepine (Carbatrol, Equetro, Tegretol), phenytoin (Dilantin), and others.

This list is not complete and there are many other drugs that can interact with trandolapril and verapamil. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

More Tarka resources Tarka Side Effects (in more detail) Tarka Use in Pregnancy & Breastfeeding Drug Images Tarka Drug Interactions Tarka Support Group 4 Reviews for Tarka - Add your own review/rating Tarka Prescribing Information (FDA) Tarka Advanced Consumer (Micromedex) - Includes Dosage Information Tarka MedFacts Consumer Leaflet (Wolters Kluwer) Compare Tarka with other medications High Blood Pressure Where can I get more information? Your pharmacist can provide more information about trandolapril and verapamil.

See also: Tarka side effects (in more detail)


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Ramipril 10 mg Capsules (Accord Healthcare Limited)


1. Name Of The Medicinal Product

Ramipril 10mg Capsules

2. Qualitative And Quantitative Composition

Each hard capsule contains ramipril 10 mg.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Hard Capsules. Size 4 with blue cap/white body imprinted with 'R' on cap and '10' on body. Contains white to off-white granular powder.

4. Clinical Particulars 4.1 Therapeutic Indications

-Ramipril Capsules are indicated for the treatment of mild to moderate hypertension.

- Cardiovascular prevention: reduction of cardiovascular morbidity and mortality in patients with:

o manifest atherothrombotic cardiovascular disease (history of coronary heart disease or stroke, or peripheral vascular disease) or

o diabetes with at least one cardiovascular risk factor (see section 5.1).

- Treatment of renal disease:

o Incipient glomerular diabetic nephropathy as defined by the presence of microalbuminuria,

o Manifest glomerular diabetic nephropathy as defined by macroproteinuria in patients with at least one cardiovascular risk factor (see section 5.1),

o Manifest glomerular non diabetic nephropathy as defined by macroproteinuria

- Treatment of symptomatic heart failure.

- Secondary prevention after acute myocardial infarction: reduction of mortality from the acute phase of myocardial infarction in patients with clinical signs of heart failure when started > 48 hours following acute myocardial infarction.

4.2 Posology And Method Of Administration

Ramipril Capsules should be taken with a glass of water. It is recommended that ramipril is taken each day at the same time of the day.

Ramipril can be taken before, with or after meals, because its absorption is not affected by food (see section 5.2). Ramipril capsules has to be swallowed with liquid. It must not be chewed or crushed.

Dosage and Administration:

Adults

Diuretic-Treated patients

Hypotension may occur following initiation of therapy with ramipril; this is more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume and/or salt depleted.

If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with ramipril (see section 4.4).

In hypertensive patients in whom the diuretic is not discontinued, therapy with ramipril should be initiated with a 1.25 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of ramipril should be adjusted according to blood pressure target.

Hypertension

The dose should be individualised according to the patient profile (see section 4.4) and blood pressure control.

Ramipril may be used in monotherapy or in combination with other classes of antihypertensive medicinal products.

Starting dose

Ramipril should be started gradually with an initial recommended dose of 2.5 mg daily.

Patients with a strongly activated renin-angiotensin-aldosterone system may experience an excessive drop in blood pressure following the initial dose. A starting dose of 1.25 mg is recommended in such patients and the initiation of treatment should take place under medical supervision (see section 4.4).

Titration and maintenance dose

The dose can be doubled at interval of two to four weeks to progressively achieve target blood pressure; the maximum permitted dose of ramipril is 10 mg daily. Usually the dose is administered once daily.

Cardiovascular prevention

Starting dose

The recommended initial dose is 2.5 mg of ramipril once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose should be gradually increased. It is recommended to double the dose after one or two weeks of treatment and - after another two to three weeks - to increase it up to the target maintenance dose of 10 mg ramipril once daily.

See also posology on diuretic treated patients above.

Treatment of renal disease

In patients with diabetes and microalbuminuria:

Starting dose:

The recommended initial dose is 1.25 mg of ramipril once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

In patients with diabetes and at least one cardiovascular risk

Starting dose:

The recommended initial dose is 2.5 mg of ramipril once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the daily dose to 5 mg ramipril after one or two weeks and then to 10 mg ramipril after a further two or three weeks is recommended. The target daily dose is 10 mg.

In patients with non- diabetic nephropathy as defined by macroproteinuria 3 g/day.

Starting dose:

The recommended initial dose is 1.25 mg of ramipril once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

Symptomatic heart failure

Starting dose

In patients stabilized on diuretic therapy, the recommended initial dose is 1.25 mg daily.

Titration and maintenance dose

Ramipril should be titrated by doubling the dose every one to two weeks up to a maximum daily dose of 10 mg. Two administrations per day are preferable.

Secondary prevention after acute myocardial infarction and with heart failure

Starting dose

After 48 hours, following myocardial infarction in a clinically and haemodynamically stable patient, the starting dose is 2.5 mg twice daily for three days. If the initial 2.5 mg dose is not tolerated a dose of 1.25 mg twice a day should be given for two days before increasing to 2.5 mg and 5 mg twice a day. If the dose cannot be increased to 2.5 mg twice a day the treatment should be withdrawn.

See also posology on diuretic treated patients above.

Titration and maintenance dose

The daily dose is subsequently increased by doubling the dose at intervals of one to three days up to the target maintenance dose of 5 mg twice daily.

The maintenance dose is divided in 2 administrations per day where possible.

If the dose cannot be increased to 2.5 mg twice a day treatment should be withdrawn. Sufficient experience is still lacking in the treatment of patients with severe (NYHA IV) heart failure immediately after myocardial infarction. Should the decision be taken to treat these patients, it is recommended that therapy be started at 1.25 mg once daily and that particular caution be exercised in any dose increase.

Special populations

Patients with renal impairment

Daily dose in patients with renal impairment should be based on creatinine clearance (see section 5.2):

- if creatinine clearance is

- if creatinine clearance is between 30-60 ml/min, it is not necessary to adjust the initial dose (2.5 mg/day); the maximal daily dose is 5 mg;

- if creatinine clearance is between 10-30 ml/min, the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg;

- in haemodialysed hypertensive patients: ramipril is slightly dialysable; the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg; the medicinal product should be administered few hours after haemodialysis is performed.

Dosage in hepatic impairment (see section 5.2):

In patients with impaired liver function the metabolism of the parent compound ramipril, and therefore the formation of the bioactive metabolite ramiprilat, is delayed due to a diminished activity of esterases in the liver, resulting in elevated plasma ramipril levels. Treatment with ramipril should therefore be initiated under close medical supervision in patients with impaired liver function and the maximum daily dose is 2.5 mg ramipril.

Elderly: Initial doses should be lower and subsequent dose titration should be more gradual because of greater chance of undesirable effects especially in very old and frail patients. A reduced initial dose of 1.25 mg ramipril should be considered.

Children: Ramipril has not been studied in children and adolescents below 18 years of age, and therefore use in this age group is not recommended.

4.3 Contraindications

Hypersensitivity to ramipril or any of the excipients or any other ACE (Angiotensin Converting Enzyme) inhibitors (see section 6.1).

History of angioneurotic oedema(hereditary, idiopathic or due to previous angioedema with ACE inhibitors or AIIRAs).

Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5)

Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney.

Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

Ramipril must not be used in patients with hypotensive or haemodynamically unstable states.

4.4 Special Warnings And Precautions For Use

Special populations

-Pregnancy: ACE inhibitors such as ramipril, or Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued ACE inhibitor/AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors/AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

-Patients at particular risk of hypotension

Patients with strongly activated renin-angiotensin-aldosterone system

Patients with strongly activated renin-angiotensin-aldosterone system are at risk of an acute pronounced fall in blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor or a concomitant diuretic is given for the first time or at first dose increase.

Significant activation of renin-angiotensin-aldosterone system is to be anticipated and medical supervision including blood pressure monitoring is necessary, for example in:

- patients with severe hypertension

- patients with decompensated congestive heart failure

- patients with haemodynamically relevant left ventricular inflow or outflow impediment (e.g. stenosis of the aortic or mitral valve)

- patients with unilateral renal artery stenosis with a second functional kidney

- patients in whom fluid or salt depletion exists or may develop (including patients with diuretics)

- patients with liver cirrhosis and/or ascites

- patients undergoing major surgery or during anaesthesia with agents that produce hypotension.

Generally, it is recommended to correct dehydration, hypovolaemia or salt depletion before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed out against the risk of volume overload).

-Transient or persistent heart failure post MI

-Patients at risk of cardiac or cerebral ischemia in case of acute hypotension

The initial phase of treatment requires special medical supervision.

-Elderly patients

See section 4.2.

- Surgery

It is recommended that treatment with angiotensin converting enzyme inhibitors such as ramipril should be discontinued where possible one day before surgery.

-Monitoring of renal function

Renal function should be assessed before and during treatment and dosage adjusted especially in the initial weeks of treatment. Particularly careful monitoring is required in patients with renal impairment (see section 4.2). There is a risk of impairment of renal function, particularly in patients with congestive heart failure or after a renal transplant.

-Angioedema :

Angioedema has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8).

In case of angioedema, ramipril must be discontinued.

Emergency therapy should be instituted promptly. Patient should be kept under observation for at least 12 to 24 hours and discharged after complete resolution of the symptoms.

Intestinal angioedema has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8). These patients presented with abdominal pain (with or without nausea or vomiting).

-Anaphylactic reactions during desensitization:

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased under ACE inhibition. A temporary discontinuation of ramipril should be considered prior to desensitization.

-Hyperkalaemia:

Hyperkalaemia has been observed in some patients treated with ACE inhibitors including ramipril. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, age (> 70 years), uncontrolled diabetes mellitus, or those using potassium salts, potassium retaining diuretics and other plasma potassium increasing active substances, or conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).

Neutropenia/agranulocytosis:

Neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been rarely seen and bone marrow depression has also been reported. It is recommended to monitor the white blood cell count to permit detection of a possible leucopoenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease (e.g. lupus erythematosus or scleroderma), and all those treated with other medicinal products that can cause changes in the blood picture (see sections 4.5 and 4.8).

Ethnic differences

ACE inhibitors cause higher rate of angioedema in black patients than in non black patients.

As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black people than in non black patients, possibly because of a higher prevalence of hypertension with low renin level in the black hypertensive population.

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Contraindicated combinations

Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Precautions for use

Potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances (including Angiotensin II antagonists, trimethoprim, tacrolimus, ciclosporin): Hyperkalaemia may occur, therefore close monitoring of serum potassium is required.

Antihypertensive agents (e.g. diuretics) and other substances that may decrease blood pressure (e.g.nitrates, tricyclic antidepressants, anaesthetics, acute alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): Potentiation of the risk of hypotension is to be anticipated (see section 4.2 for diuretics)

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of ramipril: Blood pressure monitoring is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count: Increased likelihood of haematological reactions (see section 4.4).

Lithium salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased. Lithium level must be monitored.

Antidiabetic agents including insulin: Hypoglycaemic reactions may occur. Blood glucose monitoring is recommended.

Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: Reduction of the antihypertensive effect of ramipril is to be anticipated. Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function and to an increase in kalaemia.

4.6 Pregnancy And Lactation

Pregnancy:

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitor/ Angiotensin II Receptor Antagonist (AIIRA) therapy exposure during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (See section 5.3). Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia (see sections 4.3 and 4.4).

Lactation:

Because insufficient information is available regarding the use of ramipril during breastfeeding (see section 5.2), ramipril is not recommended and alternative treatments with better established safety profiles during breast- feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects On Ability To Drive And Use Machines

Some adverse effects (e.g. symptoms of a reduction in blood pressure such as dizziness) may impair the patient's ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance (e.g. operating a vehicle or machinery).

This occurs especially at the start of treatment, when changing over from other preparations and during concomitant use of alcohol. After the first dose or subsequent increases in dose it is not advisable to drive or operate machinery for several hours.

4.8 Undesirable Effects

The safety profile of ramipril includes persistent dry cough and reactions due to hypotension. Serious adverse reactions include angioedema, hyperkalaemia, renal or hepatic impairment, pancreatitis, severe skin reactions and neutropenia/agranulocytosis.

Adverse reactions frequency is defined using the following convention:

Very common (

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

Common

Uncommon

Rare

Very rare

Not known

Cardiac disorders

 

Myocardial ischaemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, oedema peripheral

     

Blood and lymphatic system disorders

 

Eosinophilia

White blood cell count decreased (including neutropenia or agranulocytosis), red blood cell count decreased, haemoglobin decreased, platelet count decreased

 

Bone marrow failure, pancytopenia, haemolytic anaemia

Nervous system disorders

Headache, dizziness

Vertigo, paraesthesia, ageusia, dysgeusia,

Tremor, balance disorder

 

Cerebral ischaemia including ischaemic stroke and transient ischaemic attack, psychomotor skills impaired, burning sensation, parosmia

Eye disorders

 

Visual disturbance including blurred vision

Conjunctivitis

   

Ear and labyrinth disorders

   

Hearing impaired, tinnitus

   

Respiratory, thoracic and mediastinal disorders

Non-productive tickling cough, bronchitis, sinusitis, dyspnoea

Bronchospasm including asthma aggravated, nasal congestion

     

Gastrointestinal disorders

Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting

Pancreatitis (cases of fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, abdominal pain upper including gastritis, constipation, dry mouth

Glossitis

 

Aphtous stomatitis

Renal and urinary disorders

 

Renal impairment including renal failure acute, urine output increased, worsening of a pre-existing proteinuria, blood urea increased, blood creatinine increased

     

Skin and subcutaneous tissue disorders

Rash in particular maculo- papular

Angioedema; very exceptionally, the airway obstruction resulting from angioedema may have a fatal outcome; pruritus, hyperhidrosis

Exfoliative dermatitis, urticaria, onycholysis,

Photosensitivity reaction

Toxic epidermal necrolysis, Stevens- Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema, alopecia

Musculoskeletal and connective tissue disorders

Muscle spasms, myalgia

Arthralgia

     

Metabolism and nutrition disorders

Blood potassium increased

Anorexia, decreased appetite,

   

Blood sodium decreased

Vascular disorders

Hypotension, orthostatic blood pressure decreased, syncope

Flushing

Vascular stenosis, hypoperfusion, vasculitis

 

Raynaud's phenomenon

General disorders and administration site conditions

Chest pain, fatigue

Pyrexia

Asthenia

   

Immune system disorders

       

Anaphylactic or anaphylactoid reactions, antinuclear antibody increased

Hepatobiliary disorders

 

Hepatic enzymes and/or bilirubin conjugated increased,

Jaundice cholestatic, hepatocellular damage

 

Acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional).

Reproductive system and breast disorders

 

Transient erectile impotence, libido decreased

   

Gynaecomastia

Psychiatric disorders

 

Depressed mood, anxiety, nervousness, restlessness, sleep disorder including somnolence

Confusional state

 

Disturbance in attention

4.9 Overdose

Symptoms associated with overdosage of ACE inhibitors may include excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure. The patient should be closely monitored and the treatment should be symptomatic and supportive. Suggested measures include primary detoxification (gastric lavage, administration of adsorbents) and measures to restore haemodynamic stability, including, administration of alpha 1 adrenergic agonists or angiotensin II (angiotensinamide) administration. Ramiprilat, the active metabolite of ramipril is poorly removed from the general circulation by haemodialysis.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: ACE Inhibitors, plain,

ATC-code: C09A A05

Mechanism of action

Ramipril is a prodrug which, after absorption from the gastrointestinal tract, is hydrolysed in the liver to form the active angiotensin converting enzyme (ACE) inhibitor, ramiprilat which is a potent and long acting ACE inhibitor. Administration of ramipril causes an increase in plasma renin activity and a decrease in plasma concentrations of angiotensin II and aldosterone. The beneficial haemodynamic effects resulting from ACE inhibition are a consequence of the reduction in angiotensin II causing dilatation of peripheral vessels and reduction in vascular resistance. There is evidence suggesting that tissue ACE particularly in the vasculature, rather than circulating ACE, is the primary factor determining the haemodynamic effects.

Angiotensin converting enzyme is identical with kininase II, one of the enzymes responsible for the degradation of bradykinin. There is evidence that ACE inhibition by ramiprilat appears to have some effects on the kallikrein- kinin-prostaglandin systems. It is assumed that effects on these systems contribute to the hypotensive and metabolic activity of ramipril.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The average response to ACE inhibitor monotherapy was lower in black (Afro-Caribbean) hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.

Pharmacodynamic effects

Antihypertensive properties:

Administration of ramipril causes a marked reduction in peripheral arterial resistance. Generally, there are no major changes in renal plasma flow and glomerular filtration rate. Administration of ramipril to hypertensive patients results in reduction of both supine and standing blood pressure without a compensatory rise in heart rate.

The antihypertensive effect is evident within one to two hours after the drug intake; peak effect occurs 3 - 6 hours after drug intake and has been shown to be maintained for at least 24 hours after usual therapeutic doses.

The maximum antihypertensive effect of continued treatment with ramipril is generally apparent after 3 to 4 weeks. It has been shown that the antihypertensive effect is sustained under long term therapy lasting 2 years.

Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in blood pressure.

Heart failure:

In addition to conventional therapy with diuretics and optional cardiac glycosides, ramipril has been shown to be effective in patients with functional classes II-IV of the New-York Heart Association. The drug had beneficial effects on cardiac haemodynamics (decreased left and right ventricular filling pressures, reduced total peripheral vascular resistance, increased cardiac output and improved cardiac index). It also reduced neuroendocrine activation.

Clinical efficacy and safety

Cardiovascular prevention/Nephroprotection;

A preventive placebo-controlled study (the HOPE-study), was carried out in which ramipril was added to standard therapy in more than 9,200 patients.

Patients with increased risk of cardiovascular disease following either atherothrombotic cardiovascular disease (history of coronary heart disease, stroke or peripheral vascular disease) or diabetes mellitus with at least one additional risk factor (documented microalbuminuria, hypertension, elevated total cholesterol level, low high-density lipoprotein cholesterol level or cigarette smoking) were included in the study.

The study showed that ramipril statistically significantly decreases the incidence of myocardial infarction, death from cardiovascular causes and stroke, alone and combined (primary combined events).

The HOPE Study: Main Results;

 

Ramipril

Placebo

relative risk

(95% confidence interval)

p-value

 

%

%

   

All patients

n=4,645

N=4,652

   

Primary combined events

14.0

17.8

0.78 (0.70-0.86)

<0.001

Myocardial infarction

9.9

12.3

0.80 (0.70-0.90)

<0.001

Death from cardiovascular causes

6.1

8.1

0.74 (0.64-0.87)

<0.001

Stroke

3.4

4.9

0.68 (0.56-0.84)

<0.001

         

Secondary endpoints

       

Death from any cause

10.4

12.2

0.84 (0.75-0.95)

0.005

Need for Revascularisation

16.0

18.3

0.85 (0.77-0.94)

0.002

Hospitalisation for unstable angina

12.1

12.3

0.98 (0.87-1.10)

NS

Hospitalisation for heart failure

3.2

3.5

0.88 (0.70-1.10)

0.25

Complications related to diabetes

6.4

7.6

0.84 (0.72-0.98)

0.03

The MICRO-HOPE study, a predefined substudy from HOPE, investigated the effect of the addition of ramipril 10 mg to the current medical regimen versus placebo in 3,577 patients at least

The primary analysis showed that 117 (6.5 %) participants on ramipril and 149 (8.4 %) on placebo developed overt nephropathy, which corresponds to a RRR 24 %; 95 % CI [3-40], p = 0.027.

The REIN study, a multicenter randomized, double-blind parallel group, placebo-controlled study aimed at assessing the effect of treatment with ramipril on the rate of decline of glomerular function rate (GFR) in 352 normotensive or hypertensive patients (18-70 years old) suffering from mild (i.e. mean urinary protein excretion > 1 and < 3 g/24 h) or severe proteinuria (

The main analysis of patients with the most severe proteinuria (stratum prematurely disrupted due to benefit in ramipril group) showed that the mean rate of GFR decline per month was lower with ramipril than with placebo; - 0.54 (0.66) vs. -0.88 (1.03) ml/min/month, p = 0.038. The intergroup difference was thus 0.34 [0.03-0.65] per month, and around 4 ml/min/year; 23.1 % of the patients in the ramipril group reached the combined secondary endpoint of doubling of baseline serum creatinine concentration and/or end- stage renal disease (ESRD) (need for dialysis or renal transplantation) vs. 45.5 % in the placebo group (p = 0.02).


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Cardura


Generic Name: doxazosin (dox AY zo sin)
Brand Names: Cardura, Cardura XL

What is doxazosin?

Doxazosin is in a group of drugs called alpha-adrenergic (AL-fa ad-ren-ER-jik) blockers. Doxazosin relaxes your veins and arteries so that blood can more easily pass through them. It also relaxes the muscles in the prostate and bladder neck, making it easier to urinate.

Doxazosin is used to treat hypertension (high blood pressure), or to improve urination in men with benign prostatic hyperplasia (enlarged prostate).

Doxazosin may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about doxazosin? You should not use this medication if you are allergic to doxazosin or similar medicines such as alfuzosin (Uroxatral), prazosin (Minipress), silodosin (Rapaflo), tamsulosin (Flomax), or terazosin (Hytrin). Doxazosin may cause dizziness or fainting, especially when you first start taking it or when you start taking it again. Be careful if you drive or do anything that requires you to be alert. Avoid standing for long periods of time or becoming overheated during exercise and in hot weather. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. If you stop taking doxazosin for any reason, call your doctor before you start taking it again. You may need a dose adjustment.

Doxazosin can affect your pupils during cataract surgery. Tell your eye surgeon ahead of time that you are using this medication. Do not stop using doxazosin before surgery unless your surgeon tells you to.

Tell your doctor about all other medications you use, especially other blood pressure medications including diuretics (water pills).

What should I discuss with my doctor before taking doxazosin? You should not use this medication if you are allergic to doxazosin or similar medicines such as alfuzosin (Uroxatral), prazosin (Minipress), silodosin (Rapaflo), tamsulosin (Flomax), or terazosin (Hytrin).

If you have liver disease or a history of prostate cancer, you may need a dose adjustment or special tests to safely take doxazosin.

Doxazosin can affect your pupils during cataract surgery. Tell your eye surgeon ahead of time that you are using this medication. Do not stop using doxazosin before surgery unless your surgeon tells you to.

FDA pregnancy category C. It is not known whether doxazosin will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether doxazosin passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. How should I take doxazosin?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results.

Doxazosin lowers blood pressure and may cause dizziness or fainting, especially when you first start taking it, or when you start taking it again. Call your doctor if you have severe dizziness or feel like you might pass out.

You may feel very dizzy when you first wake up. Be careful when standing or sitting up from a lying position.

If you stop taking doxazosin for any reason, call your doctor before you start taking it again. You may need a dose adjustment.

Your blood pressure or prostate will need to be checked often. Visit your doctor regularly.

If you are being treated for high blood pressure, keep using this medication even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.

Some things can cause your blood pressure to get too low. This includes vomiting, diarrhea, heavy sweating, heart disease, dialysis, a low-salt diet, or taking diuretics (water pills). Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.

Store at room temperature away from moisture and heat. What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

If you miss your doses for several days in a row, contact your doctor before restarting the medication. You may need a lower dose.

What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include extreme dizziness or fainting.

What should I avoid while taking doxazosin? Doxazosin may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

To prevent dizziness, avoid standing for long periods of time or becoming overheated during exercise and in hot weather.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Drinking alcohol can increase certain side effects of doxazosin. Doxazosin side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

feeling like you might pass out;

fast or pounding heartbeats, fluttering in your chest;

trouble breathing;

swelling in your hands, ankles, or feet; or

penis erection that is painful or lasts 4 hours or longer.

Less serious side effects may include:

mild dizziness;

tired feeling, drowsiness;

headache;

nausea; or

runny nose.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect doxazosin?

Tell your doctor about all other medications you use, especially:

sildenafil (Viagra, Revatio)

tadalafil (Cialis);

vardenafil (Levitra); or

other blood pressure medications, including diuretics (water pills).

This list is not complete and other drugs may interact with doxazosin. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Cardura resources Cardura Side Effects (in more detail) Cardura Use in Pregnancy & Breastfeeding Drug Images Cardura Drug Interactions Cardura Support Group 3 Reviews for Cardura - Add your own review/rating Cardura Monograph (AHFS DI) Cardura Prescribing Information (FDA) Cardura Consumer Overview Cardura Advanced Consumer (Micromedex) - Includes Dosage Information Cardura MedFacts Consumer Leaflet (Wolters Kluwer) Doxazosin Prescribing Information (FDA) Cardura XL Prescribing Information (FDA) Cardura XL Extended-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer) Compare Cardura with other medications Benign Prostatic Hyperplasia High Blood Pressure Raynaud's Syndrome Where can I get more information? Your pharmacist can provide more information about doxazosin.

See also: Cardura side effects (in more detail)


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Tritace Tablets


1. Name Of The Medicinal Product

Tritace 1.25 mg Tablets

Tritace 2.5 mg Tablets

Tritace 5 mg Tablets

Tritace 10 mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains ramipril 1.25 mg.

Each tablet contains ramipril 2.5 mg.

Each tablet contains ramipril 5 mg.

Each tablet contains ramipril 10 mg.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet

1.25mg: White to almost white oblong tablets with score-line.

Upper stamp: 1.25 & logo (

Lower stamp: HMN & 1.25

The score-line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

2.5mg: Yellowish to yellow oblong tablets with score-line.

Upper stamp: 2.5 & logo (

Lower stamp: HMR & 2.5

The tablet can be divided into equal halves.

5mg: Pale red oblong tablets with score-line.

Upper stamp: 5 & logo (

Lower stamp: HMP & 5.

The tablet can be divided into equal halves.

10mg: White to almost white, oblong tablets with a score-line

Upper stamp: HMO/HMO

The tablet can be divided into equal halves.

4. Clinical Particulars 4.1 Therapeutic Indications

- Treatment of hypertension.

- Cardiovascular prevention: reduction of cardiovascular morbidity and mortality in patients with:

 

o manifest atherothrombotic cardiovascular disease (history of coronary heart disease or stroke, or peripheral vascular disease) or

o diabetes with at least one cardiovascular risk factor (see section 5.1).

- Treatment of renal disease:

 

o Incipient glomerular diabetic nephropathy as defined by the presence of microalbuminuria,

o Manifest glomerular diabetic nephropathy as defined by macroproteinuria in patients with at least one cardiovascular risk factor (see section 5.1),

o Manifest glomerular non diabetic nephropathy as defined by macroproteinuria

- Treatment of symptomatic heart failure.

- Secondary prevention after acute myocardial infarction: reduction of mortality from the acute phase of myocardial infarction in patients with clinical signs of heart failure when started> 48 hours following acute myocardial infarction.

4.2 Posology And Method Of Administration

Oral use

It is recommended that TRITACE is taken each day at the same time of the day.

TRITACE can be taken before, with or after meals, because food intake does not modify its bioavailability (see section 5.2). TRITACE has to be swallowed with liquid. It must not be chewed or crushed.

Adults

Diuretic-Treated patients

Hypotension may occur following initiation of therapy with TRITACE; this is more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume and/or salt depleted.

If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with TRITACE (see section 4.4).

In hypertensive patients in whom the diuretic is not discontinued, therapy with TRITACE should be initiated with a 1.25 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of TRITACE should be adjusted according to blood pressure target.

Hypertension

The dose should be individualised according to the patient profile (see section 4.4) and blood pressure control.

TRITACE may be used in monotherapy or in combination with other classes of antihypertensive medicinal products.

Starting dose

TRITACE should be started gradually with an initial recommended dose of 2.5 mg daily.

Patients with a strongly activated renin-angiotensin-aldosterone system may experience an excessive drop in blood pressure following the initial dose. A starting dose of 1.25 mg is recommended in such patients and the initiation of treatment should take place under medical supervision (see section 4.4).

Titration and maintenance dose

The dose can be doubled at interval of two to four weeks to progressively achieve target blood pressure; the maximum permitted dose of TRITACE is 10 mg daily. Usually the dose is administered once daily.

Cardiovascular prevention

Starting dose

The recommended initial dose is 2.5 mg of TRITACE once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose should be gradually increased. It is recommended to double the dose after one or two weeks of treatment and - after another two to three weeks - to increase it up to the target maintenance dose of 10 mg TRITACE once daily.

See also posology on diuretic treated patients above.

Treatment of renal disease

In patients with diabetes and microalbuminuria:

Starting dose:

The recommended initial dose is 1.25 mg of TRITACE once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

In patients with diabetes and at least one cardiovascular risk

Starting dose:

The recommended initial dose is 2.5 mg of TRITACE once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the daily dose to 5 mg TRITACE after one or two weeks and then to 10 mg TRITACE after a further two or three weeks is recommended. The target daily dose is 10 mg.

In patients with non- diabetic nephropathy as defined by macroproteinuria

Starting dose:

The recommended initial dose is 1.25 mg of TRITACE once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

Symptomatic heart failure

Starting dose

In patients stabilized on diuretic therapy, the recommended initial dose is 1.25 mg daily.

Titration and maintenance dose

TRITACE should be titrated by doubling the dose every one to two weeks up to a maximum daily dose of 10 mg. Two administrations per day are preferable.

Secondary prevention after acute myocardial infarction and with heart failure

Starting dose

After 48 hours, following myocardial infarction in a clinically and haemodynamically stable patient, the starting dose is 2.5 mg twice daily for three days. If the initial 2.5 mg dose is not tolerated a dose of 1.25 mg twice a day should be given for two days before increasing to 2.5 mg and 5 mg twice a day. If the dose cannot be increased to 2.5 mg twice a day the treatment should be withdrawn.

See also posology on diuretic treated patients above.

Titration and maintenance dose

The daily dose is subsequently increased by doubling the dose at intervals of one to three days up to the target maintenance dose of 5 mg twice daily.

The maintenance dose is divided in 2 administrations per day where possible.

If the dose cannot be increased to 2.5 mg twice a day treatment should be withdrawn. Sufficient experience is still lacking in the treatment of patients with severe (NYHA IV) heart failure immediately after myocardial infarction. Should the decision be taken to treat these patients, it is recommended that therapy be started at 1.25 mg once daily and that particular caution be exercised in any dose increase.

Special populations

Patients with renal impairment

Daily dose in patients with renal impairment should be based on creatinine clearance (see section 5.2):

- if creatinine clearance is

- if creatinine clearance is between 30-60 ml/min, it is not necessary to adjust the initial dose (2.5 mg/day); the maximal daily dose is 5 mg;

- if creatinine clearance is between 10-30 ml/min, the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg;

- in haemodialysed hypertensive patients: ramipril is slightly dialysable; the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg; the medicinal product should be administered few hours after haemodialysis is performed.

Patients with hepatic impairment (see section 5.2)

In patients with hepatic impairment, treatment with TRITACE must be initiated only under close medical supervision and the maximum daily dose is 2.5 mg TRITACE.

Elderly

Initial doses should be lower and subsequent dose titration should be more gradual because of greater chance of undesirable effects especially in very old and frail patients. A reduced initial dose of 1.25 mg ramipril should be considered.

Paediatric population

TRITACE is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy.

4.3 Contraindications

- Hypersensitivity to the active substance, to any of the excipients or any other ACE (Angiotensin Converting Enzyme) inhibitors (see section 6.1)

- History of angioedema (hereditary, idiopathic or due to previous angioedema with ACE inhibitors or AIIRAs)

- Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5)

- Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney

- 2nd and 3rd trimester of pregnancy (see sections 4.4 and 4.6)

- Ramipril must not be used in patients with hypotensive or haemodynamically unstable states.

4.4 Special Warnings And Precautions For Use

Special populations

- Pregnancy: ACE inhibitors such as ramipril, or Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued ACE inhibitor/ AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors/ AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

- Patients at particular risk of hypotension

- Patients with strongly activated renin-angiotensin-aldosterone system

Patients with strongly activated renin-angiotensin-aldosterone system are at risk of an acute pronounced fall in blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor or a concomitant diuretic is given for the first time or at first dose increase.

Significant activation of renin-angiotensin-aldosterone system is to be anticipated and medical supervision including blood pressure monitoring is necessary, for example in:

- patients with severe hypertension

- patients with decompensated congestive heart failure

- patients with haemodynamically relevant left ventricular inflow or outflow impediment (e.g. stenosis of the aortic or mitral valve)

- patients with unilateral renal artery stenosis with a second functional kidney

- patients in whom fluid or salt depletion exists or may develop (including patients with diuretics)

- patients with liver cirrhosis and/or ascites

- patients undergoing major surgery or during anaesthesia with agents that produce hypotension.

Generally, it is recommended to correct dehydration, hypovolaemia or salt depletion before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed out against the risk of volume overload).

- Transient or persistent heart failure post MI

- Patients at risk of cardiac or cerebral ischemia in case of acute hypotension

The initial phase of treatment requires special medical supervision.

- Elderly patients

See section 4.2.

- Surgery

It is recommended that treatment with angiotensin converting enzyme inhibitors such as ramipril should be discontinued where possible one day before surgery.

- Monitoring of renal function

Renal function should be assessed before and during treatment and dosage adjusted especially in the initial weeks of treatment. Particularly careful monitoring is required in patients with renal impairment (see section 4.2). There is a risk of impairment of renal function, particularly in patients with congestive heart failure or after a renal transplant.

- Angioedema

Angioedema has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8).

In case of angioedema, TRITACE must be discontinued.

Emergency therapy should be instituted promptly. Patient should be kept under observation for at least 12 to 24 hours and discharged after complete resolution of the symptoms.

Intestinal angioedema has been reported in patients treated with ACE inhibitors including TRITACE (see section 4.8). These patients presented with abdominal pain (with or without nausea or vomiting).

- Anaphylactic reactions during desensitization

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased under ACE inhibition. A temporary discontinuation of TRITACE should be considered prior to desensitization.

- Hyperkalaemia

Hyperkalaemia has been observed in some patients treated with ACE inhibitors including TRITACE. Patients at risk for development of hyperkalaemia include those with renal insufficiency, age (> 70 years), uncontrolled diabetes mellitus, or those using potassium salts, potassium retaining diuretics and other plasma potassium increasing active substances, or conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been rarely seen and bone marrow depression has also been reported. It is recommended to monitor the white blood cell count to permit detection of a possible leucopoenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease (e.g. lupus erythematosus or scleroderma), and all those treated with other medicinal products that can cause changes in the blood picture (see sections 4.5 and 4.8).

Ethnic differences

ACE inhibitors cause higher rate of angioedema in black patients than in non black patients.

As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black people than in non black patients, possibly because of a higher prevalence of hypertension with low renin level in the black hypertensive population.

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Contra-indicated combinations

Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Precautions for use

Potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances (including Angiotensin II antagonists, trimethoprim, tacrolimus, ciclosporin): Hyperkalaemia may occur, therefore close monitoring of serum potassium is required.

Antihypertensive agents (e.g. diuretics) and other substances that may decrease blood pressure (e.g.nitrates, tricyclic antidepressants, anaesthetics, acute alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): Potentiation of the risk of hypotension is to be anticipated (see section 4.2 for diuretics)

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of TRITACE: Blood pressure monitoring is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count: Increased likelihood of haematological reactions (see section 4.4).

Lithium salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased. Lithium level must be monitored.

Antidiabetic agents including insulin: Hypoglycaemic reactions may occur. Blood glucose monitoring is recommended.

Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: Reduction of the antihypertensive effect of TRITACE is to be anticipated. Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function and to an increase in kalaemia.

4.6 Pregnancy And Lactation

TRITACE is not recommended during the first trimester of pregnancy (see section 4.4) and contraindicated during the second and third trimesters of pregnancy (see section 4.3).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. ACE inhibitor/ Angiotensin II Receptor Antagonist (AIIRA) therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also 5.3 'Preclinical safety data'). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Newborns whose mothers have taken ACE inhibitors should be closely observed for hypotension, oliguria and

hyperkalaemia (see also sections 4.3 and 4.4).

Because insufficient information is available regarding the use of ramipril during breastfeeding (see section 5.2), ramipril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects On Ability To Drive And Use Machines

Some adverse effects (e.g. symptoms of a reduction in blood pressure such as dizziness) may impair the patient's ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance (e.g. operating a vehicle or machinery).

This can happen especially at the start of treatment, or when changing over from other preparations. After the first dose or subsequent increases in dose it is not advisable to drive or operate machinery for several hours.

4.8 Undesirable Effects

The safety profile of ramipril includes persistent dry cough and reactions due to hypotension. Serious adverse reactions include angioedema, hyperkalaemia, renal or hepatic impairment, pancreatitis, severe skin reactions and neutropenia/agranulocytosis.

Adverse reactions frequency is defined using the following convention:

Very common (

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

Common

Uncommon

Rare

Very rare

Not known

Cardiac disorders

 

Myocardial ischaemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, oedema peripheral

     

Blood and lymphatic system disorders

 

Eosinophilia

White blood cell count decreased (including neutropenia or agranulocytosis), red blood cell count decreased, haemoglobin decreased, platelet count decreased

 

Bone marrow failure, pancytopenia, haemolytic anaemia

Nervous system disorders

Headache, dizziness

Vertigo, paraesthesia, ageusia, dysgeusia,

Tremor, balance disorder

 

Cerebral ischaemia including ischaemic stroke and transient ischaemic attack, psychomotor skills impaired, burning sensation, parosmia

Eye disorders

 

Visual disturbance including blurred vision

Conjunctivitis

   

Ear and labyrinth disorders

   

Hearing impaired, tinnitus

   

Respiratory, thoracic and mediastinal disorders

Non-productive tickling cough, bronchitis, sinusitis, dyspnoea

Bronchospasm including asthma aggravated, nasal congestion

     

Gastrointestinal disorders

Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting

Pancreatitis (cases of fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, abdominal pain upper including gastritis, constipation, dry mouth

Glossitis

 

Aphtous stomatitis

Renal and urinary disorders

 

Renal impairment including renal failure acute, urine output increased, worsening of a pre-existing proteinuria, blood urea increased, blood creatinine increased

     

Skin and subcutaneous tissue disorders

Rash in particular maculo-papular

Angioedema; very exceptionally, the airway obstruction resulting from angioedema may have a fatal outcome; pruritus, hyperhidrosis

Exfoliative dermatitis, urticaria, onycholysis,

Photosensitivity reaction

Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema, alopecia

Musculoskeletal and connective tissue disorders

Muscle spasms, myalgia

Arthralgia

     

Metabolism and nutrition disorders

Blood potassium increased

Anorexia, decreased appetite,

   

Blood sodium decreased

Vascular disorders

Hypotension, orthostatic blood pressure decreased, syncope

Flushing

Vascular stenosis, hypoperfusion, vasculitis

 

Raynaud's phenomenon

General disorders and administration site conditions

Chest pain, fatigue

Pyrexia

Asthenia

   

Immune system disorders

       

Anaphylactic or anaphylactoid reactions, antinuclear antibody increased

Hepatobiliary disorders

 

Hepatic enzymes and/or bilirubin conjugated increased,

Jaundice cholestatic, hepatocellular damage

 

Acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional).

Reproductive system and breast disorders

 

Transient erectile impotence, libido decreased

   

Gynaecomastia

Psychiatric disorders

 

Depressed mood, anxiety, nervousness, restlessness, sleep disorder including somnolence

Confusional state

 

Disturbance in attention

4.9 Overdose

Symptoms associated with overdosage of ACE inhibitors may include excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure. The patient should be closely monitored and the treatment should be symptomatic and supportive. Suggested measures include primary detoxification (gastric lavage, administration of adsorbents) and measures to restore haemodynamic stability, including, administration of alpha 1 adrenergic agonists or angiotensin II (angiotensinamide) administration. Ramiprilat, the active metabolite of ramipril is poorly removed from the general circulation by haemodialysis.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: ACE Inhibitors, plain, ATC code C09AA05.

Mechanism of action

Ramiprilat, the active metabolite of the prodrug ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In plasma and tissue this enzyme catalyses the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduced angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilatation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The average response to ACE inhibitor monotherapy was lower in black (Afro-Caribbean) hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.

Pharmacodynamic effects

Antihypertensive properties:

Administration of ramipril causes a marked reduction in peripheral arterial resistance. Generally, there are no major changes in renal plasma flow and glomerular filtration rate. Administration of ramipril to patients with hypertension leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate.

In most patients the onset of the antihypertensive effect of a single dose becomes apparent 1 to 2 hours after oral administration. The peak effect of a single dose is usually reached 3 to 6 hours after oral administration. The antihypertensive effect of a single dose usually lasts for 24 hours.

The maximum antihypertensive effect of continued treatment with ramipril is generally apparent after 3 to 4 weeks. It has been shown that the antihypertensive effect is sustained under long term therapy lasting 2 years.

Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in blood pressure.

Heart failure:

In addition to conventional therapy with diuretics and optional cardiac glycosides, ramipril has been shown to be effective in patients with functional classes II-IV of the New-York Heart Association. The drug had beneficial effects on cardiac haemodynamics (decreased left and right ventricular filling pressures, reduced total peripheral vascular resistance, increased cardiac output and improved cardiac index). It also reduced neuroendocrine activation.

Clinical efficacy and safety

Cardiovascular prevention/Nephroprotection;

A preventive placebo-controlled study (the HOPE-study), was carried out in which ramipril was added to standard therapy in more than 9,200 patients. Patients with increased risk of cardiovascular disease following either atherothrombotic cardiovascular disease (history of coronary heart disease, stroke or peripheral vascular disease) or diabetes mellitus with at least one additional risk factor (documented microalbuminuria, hypertension, elevated total cholesterol level, low high-density lipoprotein cholesterol level or cigarette smoking) were included in the study.

The study showed that ramipril statistically significantly decreases the incidence of myocardial infarction, death from cardiovascular causes and stroke, alone and combined (primary combined events).

The HOPE Study: Main Results;

 

Ramipril

Placebo

relative risk

(95% confidence interval)

p-value

 

%

%

   

All patients

n=4,645

N=4,652

 

 

Primary combined events

14.0

17.8

0.78 (0.70-0.86)

<0.001

Myocardial infarction

9.9

12.3

0.80 (0.70-0.90)

<0.001

Death from cardiovascular causes

6.1

8.1

0.74 (0.64-0.87)

<0.001

Stroke

3.4

4.9

0.68 (0.56-0.84)

<0.001

         

Secondary endpoints

 

 

 

 

Death from any cause

10.4

12.2

0.84 (0.75-0.95)

0.005

Need for Revascularisation

16.0

18.3

0.85 (0.77-0.94)

0.002

Hospitalisation for unstable angina

12.1

12.3

0.98 (0.87-1.10)

NS

Hospitalisation for heart failure

3.2

3.5

0.88 (0.70-1.10)

0.25

Complications related to diabetes

6.4

7.6

0.84 (0.72-0.98)

0.03

The MICRO-HOPE study, a predefined substudy from HOPE, investigated the effect of the addition of ramipril 10 mg to the current medical regimen versus placebo in 3,577 patients at least

The primary analysis showed that 117 (6.5 %) participants on ramipril and 149 (8.4 %) on placebo developed overt nephropathy, which corresponds to a RRR 24 %; 95 % CI [3-40], p = 0.027.

The REIN study, a multicenter randomized, double-blind parallel group, placebo-controlled study aimed at assessing the effect of treatment with ramipril on the rate of decline of glomerular function rate (GFR) in 352 normotensive or hypertensive patients (18-70 years old) suffering from mild (i.e. mean urinary protein excretion> 1 and < 3 g/24 h) or severe proteinuria (

The main analysis of patients with the most severe proteinuria (stratum prematurely disrupted due to benefit in ramipril group) showed that the mean r


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Tritace Tablet Titration Pack


1. Name Of The Medicinal Product

Tritace Tablet Titration Pack 2.5 mg, 5 mg, 10 mg tablets

2. Qualitative And Quantitative Composition

Tablets

Each 2.5 mg tablet contains ramipril 2.5 mg

Each 5 mg tablet contains ramipril 5 mg

Each 10 mg tablet contain ramipril 10 mg

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablets 2.5 mg

Yellowish to yellow oblong tablets with score-line.

Upper stamp: 2.5 & logo (

Lower stamp: HMR & 2.5

The tablet can be divided into equal halves.

Tablets 5 mg

Pale red oblong tablets with score-line.

Upper stamp: 5 & logo (

Lower stamp: HMP & 5

The tablet can be divided into equal halves

Tablets 10 mg

White to almost white oblong tablets with score-line.

Upper stamp: HMO/HMO

The tablet can be divided into equal halves.

4. Clinical Particulars 4.1 Therapeutic Indications

- Treatment of hypertension.

- Cardiovascular prevention: reduction of cardiovascular morbidity and mortality in patients with:

• manifest atherothrombotic cardiovascular disease (history of coronary heart disease or stroke, or peripheral vascular disease) or

• diabetes with at least one cardiovascular risk factor (see section 5.1).

- Treatment of renal disease:

• Incipient glomerular diabetic nephropathy as defined by the presence of microalbuminuria,

• Manifest glomerular diabetic nephropathy as defined by macroproteinuria in patients with at least one cardiovascular risk factor (see section 5.1),

• Manifest glomerular non diabetic nephropathy as defined by macroproteinuria

- Treatment of symptomatic heart failure.

- Secondary prevention after acute myocardial infarction: reduction of mortality from the acute phase of myocardial infarction in patients with clinical signs of heart failure when started > 48 hours following acute myocardial infarction.

4.2 Posology And Method Of Administration

Oral use.

It is recommended that TRITACE is taken each day at the same time of the day.

TRITACE can be taken before, with or after meals, because food intake does not modify its bioavailability (see section 5.2).

TRITACE has to be swallowed with liquid. It must not be chewed or crushed.

Adults

Diuretic-Treated patients

Hypotension may occur following initiation of therapy with TRITACE; this is more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume and/or salt depleted. If possible, the diuretic should be discontinued 2 to 3 days before beginning therapy with TRITACE (see section 4.4).

In hypertensive patients in whom the diuretic is not discontinued, therapy with TRITACE should be initiated with a 1.25 mg dose. Renal function and serum potassium should be monitored. The subsequent dosage of TRITACE should be adjusted according to blood pressure target.

Hypertension

The dose should be individualised according to the patient profile (see section 4.4) and blood pressure control.

TRITACE may be used in monotherapy or in combination with other classes of antihypertensive medicinal products.

Starting dose

TRITACE should be started gradually with an initial recommended dose of 2.5 mg daily.

Patients with a strongly activated renin-angiotensin-aldosterone system may experience an excessive drop in blood pressure following the initial dose. A starting dose of 1.25 mg is recommended in such patients and the initiation of treatment should take place under medical supervision (see section 4.4).

Titration and maintenance dose

The dose can be doubled at interval of two to four weeks to progressively achieve target blood pressure; the maximum permitted dose of TRITACE is 10 mg daily. Usually the dose is administered once daily.

Cardiovascular prevention

Starting dose

The recommended initial dose is 2.5 mg of TRITACE once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose should be gradually increased. It is recommended to double the dose after one or two weeks of treatment and - after another two to three weeks - to increase it up to the target maintenance dose of 10 mg TRITACE once daily.

See also posology on diuretic treated patients above.

Treatment of renal disease

In patients with diabetes and microalbuminuria:

Starting dose:

The recommended initial dose is 1.25 mg of TRITACE once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

In patients with diabetes and at least one cardiovascular risk

Starting dose:

The recommended initial dose is 2.5 mg of TRITACE once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the daily dose to 5 mg TRITACE after one or two weeks and then to 10 mg TRITACE after a further two or three weeks is recommended. The target daily dose is 10 mg.

In patients with non- diabetic nephropathy as defined by macroproteinuria

Starting dose:

The recommended initial dose is 1.25 mg of TRITACE once daily.

Titration and maintenance dose

Depending on the patient's tolerability to the active substance, the dose is subsequently increased. Doubling the once daily dose to 2.5 mg after two weeks and then to 5 mg after a further two weeks is recommended.

Symptomatic heart failure

Starting dose

In patients stabilized on diuretic therapy, the recommended initial dose is 1.25 mg daily.

Titration and maintenance dose

TRITACE should be titrated by doubling the dose every one to two weeks up to a maximum daily dose of 10 mg. Two administrations per day are preferable.

Secondary prevention after acute myocardial infarction and with heart failure

Starting dose

After 48 hours, following myocardial infarction in a clinically and haemodynamically stable patient, the starting dose is 2.5 mg twice daily for three days. If the initial 2.5 mg dose is not tolerated a dose of 1.25 mg twice a day should be given for two days before increasing to 2.5 mg and 5 mg twice a day. If the dose cannot be increased to 2.5 mg twice a day the treatment should be withdrawn.

See also posology on diuretic treated patients above.

Titration and maintenance dose

The daily dose is subsequently increased by doubling the dose at intervals of one to three days up to the target maintenance dose of 5 mg twice daily.

The maintenance dose is divided in 2 administrations per day where possible.

If the dose cannot be increased to 2.5 mg twice a day treatment should be withdrawn. Sufficient experience is still lacking in the treatment of patients with severe (NYHA IV) heart failure immediately after myocardial infarction. Should the decision be taken to treat these patients, it is recommended that therapy be started at 1.25 mg once daily and that particular caution be exercised in any dose increase.

Special populations

Patients with renal impairment

Daily dose in patients with renal impairment should be based on creatinine clearance (see section 5.2):

- if creatinine clearance is

- if creatinine clearance is between 30-60 ml/min, it is not necessary to adjust the initial dose (2.5 mg/day); the maximal daily dose is 5 mg;

- if creatinine clearance is between 10-30 ml/min, the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg;

- in haemodialysed hypertensive patients: ramipril is slightly dialysable; the initial dose is 1.25 mg/day and the maximal daily dose is 5 mg; the medicinal product should be administered few hours after haemodialysis is performed.

Patients with hepatic impairment (see section 5.2)

In patients with hepatic impairment, treatment with TRITACE must be initiated only under close medical supervision and the maximum daily dose is 2.5 mg TRITACE.

Elderly

Initial doses should be lower and subsequent dose titration should be more gradual because of greater chance of undesirable effects especially in very old and frail patients. A reduced initial dose of 1.25 mg ramipril should be considered.

Paediatric population

The safety and efficacy of ramipril in children has not yet been established. Currently available data for TRITACE are described in sections 4.8, 5.1, 5.2 and 5.3 but no specific recommendation on posology can be made.

4.3 Contraindications

- Hypersensitivity to the active substance, to any of the excipients or any other ACE (Angiotensin Converting Enzyme) inhibitors (see section 6.1)

- History of angioedema (hereditary, idiopathic or due to previous angioedema with ACE inhibitors or AIIRAs)

- Extracorporeal treatments leading to contact of blood with negatively charged surfaces (see section 4.5)

- Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney

- Second and third trimesters of pregnancy (see sections 4.4 and 4.6)

- Ramipril must not be used in patients with hypotensive or haemodynamically unstable states.

4.4 Special Warnings And Precautions For Use

Special populations

Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

- Patients at particular risk of hypotension

- Patients with strongly activated renin-angiotensin-aldosterone system

Patients with strongly activated renin-angiotensin-aldosterone system are at risk of an acute pronounced fall in blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor or a concomitant diuretic is given for the first time or at first dose increase.

Significant activation of renin-angiotensin-aldosterone system is to be anticipated and medical supervision including blood pressure monitoring is necessary, for example in:

- patients with severe hypertension

- patients with decompensated congestive heart failure

- patients with haemodynamically relevant left ventricular inflow or outflow impediment (e.g. stenosis of the aortic or mitral valve)

- patients with unilateral renal artery stenosis with a second functional kidney

- patients in whom fluid or salt depletion exists or may develop (including patients with diuretics)

- patients with liver cirrhosis and/or ascites

- patients undergoing major surgery or during anaesthesia with agents that produce hypotension.

Generally, it is recommended to correct dehydration, hypovolaemia or salt depletion before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed out against the risk of volume overload).

- Transient or persistent heart failure post MI

- Patients at risk of cardiac or cerebral ischemia in case of acute hypotension

The initial phase of treatment requires special medical supervision.

- Elderly patients

See section 4.2.

Surgery

It is recommended that treatment with angiotensin converting enzyme inhibitors such as ramipril should be discontinued where possible one day before surgery.

Monitoring of renal function

Renal function should be assessed before and during treatment and dosage adjusted especially in the initial weeks of treatment. Particularly careful monitoring is required in patients with renal impairment (see section 4.2). There is a risk of impairment of renal function, particularly in patients with congestive heart failure or after a renal transplant.

Angioedema

Angioedema has been reported in patients treated with ACE inhibitors including ramipril (see section 4.8).

In case of angioedema, TRITACE must be discontinued.

Emergency therapy should be instituted promptly. Patient should be kept under observation for at least 12 to 24 hours and discharged after complete resolution of the symptoms.

Intestinal angioedema has been reported in patients treated with ACE inhibitors including TRITACE (see section 4.8). These patients presented with abdominal pain (with or without nausea or vomiting).

Anaphylactic reactions during desensitization

The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased under ACE inhibition. A temporary discontinuation of TRITACE should be considered prior to desensitization.

Hyperkalaemia

Hyperkalaemia has been observed in some patients treated with ACE inhibitors including TRITACE. Patients at risk for development of hyperkalaemia include those with renal insufficiency, age (> 70 years), uncontrolled diabetes mellitus, or those using potassium salts, potassium retaining diuretics and other plasma potassium increasing active substances, or conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see section 4.5).

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been rarely seen and bone marrow depression has also been reported. It is recommended to monitor the white blood cell count to permit detection of a possible leucopoenia. More frequent monitoring is advised in the initial phase of treatment and in patients with impaired renal function, those with concomitant collagen disease (e.g. lupus erythematosus or scleroderma), and all those treated with other medicinal products that can cause changes in the blood picture (see sections 4.5 and 4.8).

Ethnic differences

ACE inhibitors cause higher rate of angioedema in black patients than in non black patients. As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black people than in non black patients, possibly because of a higher prevalence of hypertension with low renin level in the black hypertensive population.

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Contra-indicated combinations

Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate due to increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Precautions for use

Potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances (including Angiotensin II antagonists, trimethoprim, tacrolimus, ciclosporin): Hyperkalaemia may occur, therefore close monitoring of serum potassium is required.

Antihypertensive agents (e.g. diuretics) and other substances that may decrease blood pressure (e.g. nitrates, tricyclic antidepressants, anaesthetics, acute alcohol intake, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): Potentiation of the risk of hypotension is to be anticipated (see section 4.2 for diuretics)

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of TRITACE: Blood pressure monitoring is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count: Increased likelihood of haematological reactions (see section 4.4).

Lithium salts: Excretion of lithium may be reduced by ACE inhibitors and therefore lithium toxicity may be increased. Lithium level must be monitored.

Antidiabetic agents including insulin: Hypoglycaemic reactions may occur. Blood glucose monitoring is recommended.

Non-steroidal anti-inflammatory drugs and acetylsalicylic acid: Reduction of the antihypertensive effect of TRITACE is to be anticipated. Furthermore, concomitant treatment of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function and to an increase in kalaemia.

4.6 Pregnancy And Lactation

Pregnancy

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).

Lactation

Because insufficient information is available regarding the use of ramipril during breastfeeding (see section 5.2), Tritace is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects On Ability To Drive And Use Machines

Some adverse effects (e.g. symptoms of a reduction in blood pressure such as dizziness) may impair the patient's ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance (e.g. operating a vehicle or machinery).

This can happen especially at the start of treatment, or when changing over from other preparations. After the first dose or subsequent increases in dose it is not advisable to drive or operate machinery for several hours.

4.8 Undesirable Effects

The safety profile of ramipril includes persistent dry cough and reactions due to hypotension. Serious adverse reactions include angioedema, hyperkalaemia, renal or hepatic impairment, pancreatitis, severe skin reactions and neutropenia/agranulocytosis.

Adverse reactions frequency is defined using the following convention:

Very common (

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

Common

Uncommon

Rare

Very rare

Not known

Cardiac disorders

 

Myocardial ischaemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, oedema peripheral

     

Blood and lymphatic system disorders

 

Eosinophilia

White blood cell count decreased (including neutropenia or agranulocytosis), red blood cell count decreased, haemoglobin decreased, platelet count decreased

 

Bone marrow failure, pancytopenia, haemolytic anaemia

Nervous system disorders

Headache, dizziness

Vertigo, paraesthesia, ageusia, dysgeusia,

Tremor, balance disorder

 

Cerebral ischaemia including ischaemic stroke and transient ischaemic attack, psychomotor skills impaired, burning sensation, parosmia

Eye disorders

 

Visual disturbance including blurred vision

Conjunctivitis

   

Ear and labyrinth disorders

   

Hearing impaired, tinnitus

   

Respiratory, thoracic and mediastinal disorders

Non-productive tickling cough, bronchitis, sinusitis, dyspnoea

Bronchospasm including asthma aggravated, nasal congestion

     

Gastrointestinal disorders

Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting

Pancreatitis (cases of fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, abdominal pain upper including gastritis, constipation, dry mouth

Glossitis

 

Aphtous stomatitis

Renal and urinary disorders

 

Renal impairment including renal failure acute, urine output increased, worsening of a pre-existing proteinuria, blood urea increased, blood creatinine increased

     

Skin and subcutaneous tissue disorders

Rash in particular maculo-papular

Angioedema; very exceptionally, the airway obstruction resulting from angioedema may have a fatal outcome; pruritus, hyperhidrosis

Exfoliative dermatitis, urticaria, onycholysis,

Photosensitivity reaction

Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema, alopecia

Musculoskeletal and connective tissue disorders

Muscle spasms, myalgia

Arthralgia

     

Metabolism and nutrition disorders

Blood potassium increased

Anorexia, decreased appetite,

   

Blood sodium decreased

Vascular disorders

Hypotension, orthostatic blood pressure decreased, syncope

Flushing

Vascular stenosis, hypoperfusion, vasculitis

 

Raynaud's phenomenon

General disorders and administration site conditions

Chest pain, fatigue

Pyrexia

Asthenia

   

Immune system disorders

       

Anaphylactic or anaphylactoid reactions, antinuclear antibody increased

Hepatobiliary disorders

 

Hepatic enzymes and/or bilirubin conjugated increased,

Jaundice cholestatic, hepatocellular damage

 

Acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional).

Reproductive system and breast disorders

 

Transient erectile impotence, libido decreased

   

Gynaecomastia

Psychiatric disorders

 

Depressed mood, anxiety, nervousness, restlessness, sleep disorder including somnolence

Confusional state

 

Disturbance in attention

Paediatric Population

The safety of ramipril was monitored in 325 children and adolescents, aged 2-16 years old during 2 clinical trials. Whilst the nature and severity of the adverse events are similar to that of the adults, the frequency of the following is higher in the children:

Tachycardia, nasal congestion and rhinitis, “common” (i.e.

Conjunctivitis “common” (i.e.

Tremor and urticaria “uncommon” (i.e.

The overall safety profile for ramipril in paediatric patients dose not differ significantly from the safety profile in adults.

4.9 Overdose

Symptoms associated with overdosage of ACE inhibitors may include excessive peripheral vasodilatation (with marked hypotension, shock), bradycardia, electrolyte disturbances, and renal failure. The patient should be closely monitored and the treatment should be symptomatic and supportive. Suggested measures include primary detoxification (gastric lavage, administration of adsorbents) and measures to restore haemodynamic stability, including, administration of alpha 1 adrenergic agonists or angiotensin II (angiotensinamide) administration. Ramiprilat, the active metabolite of ramipril is poorly removed from the general circulation by haemodialysis.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: ACE Inhibitors, plain, ATC code C09AA05.

Mechanism of action

Ramiprilat, the active metabolite of the prodrug ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In plasma and tissue this enzyme catalyses the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. Reduced angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilatation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The average response to ACE inhibitor monotherapy was lower in black (Afro-Caribbean) hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.

Pharmacodynamic effects

Antihypertensive properties:

Administration of ramipril causes a marked reduction in peripheral arterial resistance. Generally, there are no major changes in renal plasma flow and glomerular filtration rate. Administration of ramipril to patients with hypertension leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate.

In most patients the onset of the antihypertensive effect of a single dose becomes apparent 1 to 2 hours after oral administration. The peak effect of a single dose is usually reached 3 to 6 hours after oral administration. The antihypertensive effect of a single dose usually lasts for 24 hours.

The maximum antihypertensive effect of continued treatment with ramipril is generally apparent after 3 to 4 weeks. It has been shown that the antihypertensive effect is sustained under long term therapy lasting 2 years.

Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in blood pressure.

Heart failure:

In addition to conventional therapy with diuretics and optional cardiac glycosides, ramipril has been shown to be effective in patients with functional classes II-IV of the New-York Heart Association. The drug had beneficial effects on cardiac haemodynamics (decreased left and right ventricular filling pressures, reduced total peripheral vascular resistance, increased cardiac output and improved cardiac index). It also reduced neuroendocrine activation.

Clinical efficacy and safety

Cardiovascular prevention/Nephroprotection;

A preventive placebo-controlled study (the HOPE-study), was carried out in which ramipril was added to standard therapy in more than 9,200 patients. Patients with increased risk of cardiovascular disease following either atherothrombotic cardiovascular disease (history of coronary heart disease, stroke or peripheral vascular disease) or diabetes mellitus with at least one additional risk factor (documented microalbuminuria, hypertension, elevated total cholesterol level, low high-density lipoprotein cholesterol level or cigarette smoking) were included in the study.

The study showed that ramipril statistically significantly decreases the incidence of myocardial infarction, death from cardiovascular causes and stroke, alone and combined (primary combined events).

The HOPE Study: Main Results;

 

Ramipril

Placebo

relative risk

(95% confidence interval)

p-value

 

%

%

   

All patients

n=4,645

N=4,652

 

 

Primary combined events

14.0

17.8

0.78 (0.70-0.86)

<0.001

Myocardial infarction

9.9

12.3

0.80 (0.70-0.90)

<0.001

Death from cardiovascular causes

6.1

8.1

0.74 (0.64-0.87)

<0.001

Stroke

3.4

4.9

0.68 (0.56-0.84)

<0.001

         

Secondary endpoints

 

 

 

 

Death from any cause

10.4

12.2

0.84 (0.75-0.95)

0.005

Need for Revascularisation

16.0

18.3

0.85 (0.77-0.94)

0.002

Hospitalisation for unstable angina

12.1

12.3

0.98 (0.87-1.10)

NS

Hospitalisation for heart failure

3.2

3.5

0.88 (0.70-1.10)

0.25

Complications related to diabetes

6.4

7.6

0.84 (0.72-0.98)

0.03

The MICRO-HOPE study, a predefined substudy from HOPE, investigated the effect of the addition of ramipril 10 mg to the current medical regimen versus placebo in 3,577 patients at least

The primary analysis showed that 117 (6.5 %) participants on ramipril and 149 (8.4 %) on placebo developed overt nephropathy, which corresponds to a RRR 24 %; 95 % CI [3-40], p = 0.027.

The REIN study, a multicenter randomized, double-blind parallel group, placebo-controlled study aimed at a


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Altace


Pronunciation: RA-mi-pril
Generic Name: Ramipril
Brand Name: Altace

Altace may cause injury or death to the fetus if taken after the third month of pregnancy. If you think you may be pregnant, contact your doctor right away.


Altace is used for:

Treating high blood pressure or decreasing the risk of heart attack, stroke, and death in certain patients. It may be used alone or with other medicines. It is used along with other medicines to manage heart failure and improve survival after a heart attack. It may also be used for other conditions as determined by your doctor.

Altace is an angiotensin-converting enzyme (ACE) inhibitor. It works by relaxing blood vessels. This helps to lower blood pressure.

Do NOT use Altace if: you are allergic to any ingredient in Altace or to another ACE inhibitor (eg, lisinopril) you have a history of angioedema (swelling of the hands, face, lips, eyes, throat, or tongue; difficulty swallowing or breathing; or hoarseness) caused by treatment with an ACE inhibitor you are in your second or third trimester of pregnancy you are taking telmisartan

Contact your doctor or health care provider right away if any of these apply to you.

Before using Altace:

Some medical conditions may interact with Altace. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

if you are pregnant, planning to become pregnant, or are breast-feeding if you are able to become pregnant if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement if you have allergies to medicines, foods, or other substances if you have a history of heart problems (eg, aortic stenosis, heart failure), blood vessel problems, blood flow problems, bone marrow problems, kidney problems (eg, renal artery stenosis), certain liver problems (eg, ascites, cirrhosis), or diabetes if you have a history of angioedema, a stroke, or a recent heart attack, or you have had a kidney transplant if you have an autoimmune disease (eg, lupus, rheumatoid arthritis, scleroderma) if you are dehydrated or have low blood volume, high blood potassium levels, or low blood sodium levels, or if you are on a low-salt (sodium) diet if you are receiving treatments to reduce sensitivity to bee stings if you are on dialysis or are scheduled to have surgery or undergo anesthesia

Some MEDICINES MAY INTERACT with Altace. Tell your health care provider if you are taking any other medicines, especially any of the following:

Diuretics (eg, furosemide, hydrochlorothiazide) because the risk of low blood pressure may be increased Aldosterone blockers (eg, eplerenone), nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen), potassium-sparing diuretics (eg, spironolactone, triamterene), potassium supplements, or trimethoprim because the risk of high blood potassium levels may be increased Telmisartan because the risk of kidney problems may be increased Certain gold-containing medicines (eg, sodium aurothiomalate) because flushing, nausea, vomiting, and low blood pressure may occur Lithium or thiopurines (eg, azathioprine) because the risk of their side effects may be increased by Altace

This may not be a complete list of all interactions that may occur. Ask your health care provider if Altace may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Altace:

Use Altace as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Take Altace by mouth with or without food. Swallow this tablet whole unless your doctor tells you otherwise. Continue to take Altace even if you feel well. Do not miss any doses. If you miss a dose of Altace, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Altace.

Important safety information: Altace may cause dizziness, lightheadedness, or fainting. These effects may be worse if you take it with alcohol or certain medicines. Use Altace with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it. Altace may cause dizziness, lightheadedness, or fainting; alcohol, hot weather, exercise, or fever may increase these effects. To prevent them, sit up or stand slowly, especially in the morning. Sit or lie down at the first sign of any of these effects. Altace may cause a serious side effect called angioedema. Contact your doctor at once if you develop swelling of the hands, face, lips, eyes, throat, or tongue; difficulty swallowing or breathing; or hoarseness. Altace may not work as well in black patients. They may also be at greater risk of side effects. Contact your doctor if your symptoms do not improve or if they become worse. Dehydration, excessive sweating, vomiting, or diarrhea may increase the risk of low blood pressure. Contact your health care provider at once if any of these occur. Rarely, Altace may lower the ability of your body to fight infection. This risk may be greater if you have certain other health problems (eg, kidney problems, collagen vascular disease). Avoid contact with people who have colds or infections. Tell your doctor if you notice signs of infection like fever, sore throat, rash, or chills. Check with your doctor before you use a salt substitute or a product that has potassium in it. Tell your doctor or dentist that you take Altace before you receive any medical or dental care, emergency care, or surgery. Patients who take medicine for high blood pressure often feel tired or run down for a few weeks after starting treatment. Be sure to take your medicine even if you may not feel "normal." Tell your doctor if you develop any new symptoms. If you have high blood pressure, do not use nonprescription products that contain stimulants. These products may include diet pills or cold medicines. Contact your doctor if you have any questions or concerns. Diabetes patients - Altace may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine. Lab tests, including blood pressure, blood electrolyte levels, heart function, or kidney or liver function, may be performed while you use Altace. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments. Use Altace with caution in the ELDERLY; they may be more sensitive to its effects. Altace should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed. PREGNANCY AND BREAST-FEEDING: Altace may cause birth defects or fetal death if you take it while you are pregnant. If you think you may be pregnant, contact your doctor right away. It is not known if Altace is found in breast milk. Do not breast-feed while taking Altace. Possible side effects of Altace:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Cough; dizziness; headache; tiredness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the hands, eyes, mouth, face, lips, throat, or tongue; hoarseness); chest pain; dark urine; decreased urination; difficulty swallowing; infection (eg, fever, chills, persistent sore throat); irregular heartbeat; loss of appetite; pale stools; red, swollen, blistered, or peeling skin; seizures; stomach pain (with or without nausea or vomiting); symptoms of low blood pressure (eg, fainting, severe dizziness, lightheadedness); yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Altace side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include fainting; severe dizziness or lightheadedness; weakness.

Proper storage of Altace:

Store Altace between 68 and 77 degrees F (20 and 25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Altace out of the reach of children and away from pets.

General information: If you have any questions about Altace, please talk with your doctor, pharmacist, or other health care provider. Altace is to be used only by the patient for whom it is prescribed. Do not share it with other people. If your symptoms do not improve or if they become worse, check with your doctor. Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Altace. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012 Database Edition 12.1.1.002 Copyright © 2012 Wolters Kluwer Health, Inc. More Altace resources Altace Side Effects (in more detail) Altace Dosage Altace Use in Pregnancy & Breastfeeding Drug Images Altace Drug Interactions Altace Support Group 6 Reviews for Altace - Add your own review/rating Altace Prescribing Information (FDA) Altace Consumer Overview Altace Monograph (AHFS DI) Altace Advanced Consumer (Micromedex) - Includes Dosage Information Ramipril Prescribing Information (FDA) Ramipril Professional Patient Advice (Wolters Kluwer) Compare Altace with other medications Diabetic Kidney Disease Heart Attack Heart Failure High Blood Pressure Left Ventricular Dysfunction
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Mavik


Generic Name: trandolapril (tran DOE la pril)
Brand Names: Mavik

What is Mavik (trandolapril)?

Trandolapril is an ACE inhibitor. ACE stands for angiotensin converting enzyme.

Trandolapril is used to treat high blood pressure (hypertension), and to improve survival after a heart attack.

Trandolapril may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Mavik (trandolapril)? Do not use trandolapril if you are pregnant. It could harm the unborn baby. Stop using this medication and tell your doctor right away if you become pregnant. You should not use this medicine if you are allergic to trandolapril or similar medicines, such as benazepril (Lotensin), captopril (Capoten), fosinopril (Monopril), enalapril (Vasotec), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), or ramipril (Altace). Avoid drinking alcohol. It can further lower your blood pressure and may increase some of the side effects of trandolapril. Do not use salt substitutes or potassium supplements while taking trandolapril, unless your doctor has told you to. Follow your doctor's instructions about the type and amount of liquids you should drink while taking trandolapril. Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting. What should I discuss with my healthcare provider before taking Mavik (trandolapril)? You should not use this medicine if you are allergic to trandolapril or to any other ACE inhibitor, such as benazepril (Lotensin), captopril (Capoten), fosinopril (Monopril), enalapril (Vasotec), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), or ramipril (Altace).

To make sure you can safely take trandolapril, tell your doctor if you have any of these other conditions:

kidney disease (or if you are on dialysis);

liver disease;

heart disease or congestive heart failure;

diabetes; or

a connective tissue disease such as Marfan syndrome, Sjogren's syndrome, lupus, scleroderma, or rheumatoid arthritis.

FDA pregnancy category D. Do not use trandolapril if you are pregnant. Stop using this medication and tell your doctor right away if you become pregnant. Trandolapril can cause injury or death to the unborn baby if you take the medicine during your second or third trimester. Use effective birth control while taking trandolapril. Trandolapril can pass into breast milk and may harm a nursing baby. You should not breast-feed while you are using trandolapril. How should I take Mavik (trandolapril)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results.

Trandolapril can be taken with or without food.

Conditions that may cause very low blood pressure include: vomiting, diarrhea, heavy sweating, heart disease, dialysis, a low salt diet, or taking diuretics (water pills). Follow your doctor's instructions about the type and amount of liquids you should drink while taking trandolapril. Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.

Your blood pressure will need to be checked often. Your kidney or liver function may also need to be tested. Visit your doctor regularly.

If you need surgery, tell the surgeon ahead of time that you are using trandolapril.

If you are being treated for high blood pressure, keep using this medication even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.

Store at room temperature away from moisture and heat. What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include feeling extremely dizzy or light-headed, or fainting.

What should I avoid while taking Mavik (trandolapril)? Avoid drinking alcohol. It can further lower your blood pressure and may increase some of the side effects of trandolapril. Do not use salt substitutes or potassium supplements while taking trandolapril, unless your doctor has told you to. Mavik (trandolapril) side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; severe stomach pain; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

urinating less than usual, or not at all;

swelling, weight gain, feeling short of breath;

feeling like you might pass out;

chest pain, trouble breathing;

pounding heartbeats or fluttering in your chest;

fever, chills, body aches, flu symptoms;

easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

high potassium (slow heart rate, weak pulse, muscle weakness, tingly feeling); or

low calcium (numbness or tingly feeling around your mouth, fast or slow heart rate, muscle tightness or contraction, overactive reflexes).

Less serious side effects may include:

cold symptoms such as stuffy nose, sneezing, sore throat;

cough;

muscle pain;

dizziness, drowsiness, headache;

sleep problems (insomnia);

upset stomach, diarrhea, constipation; or

mild skin itching or rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Mavik (trandolapril)?

Tell your doctor about all other medicines you use, especially:

gold injections to treat arthritis;

lithium (Lithobid, Eskalith);

a diuretic (water pill); or

aspirin or other NSAIDs (non-steroidal anti-inflammatory drugs) such as ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others.

This list is not complete and other drugs may interact with trandolapril. Tell your doctor about all medications you use. This includes prescription, over the counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Mavik resources Mavik Side Effects (in more detail) Mavik Use in Pregnancy & Breastfeeding Drug Images Mavik Drug Interactions Mavik Support Group 0 Reviews for Mavik - Add your own review/rating Mavik Prescribing Information (FDA) Mavik MedFacts Consumer Leaflet (Wolters Kluwer) Mavik Monograph (AHFS DI) Mavik Advanced Consumer (Micromedex) - Includes Dosage Information Trandolapril Prescribing Information (FDA) Trandolapril Professional Patient Advice (Wolters Kluwer) Compare Mavik with other medications Diabetic Kidney Disease Heart Attack Heart Failure High Blood Pressure Left Ventricular Dysfunction Where can I get more information? Your pharmacist can provide more information about trandolapril.

See also: Mavik side effects (in more detail)


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Accuretic


Generic Name: hydrochlorothiazide and quinapril (HYE droe klor oh THY a zide and KWIN a pril)
Brand Names: Accuretic

What is Accuretic (hydrochlorothiazide and quinapril)?

Hydrochlorothiazide is a thiazide diuretic (water pill) that helps prevent your body from absorbing too much salt, which can cause fluid retention.

Quinapril is in a group of drugs called ACE inhibitors. ACE stands for angiotensin converting enzyme. Quinapril lowers blood pressure and also relieves symptoms of fluid retention.

The combination of hydrochlorothiazide and quinapril is used to treat hypertension (high blood pressure).

Hydrochlorothiazide and quinapril may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Accuretic (hydrochlorothiazide and quinapril)? Do not use this medication if you are unable to urinate.

You should not use this medication if you are allergic to any other ACE inhibitor, such as benazepril (Lotensin), captopril (Capoten), fosinopril (Monopril), enalapril (Vasotec), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), or trandolapril (Mavik).

Before taking hydrochlorothiazide and quinapril, tell your doctor if you have kidney disease (or are on dialysis), liver disease, glaucoma, congestive heart failure, gout, lupus, diabetes, or an allergy to sulfa drugs or penicillin.

Do not use this medication if you are pregnant. It could harm the unborn baby.

Do not use potassium supplements or salt substitutes while you are taking hydrochlorothiazide and quinapril, unless your doctor has told you to.

Conditions that may cause very low blood pressure include: vomiting, diarrhea, heavy sweating, heart disease, dialysis, a low-salt diet, or taking diuretics (water pills). Follow your doctor's instructions about the type and amount of liquids you should drink while taking hydrochlorothiazide and quinapril. Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.

What should I discuss with my healthcare provider before taking Accuretic (hydrochlorothiazide and quinapril)? Do not use this medication if you are allergic to hydrochlorothiazide or quinapril, or if you are unable to urinate.

You should not use this medication if you are allergic to other ACE inhibitor, such as benazepril (Lotensin), captopril (Capoten), fosinopril (Monopril), enalapril (Vasotec), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), or trandolapril (Mavik).

To make sure you can safely take hydrochlorothiazide and quinapril, tell your doctor if you have any of these other conditions:

kidney disease (or if you are on dialysis); liver disease;

glaucoma;

congestive heart failure;

gout;

lupus;

diabetes; or

an allergy to sulfa drugs or penicillin.

FDA pregnancy category D. Do not use hydrochlorothiazide and quinapril if you are pregnant. Stop using this medication and tell your doctor right away if you become pregnant. Use effective birth control while taking hydrochlorothiazide and quinapril. Hydrochlorothiazide can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. How should I take Accuretic (hydrochlorothiazide and quinapril)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results.

Take this medicine with a full glass of water.

Conditions that may cause very low blood pressure include: vomiting, diarrhea, heavy sweating, heart disease, dialysis, a low-salt diet, or taking diuretics (water pills). Follow your doctor's instructions about the type and amount of liquids you should drink while taking hydrochlorothiazide and quinapril. Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.

Your blood pressure will need to be checked often. Your blood and urine may also be tested if you have been vomiting or are dehydrated. Visit your doctor regularly.

Hydrochlorothiazide can interfere with the results of a thyroid test. Tell any doctor who treats you that you are using a thiazide diuretic.

Keep using this medication even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.

Store at room temperature away from moisture, heat, and light.

See also: Accuretic dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include nausea, weakness, dizziness, dry mouth, thirst, muscle pain or weakness, or feeling like you might pass out.

What should I avoid while taking Accuretic (hydrochlorothiazide and quinapril)?

Avoid becoming overheated or dehydrated during exercise and in hot weather. Follow your doctor's instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall. Drinking alcohol can further lower your blood pressure and may increase certain side effects of hydrochlorothiazide and quinapril.

Do not use potassium supplements or salt substitutes while you are taking hydrochlorothiazide and quinapril, unless your doctor has told you to.

Accuretic (hydrochlorothiazide and quinapril) side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; severe stomach pain; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

eye pain, vision problems;

high potassium (slow heart rate, weak pulse, muscle weakness, tingly feeling);

low potassium (confusion, uneven heart rate, extreme thirst, increased urination, leg discomfort, muscle weakness or limp feeling);

dry mouth, thirst, nausea, vomiting;

feeling weak, drowsy, restless, or light-headed;

a red, blistering, peeling skin rash;

jaundice (yellowing of the skin or eyes);

urinating less than usual or not at all;

swelling, weight gain, feeling short of breath; or

fever, chills, body aches, flu symptoms.

Less serious side effects may include:

cough;

dizziness, headache, tired feeling;

muscle or back pain;

runny nose;

sleep problems (insomnia);

diarrhea, constipation, upset stomach; or

mild skin rash, increased sweating.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Accuretic (hydrochlorothiazide and quinapril)? Cold or allergy medicine, sedatives, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety can add to some of the side effects of hydrochlorothiazide and quinapril. Tell your doctor if you regularly use any of these medicines.

Tell your doctor about all other medicines you use, especially:

other diuretics (water pills) or blood pressure medications;

gold injections to treat arthritis;

lithium (Lithobid, Eskalith);

a tetracycline antibiotic such as doxycycline (Doryx, Oracea, Periostat, Vibramycin), minocycline (Dynacin, Minocin, Solodyn), or tetracycline (Ala-Tet, Brodspec, Panmycin, Sumycin, Tetracap);

cholestyramine (Prevalite, Questran) or colestipol (Colestid);

steroids (prednisone and others);

NSAIDs (non-steroidal anti-inflammatory drugs) such as aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others; or

insulin or oral diabetes medication.

This list is not complete and other drugs may interact with hydrochlorothiazide and quinapril. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Accuretic resources Accuretic Side Effects (in more detail) Accuretic Dosage Accuretic Use in Pregnancy & Breastfeeding Drug Images Accuretic Drug Interactions Accuretic Support Group 0 Reviews for Accuretic - Add your own review/rating Accuretic MedFacts Consumer Leaflet (Wolters Kluwer) Accuretic Prescribing Information (FDA) Quinaretic Prescribing Information (FDA) Compare Accuretic with other medications High Blood Pressure Where can I get more information? Your pharmacist can provide more information about hydrochlorothiazide and quinapril.

See also: Accuretic side effects (in more detail)


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Triapin tablets


1. Name Of The Medicinal Product

Triapin 5mg/5mg prolonged release tablets

2. Qualitative And Quantitative Composition

Each tablet contains 5 mg of felodipine and 5 mg of ramipril.

Each tablet contains 51.5 mg lactose anhydrous.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Triapin 5mg/5mg tablets are circular (diameter approx 9 mm), reddish-brown coloured, biconvex and engraved on one side and marked 5 on the other side.

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of essential hypertension. Triapin fixed dose combination is indicated in patients whose blood pressure is not adequately controlled on felodipine or ramipril alone.

4.2 Posology And Method Of Administration

Posology

Use in adults, including elderly:

One tablet Triapin once daily, which is also the maximum dose.

Special populations

Use in patients with impaired liver function:

See sections 4.3 and 4.4.

Use in patients with impaired renal function or patients already on diuretic treatment:

See sections 4.3 and 4.4.

Individual dose titration with the components can be recommended and when clinically appropriate, direct change from monotherapy to the fixed combination may be considered.

Paediatric population:

Triapin is not recommended for use in children due to a lack of data.

Method of administration

Triapin tablets should be swallowed whole with a sufficient amount of liquid. The tablets must not be divided, crushed or chewed.

The tablet can be administered without food or following a light meal not rich in fat or carbohydrate.

4.3 Contraindications

Triapin must not be used:

• in patients with hypersensitivity to felodipine (or other dihydropyridines), ramipril, other angiotensin converting enzyme (ACE) inhibitors or any of the excipients of Triapin.

• in patients with a history of angioedema.

• in unstable haemodynamic conditions: cardiovascular shock, untreated heart failure, acute myocardial infarction, unstable angina pectoris, stroke.

• in patients with AV block II or III.

• in patients with severely impaired hepatic function.

• in patients with severely impaired renal function (creatinine clearance less than 20 ml/min) and in patients on dialysis.

• during pregnancy.

• during lactation.

4.4 Special Warnings And Precautions For Use

Angioedema

Angioedema occurring during treatment with an ACE inhibitor necessitates immediate discontinuation of the medicinal product. Angioedema may involve the tongue, glottis or larynx and, if so, may necessitate emergency measures.

Angioedema of the face, extremities, lips, tongue, glottis or larynx has been reported in patients treated with ACE inhibitors. Emergency therapy should be given including, but not necessarily limited to, immediate subcutaneous adrenalin solution 1:1000 (0.3 to 0.5 ml) or slow intravenous adrenalin 1 mg/ml (observe dilution instructions) with control of ECG and blood pressure. The patient should be hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has occurred.

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C1-esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Compared with non-black patients, a higher incidence of angioedema has been reported in black patients treated with ACE inhibitors.

Renal function

Renal function should be monitored, particularly in the initial weeks of treatment with ACE inhibitors. Caution should be observed in patients with an activated renin-angiotensin system.

Patients with mild to moderately impaired renal function (creatinine clearance 20-60 ml/min) and patients already on diuretic treatment: For dosage see the respective monoproducts.

Hyperkalaemia

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including ramipril. Patients at risk for the development of hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes; or those patients taking other medicinal products associated with increases in serum potassium (e.g. heparin). If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended.

Proteinuria

It may occur particularly in patients with existing renal function impairment or on relatively high doses of ACE inhibitors.

Renovascular hypertension/renal artery stenosis

There is an increased risk of severe hypotension and renal insufficiency when patients with renovascular hypertension and pre-existing bilateral renal artery stenosis or stenosis of the artery to a solitary kidney are treated with ACE inhibitors. Loss of renal function may occur with only mild changes in serum creatinine even in patients with unilateral renal artery stenosis.

There is no experience regarding the administration of Triapin in patients with a recent kidney transplantation.

Hepatic failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progress to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Patients with mild to moderately impaired liver function:

For dosage see respective monoproducts.

Surgery/Anaesthesia

Hypotension may occur in patients undergoing major surgery or during treatment with anaesthetic agents that are known to lower blood pressure. If hypotension occurs, it may be corrected by volume expansion.

Aortic stenosis/Hypertrophic cardiomyopathy

ACE inhibitors should be used with caution in patients with haemodynamically relevant left-ventricular or outflow impediment (e.g. stenosis of the aortic or mitral valve, obstructive cardiomyopathy). The initial phase of treatment requires special medical supervision.

Symptomatic hypotension

In some patients, symptomatic hypotension may be observed after the initial dose, mainly in patients with heart failure (with or without renal insufficiency) treated with high doses of loop diuretics, in hyponatraemia or in reduced renal function. Therefore, Triapin should only be given to such patients after special considerations and after the doses of the individual components have been carefully titrated. Triapin should only be given if the patient is in a stable circulatory condition (see section 4.3). In hypertensive patients without cardiac and renal insufficiency, hypotension may occur especially in patients with decreased blood volume due to diuretic therapy, salt restriction, diarrhoea or vomiting.

Patients who would be at particular risk from an undesirably pronounced reduction in blood pressure (e.g. patients with coronary or cerebrovascular insufficiency) should be treated with ramipril and felodipine in a free combination. If satisfactory and stable blood pressure control is achieved with the doses of ramipril and felodipine included in Triapin, the patient can be switched to this combination. In some cases, felodipine may cause hypotension with tachycardia, which may aggravate angina pectoris.

Neutropenia/Agranulocytosis

Triapin may cause agranulocytosis and neutropenia. These undesirable effects have also been shown with other ACE inhibitors, rarely in uncomplicated patients but more frequently in patients with some degree of renal impairment, especially when it is associated with collagen vascular disease (e.g. systemic lupus erythematodes, scleroderma) and therapy with immunosuppressive agents. Monitoring of white blood cell counts should be considered for patients who have collagen vascular disease, especially if the disease is associated with impaired renal function. Neutropenia and agranulocytosis are reversible after discontinuation of the ACE inhibitor. Should symptoms such as fever, swelling of the lymph nodes, and/or inflammation of the throat occur in the course of therapy with Triapin, the treating physician must be consulted and the white blood picture investigated immediately.

Cough

During treatment with an ACE inhibitor a dry cough may occur which disappears after discontinuation.

Concomitant treatment with ACE inhibitors and antidiabetics

Concomitant treatment with ACE inhibitors and antidiabetics (insulin and oral antidiabetics) may lead to an enhanced hypoglycaemic effect with the risk of hypoglycaemia. This effect may be most pronounced at the beginning of treatment and in patients with impaired renal function.

Felodipine is metabolised by CYP3A4. Therefore, combination with medicinal products which are potent CYP3A4 inhibitors or inducers should be avoided. For the same reason, the concomitant intake of grapefruit juice should be avoided (see section 4.5).

Lithium

The combination of lithium and ACE inhibitors is not recommended.

(see section 4.5).

LDL-apheresis

Concomitant use of ACE inhibitors and extracorporeal treatments leading to contact of blood with negatively charged surfaces should be avoided since it may lead to severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or haemofiltration with certain high-flux (e.g. polyacrylonitrile) membranes and low-density lipoprotein apheresis with dextran sulphate.

Desensitisation therapy

Increased likelihood and greater severity of anaphylactic and anaphylactoid reactions to insect venom (e.g. bee and wasp) as for other ACE inhibitors.

Ethnic differences

As with other angiotensin converting enzyme inhibitors, ramipril is apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.

Children, patients with creatinine clearance under 20 ml/min and dialysis-treated patients

No experience is available. Triapin should not be given to these patient groups.

Lactose

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Not recommended associations

Potassium salts, potassium-retaining diuretics: Rise in serum potassium concentration is to be anticipated. Concomitant treatment with potassium-retaining diuretics (e.g. spironolactone, triamterene, or amiloride) or with potassium salts requires close monitoring of serum potassium.

Felodipine is a CYP3A4 substrate. Medicinal products that induce or inhibit CYP3A4 will have large influence on felodipine plasma concentrations.

Medicinal products that increase the metabolism of felodipine through induction of cytochrome P450 3A4 include carbamazepine, phenytoin, phenobarbital and rifampin as well as St John's wort (Hypericum perforatum). During concomitant administration of felodipine with carbamazepine, phenytoin, phenobarbital, AUC decreased by 93% and Cmax by 82%. A similar effect is expected with St John's wort. Combination with CYP3A4 inducers should be avoided.

Potent inhibitors of cytochrome P450 3A4 include azole antifungals, macrolide antibiotics, telithomycin and HIV protease inhibitors. During concomitant administration of felodipine with itraconazole, Cmax increased 8-fold and AUC 6-fold. During concomitant administration of felodipine with erythromycin, Cmax and AUC increased approximately 2.5-fold. Combination with potent CYP3A4 inhibitors should be avoided.

Grapefruit juice inhibits cytochrome P450 3A4. Concomitant administration of felodipine with grapefruit juice increased felodipine Cmax and AUC approximately 2-fold. The combination should be avoided.

Caution is recommended with concomitant use

Lithium

Excretion of lithium may be reduced by ACE inhibitors, leading to lithium toxicity. Lithium levels must, therefore, be monitored.

Antihypertensive agents and other substances with blood pressure lowering potential (e.g. nitrates, antipsychotics, narcotics, anaesthetics)

Potentiation of the antihypertensive effect of Triapin is to be anticipated.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood picture: Increased likelihood of haematological reactions.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Attenuation of the effect of ramipril is to be expected. Furthermore, concomitant treatment with ACE inhibitors and such medicinal products may lead to an increased risk of worsening of the renal function and an increase in serum potassium.

Vasopressor sympathomimetics

These may reduce the antihypertensive effect of Triapin. Particularly close blood pressure monitoring is recommended.

Insulins, metformin, sulphonylureas

Concomitant treatment with ACE inhibitors and antidiabetic agents may cause a pronounced hypoglycaemic effect with the risk of hypoglycaemia. This effect is most pronounced at the beginning of treatment.

Theophylline

Concomitant administration of felodipine and oral theophylline reduces theophylline absorption by approximately 20%. This is probably of minor clinical importance.

Tacrolimus

Felodipine may increase the concentration of tacrolimus. When used together, the tacrolimus serum concentration should be followed and the tacrolimus dose may need to be adjusted.

Heparin

Rise in serum potassium concentration possible.

Salt

Increased dietary salt intake may attenuate the antihypertensive effect of Triapin.

Alcohol

Increased vasodilatation. The antihypertensive effect of Triapin may increase.

4.6 Pregnancy And Lactation

Pregnancy

Triapin is contra-indicated (see section, 4.3.) in pregnancy.

Calcium antagonists may inhibit contractions of the uterus during labour. Definite evidence that labour is prolonged in full-term pregnancy is lacking. Risk of foetal hypoxia may occur if the mother is hypotensive and perfusion of the uterus is reduced due to redistribution of the blood-flow through peripheral vasodilatation. In animal experiments, calcium antagonists have caused embryotoxic and/or teratogenic effects, especially in the form of distal skeletal malformations in several species.

Appropriate and well-controlled studies with ramipril have not been done in humans. ACE inhibitors cross the placenta and can cause foetal and neonatal morbidity and mortality when administered to pregnant women.

Fetal exposure to ACE inhibitors during the second and third trimesters has been associated with neonatal hypotension, renal failure, face or skull deformities and/or death. Maternal oligohydramnios have also been reported reflecting decreasing renal function in the fetus. Limb contractures, craniofacial deformities, hypoplastic lung development and intrauterine growth retardation have been reported in association with oligohydramnios. Intrauterine growth retardation, prematurity, persistent ductus arteriosus and fetal death have also been reported, but it is not clear whether they are related to the ACE inhibitor or to the underlying maternal disease. Whether exposure limited to the first trimester can adversely effect fetal outcome is not known.

Breastfeeding

In animals, ramipril is excreted in milk. No information is available on whether or not ramipril is excreted in human breast-milk. Felodipine is excreted in human breast-milk.

Women must not breast-feed during treatment with Triapin (see section 4.3).

4.7 Effects On Ability To Drive And Use Machines

Some undesirable effects (e.g. some symptoms of reduction in blood pressure such as dizziness) may be accompanied by an impairment of the ability to concentrate and react. This may constitute a risk in situations where these abilities are of special importance, e.g., when driving a car or operating machinery.

4.8 Undesirable Effects

The frequencies used in the tables throughout this section are:

very common (

The following undesirable effects may occur in connection with felodipine treatment

Frequencies/Organ System

Common

Uncommon

Rare

Very rare

Immune system disorders

     

Hypersensitivity reactions

Metabolism and nutrition disorders

     

Hyperglycaemia

Psychiatric Disorders

   

Impotence/ sexual dysfunction

 

Nervous System Disorders

Headache

Dizziness, paraesthesiae

Syncope

 

Cardiac disorders

 

Tachycardia, palpitations

   

Vascular disorders

Flush, peripheral oedema

   

Leucocytoclastic vasculitis

Gastrointestinal Disorders

 

Nausea, abdominal pain

Vomiting

Gingival hyperplasia, gingivitis

Hepatobiliary

     

Increased liver enzymes

Skin and Subcutaneous Tissue Disorders

 

Rash, pruritus

Urticaria

Photosensitivity reactions, angioedema

Musculoskeletal and Connective Tissue Disorders

   

Arthralgia, myalgia

 

Renal and urinary disorders

     

Pollakisuria

General Disorders and Administration Site conditions

 

Fatigue

 

Fever

The following undesirable effects may occur in connection with ramipril treatment

Frequencies/Organ System

Common

Uncommon

Rare

Very rare

Not Known

Blood and lymphatic system disorders

 

Eosinophilia

White blood cell count decreased (including neutropenia or agranulocytosis), red blood cell count decreased, haemoglobin decreased, platelet count decreased

 

Bone marrow failure, pancytopenia, haemolytic anaemia

Immune system disorders

       

Anaphylactic or anaphylactoid reactions, antinuclear antibody increased

Metabolism and nutrition disorders

Blood potassium increased

Anorexia, decreased

   

Blood sodium decreased

Psychiatric disorders

 

Depressed mood, anxiety, nervousness, restlessness, sleep disorder including somnolence

Confusional state

 

Disturbance in attention

Nervous system disorders

Headache, dizziness

Vertigo, paraethesia, ageusia, dysgeusia

Tremor, balance disorder

 

Cerebral ischaemia including ischaemic attack, psychomotor skills impaired, burning sensation, parosmia

Eye disorders

 

Visual disturbance including blurred vision

Conjunctivitis

   

Ear and labyrinth disorders

   

Hearing impaired, tinnitus

   

Cardiac disorders

 

Myocardial ischaemia including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, oedema peripheral

     

Vascular disorders

Hypotension, orthostatic blood pressure decreased, syncope

Flushing

Vascular stenosis, hypoperfusion, vasculitis

 

Raynaud's phenomenon

Respiratory, thoracic and mediastinal disorders

Non-productive tickling cough, bronchitis, sinusitis, dyspnoea

Bronchospasm including asthma aggravated, nasal congestion

     

Gastrointestinal disorders

Gastrointestinal inflammation, digestive disturbances, abdominal discomfort, dyspepsia, diarrhoea, nausea, vomiting

Pancreatitis (cases of fatal outcome have been very exceptionally reported with ACE inhibitors), pancreatic enzymes increased, small bowel angioedema, abdominal pain upper including gastritis, constipation, dry mouth

Glossitis

 

Aphtous stomatitis

Hepatobiliary disorders

 

Hepatic enzymes and/or bilirubin conjugated increased

Jaundice cholestatic, hepatocellular damage

 

Acute hepatic failure, cholestatic or cytolytic hepatitis (fatal outcome has been very exceptional).

Skin and subcutaneous tissue disorders

Rash in particular maculo-papular

Angioedema; very exceptionally, the airway obstruction resulting from angiodema may have a fatal outcome; pruritus, hyperhidrosis

Exfoliative dermatitis, urticaria, onycholysis

Photosensitivity reaction

Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, psoriasis aggravated, dermatitis psoriasiform, pemphigoid or lichenoid exanthema or enanthema, alopecia

Musculoskeletal and connective tissue disorders

Muscle spasms, myalgia

Arthralgia

     

Renal and urinary disorders

 

Renal impairment including renal failure acute, urine output increased, worsening of pre-existing proteinuria, blood urea increased, blood creatinine increased

     

Reproductive system and breast disorders

 

Transient erectile impotence, libido decreased

   

Gynaecomastia

General disorders and administration site conditions

Chest pain, fatigue

Pyrexia

Asthenia

    4.9 Overdose

Symptoms

Overdosage may cause excessive peripheral vasodilatation with marked hypotension, bradycardia, shock, electrolyte disturbances and renal failure.

Management

Primary detoxification by, for example, gastric lavage, administration of adsorbents and/or sodium sulphate (if possible during the first 30 minutes). In case of hypotension, administration of ?1-adrenergic sympathomimetics and angiotensin II must be considered in addition to volume and salt substitution. Bradycardia or extensive vagal reactions should be treated by administering atropine.

No experience is available concerning the efficacy of forced diuresis, alteration in urine pH, haemofiltration, or dialysis in speeding up the elimination of ramipril or ramiprilat. If dialysis or haemofiltration is nevertheless considered, see also under 4.4 Special Warnings and Special Precautions for use.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antihypertensive drugs. ATC code: C09B B05

Both the calcium antagonist felodipine and the ACE inhibitor ramipril reduce blood pressure by dilation of the peripheral blood vessels. Calcium antagonists dilate the arterial beds while ACE inhibitors dilate both arterial and venous beds. Vasodilatation and thereby reduction of blood pressure may lead to activation of the sympathetic nervous system and the renin-angiotensin system. Inhibition of ACE results in decreased plasma angiotensin II.

The onset of the antihypertensive effect of a single dose of Triapin is 1 to 2 hours. The maximum antihypertensive effect is achieved within 2 to 4 weeks and is maintained during long-term therapy. The blood pressure reduction is maintained throughout the 24-hour dosage interval. Morbidity and mortality data are not available.

Felodipine is a vascular selective calcium antagonist, which lowers arterial blood pressure by decreasing peripheral vascular resistance via a direct relaxant action on vascular smooth muscles. Due to its selectivity for smooth muscle in the arterioles, felodipine, in therapeutic doses, has no direct effect on cardiac contractility or conduction. The renal vascular resistance is decreased by felodipine. The normal glomerular filtration rate is not influenced. In patients with impaired renal function, the glomerular filtration rate may increase. Felodipine possesses a mild natriuretic/diuretic effect and fluid retention does not occur.

Ramipril is a prodrug which hydrolyses to the active metabolite ramiprilat, a potent and long-acting ACE (angiotensin converting enzyme) inhibitor. In plasma and tissue, ACE catalyses the conversion of angiotensin I to the vasoconstrictor angiotensin II and also the breakdown of the vasodilator bradykinin. The vasodilatation induced by the ACE inhibitor reduces blood pressure pre-load and after-load. Since angiotensin II also stimulates the release of aldosterone, ramiprilat reduces secretion of aldosterone. Ramipril reduces peripheral arterial resistance without major changes in renal plasma flow or glomerular filtration rate. In hypertensive patients, ramipril leads to a reduction in supine and standing blood pressure without a compensatory rise in heart rate.

5.2 Pharmacokinetic Properties

General characteristics of the active substances

Felodipine ER (extended-release formulation): The bioavailability is approximately 15% and is not influenced by concomitant intake of food. The peak plasma concentration is reached after 3 to 5 hours. Binding to plasma proteins is more than 99%. The distribution volume at steady state is 10 l/kg. The half-life for felodipine in the elimination phase is approximately 25 hours and steady state is reached after 5 days. There is no risk of accumulation during long-term treatment. Mean clearance is 1200 ml/min. Decreased clearance in elderly patients leads to higher plasma concentrations of felodipine. Age only partly explains the inter-individual variation in plasma concentration, however. Felodipine is metabolised in the liver and all identified metabolites are devoid of vasodilating properties. Approximately 70% of a given dose is excreted as metabolites in the urine and about 10% with the faeces. Less than 0.5% of the dose is excreted unchanged in the urine. Impaired renal function does not influence the plasma concentration of felodipine.

Ramipril: The pharmacokinetic parameters of ramiprilat are calculated after intravenous administration of ramipril. Ramipril is metabolised in the liver, and aside from the active metabolite ramiprilat, pharmacologically inactive metabolites have been identified. The formation of active ramiprilat may be decreased in patients with impaired liver function. The metabolites are excreted mainly via the kidneys. The bioavailability of ramiprilat is approximately 28% after oral administration of ramipril. After intravenous administration of 2.5 mg ramipril, approximately 53% of the dose is converted to ramiprilat. A maximum serum concentration of ramiprilat is achieved after 2 to 4 hours. Absorption and bioavailability are not influenced by concomitant intake of food. The protein binding of ramiprilat is approximately 55%. The distribution volume is approximately 500 litres. The effective half-life, after repeated daily dosage of 5 to 10 mg, is 13 to 17 hours. Steady-state is achieved after approximately 4 days. Renal clearance is 70 to 100 ml/min and total clearance is approximately 380 ml/min. Impaired renal function delays the elimination of ramiprilat and excretion in the urine is reduced.

Characteristics of the combination product

In Triapin the pharmacokinetics of ramipril, ramiprilat and felodipine are essentially unaltered compared to the monoproducts, felodipine ER tablets and ramipril tablets. Felodipine does not influence the ACE inhibition caused by ramiprilat. The fixed combination tablets are thus regarded as bioequivalent to the free combination.

5.3 Preclinical Safety Data

Repeated-dose toxicity studies performed with the combination in rats and monkeys did not demonstrate any synergistic effects.

Non-clinical data for felodipine and ramipril reveal no special hazard for humans based on conventional studies of genotoxicity and carcinogenic potential.

Reproduction toxicity

Felodipine: In investigations on fertility and general reproductive performance in rats, a prolongation of parturition resulting in difficult labour/increased foetal deaths and early postnatal deaths was observed. Reproduction toxicity studies in rabbits have shown a dose-related reversible enlargement of the mammary glands of the parent animals and dose-related digital anomalies in the foetuses.

Ramipril: Studies in rats, rabbits and monkeys did not disclose any teratogenic properties. Daily doses during pregnancy and lactation in rats produced irreversible renal pelvis dilatation in the offspring.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Cellulose microcrystalline

Hyprolose

Hypromellose

Iron oxides E172

Lactose anhydrous

Macrogol 6000

Macrogolglycerol hydroxystearate

Maize starch

Paraffin

Propyl gallate

Sodium aluminium silicate

Sodium stearyl fumarate

Titanium dioxide E 171

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Triapin: 30 months

6.4 Special Precautions For Storage

Do not store above 30°C.

6.5 Nature And Contents Of Container

PVC/PVDC blisters: 28 tablets

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

PL 04425/0320

9. Date Of First Authorisation/Renewal Of The Authorisation

15th April 2002

15th January 2008

10. Date Of Revision Of The Text

31 August 2011

LEGAL STATUS

POM


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hydrochlorothiazide and captopril


Generic Name: hydrochlorothiazide and captopril (hye droe klor oh THY a zide and KAP toe pril)
Brand Names: Capozide 25/15, Capozide 25/25, Capozide 50/15, Capozide 50/25

What is hydrochlorothiazide and captopril?

Hydrochlorothiazide is a thiazide diuretic (water pill) that helps prevent your body from absorbing too much salt, which can cause fluid retention.

Captopril is in a group of drugs called ACE inhibitors. ACE stands for angiotensin converting enzyme. Captopril lowers blood pressure and also relieves symptoms of fluid retention.

The combination of hydrochlorothiazide and captopril is used to treat hypertension (high blood pressure).

Hydrochlorothiazide and captopril may also be used for purposes not listed in this medication guide.

What is the most important information I should know about hydrochlorothiazide and captopril? You should not use this medication if you are allergic to hydrochlorothiazide or captopril, or if you have a history of asthma or allergies, or you are unable to urinate.

You should not use this medication if you are allergic to any other ACE inhibitor, such as benazepril (Lotensin), fosinopril (Monopril), enalapril (Vasotec), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), or trandolapril (Mavik).

Before taking hydrochlorothiazide and captopril, tell your doctor if you have kidney disease (or are on dialysis), liver disease, glaucoma, congestive heart failure, gout, lupus, diabetes, or an allergy to sulfa drugs or penicillin.

Do not use hydrochlorothiazide and captopril if you are pregnant. It could harm the unborn baby.

Do not use potassium supplements or salt substitutes while you are taking hydrochlorothiazide and captopril, unless your doctor has told you to.

Conditions that may cause very low blood pressure include: vomiting, diarrhea, heavy sweating, heart disease, dialysis, a low-salt diet, or taking diuretics (water pills). Follow your doctor's instructions about the type and amount of liquids you should drink while taking hydrochlorothiazide and captopril. Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.

What should I discuss with my healthcare provider before taking hydrochlorothiazide and captopril? Do not use this medication if you are allergic to hydrochlorothiazide or captopril, or if you have:

a history of asthma or allergies; or

if you are unable to urinate.

You should not use this medication if you are allergic to any other ACE inhibitor, such as benazepril (Lotensin), fosinopril (Monopril), enalapril (Vasotec), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), or trandolapril (Mavik).

To make sure you can safely take hydrochlorothiazide and captopril, tell your doctor if you have any of these other conditions:

kidney disease (or if you are on dialysis); liver disease;

glaucoma;

congestive heart failure;

gout;

lupus;

diabetes; or

an allergy to sulfa drugs or penicillin

FDA pregnancy category D. Do not use hydrochlorothiazide and captopril if you are pregnant. It could harm the unborn baby. Stop using this medication and tell your doctor right away if you become pregnant. Use effective birth control while taking hydrochlorothiazide and captopril. Hydrochlorothiazide can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. How should I take hydrochlorothiazide and captopril?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results.

Take each dose with a full glass of water.

Conditions that may cause very low blood pressure include: vomiting, diarrhea, heavy sweating, heart disease, dialysis, a low-salt diet, or taking diuretics (water pills). Follow your doctor's instructions about the type and amount of liquids you should drink while taking hydrochlorothiazide and captopril. Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.

Your blood pressure will need to be checked often. Your blood and urine may also be tested if you have been vomiting or are dehydrated. Visit your doctor regularly.

Hydrochlorothiazide can interfere with the results of a thyroid test. Tell any doctor who treats you that you are using a thiazide diuretic.

Keep using this medicine as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.

Store at room temperature away from moisture, heat, and light.

See also: Hydrochlorothiazide and captopril dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include nausea, weakness, dizziness, dry mouth, thirst, muscle pain or weakness, or feeling like you might pass out.

What should I avoid while taking hydrochlorothiazide and captopril?

Avoid becoming overheated or dehydrated during exercise and in hot weather. Follow your doctor's instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall. Drinking alcohol can further lower your blood pressure and may increase certain side effects of hydrochlorothiazide and captopril.

Do not use potassium supplements or salt substitutes while you are taking hydrochlorothiazide and captopril, unless your doctor has told you to.

Hydrochlorothiazide and captopril side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; severe stomach pain; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

eye pain, vision problems;

high potassium (slow heart rate, weak pulse, muscle weakness, tingly feeling);

low potassium (confusion, uneven heart rate, extreme thirst, increased urination, leg discomfort, muscle weakness or limp feeling);

dry mouth, thirst, nausea, vomiting;

feeling weak, drowsy, restless, or light-headed;

a red, blistering, peeling skin rash;

jaundice (yellowing of the skin or eyes);

urinating less than usual or not at all;

swelling, weight gain, feeling short of breath; or

fever, chills, body aches, flu symptoms.

Less serious side effects may include:

cough;

dizziness, headache, tired feeling;

blurred vision;

diarrhea, constipation, upset stomach; or

mild skin rash, increased sweating.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Hydrochlorothiazide and captopril Dosing Information

Usual Adult Dose for Congestive Heart Failure:

Initial dose: 1 tablet of (captopril-hydrochlorothiazide 25 mg/15 mg) orally once a day, one hour before meals. Determine dosage by individual titration.
Maintenance dose: May use additional captopril or hydrochlorothiazide as individual components or change to an increased strength of the combination tablet. May give the combination tablet in divided doses up to 3 times a day. In general, daily doses of captopril should not exceed 150 mg and of hydrochlorothiazide should not exceed 50 mg.

Usual Adult Dose for Hypertension:

Initial dose: 1 tablet of (captopril-hydrochlorothiazide 25 mg/15 mg) orally once a day, one hour before meals. Determine dosage by individual titration.
Maintenance dose: May use additional captopril or hydrochlorothiazide as individual components or change to an increased strength of the combination tablet. May give the combination tablet in divided doses up to 3 times a day. In general, daily doses of captopril should not exceed 150 mg and of hydrochlorothiazide should not exceed 50 mg.

What other drugs will affect hydrochlorothiazide and captopril? Cold or allergy medicine, sedatives, narcotic pain medicine, sleeping pills, muscle relaxers, and medicine for seizures, depression or anxiety can add to the side effects of hydrochlorothiazide and captopril. Tell your doctor if you regularly use any of these medicines, or any other blood pressure medications.

Tell your doctor about all other medicines you use, especially:

gold injections to treat arthritis;

other diuretics (water pills) or blood pressure medications;

lithium (Lithobid, Eskalith);

a blood thinner such as warfarin (Coumadin, Jantoven);

digoxin (Lanoxin);

nitroglycerin (Nitrolingual, Nitrostat, Nitro-Dur, and others);

cholestyramine (Prevalite, Questran) or colestipol (Colestid);

steroids (prednisone and others);

NSAIDs (non-steroidal anti-inflammatory drugs) such as aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn, Naprelan, Treximet), celecoxib (Celebrex), diclofenac (Arthrotec, Cambia, Cataflam, Voltaren, Flector Patch, Pennsaid, Solareze), indomethacin (Indocin), meloxicam (Mobic), and others; or

insulin or diabetes medicine taken by mouth.

This list is not complete and other drugs may interact with hydrochlorothiazide and captopril. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More hydrochlorothiazide and captopril resources Hydrochlorothiazide and captopril Side Effects (in more detail) Hydrochlorothiazide and captopril Dosage Hydrochlorothiazide and captopril Use in Pregnancy & Breastfeeding Drug Images Hydrochlorothiazide and captopril Drug Interactions Hydrochlorothiazide and captopril Support Group 0 Reviews for Hydrochlorothiazide and captopril - Add your own review/rating Compare hydrochlorothiazide and captopril with other medications Heart Failure High Blood Pressure Where can I get more information? Your pharmacist can provide more information about hydrochlorothiazide and captopril.

See also: hydrochlorothiazide and captopril side effects (in more detail)


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Trandolapril 0.5mg, 1mg, 2mg, 4mg Capsules


Trandolapril 0.5mg, 1mg, 2mg and 4mg Capsules

Read all of this leaflet carefully before you start using this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or pharmacist. This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. In this leaflet: 1. What Trandolapril capsules are and what they are used for 2. Before you use Trandolapril capsules 3. How to use Trandolapril capsules 4. Possible side effects 5. How to store Trandolapril capsules 6. Further information What Trandolapril Capsules Are And What They Are Used For

Trandolapril, the active ingredient in Trandolapril capsules belongs to a group of medicines called angiotensin-converting enzyme inhibitors (sometimes called ACE inhibitors). ACE inhibitors work by relaxing the blood vessels which makes it easier for the heart to pump blood around the body. This helps to lower the blood pressure.

Trandolapril capsules are used to treat high blood pressure. They may also be used to protect the heart after a heart attack.

Before You Use Trandolapril Capsules Do not use Trandolapril capsules if: You are allergic to trandolapril, other ACE inhibitors (e.g. perindopril or ramipril) or any of the other ingredients listed in section 6 You have ever had the condition known as angioedema (an itchy rash such as nettle rash or hives) or Quinke’s oedema (this is a severe allergic skin condition) associated with administration of an ACE inhibitor You are more than 3 months pregnant. (It is also better to avoid Trandolapril in early pregnancy – see pregnancy section.) Take special care with Trandolapril capsules if:

It is possible that you may develop problems with low blood pressure and reduced kidney function if you are a patient at risk being treated with Trandolapril capsules. This may cause you to faint. You must be placed in a side position and someone in your surroundings must call an ambulance or the emergency services.

Tell your doctor if

You have been taking diuretics (water tablets) for a long time or you have been on a low salt diet You recently had severe or prolonged vomiting or diarrhoea You ever had an allergic reaction (named Quincke’s oedema or angioedeme) to any other ACE inhibitors (e.g. perindopril or ramipril – including swelling in the face, lips, tongue or throat with difficulty in swallowing or breathing) You suffer from a condition known as collagen vascular disease (this is sometimes called connective tissue disease, for example lupus or scleroderma) You suffer from diabetes mellitus You suffer from heart failure You are on kidney dialysis (some kinds of dialysis membrane may not be suitable) You have liver or kidney problems including transplantation You are going to be anaesthetised before an operation You have a narrowing of one of the valves in the heart (aorta stenosis) or in the outflow from the left chamber of the heart You are being treated with medicine that lowers your immune response You develop a cough. Your doctor may choose another medicine for you You are to undergo LDL apheresis (which is removal of cholesterol from your blood by a machine) You are going to have desensitisation treatment to reduce the effects of an allergy to bee or wasp stings You think you are (or might become) pregnant. Trandolapril is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section). Using other medicines

Other medication can affect the efficacy and safety of this medication. On the other hand, Trandolapril capsules can affect the efficacy and safety of other medication. Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription, herbal products or natural products. Remember to tell your doctor about Trandolapril capsules if you receive another medication during your treatment or shortly after your treatment with Trandolapril capsules. It is especially important to inform your doctor if you use:

Other medicines for high blood pressure including water tablets such as bendroflumethiazide Diuretics (water tablets) that retain potassium such as spironolactone, amiloride and triamterene or potassium canrenoate and potassium supplements Anti-inflammatory pain killers (NSAIDs – e.g. ibuprofen, diclofenac, indometacin, acetylsalicylic acid and COX-2 inhibitors) Lithium or tricyclic antidepressant (e.g. amitriptyline, dosulepin) Medicines for diabetes (such as insulin, glibenclamide or gliclazide) Antacids Allopurinol (for gout) or procainamide (for abnormal heart rhythms) Immunosuppressants (e.g. ciclosporin), steroid medication (e.g. prednisolone, hydrocortisone) or anticancer medication Antipsychotic drugs such as chlorpromazine, thioridazine, flupentixol

If you need to have an operation, it is important that you tell the surgeon or dentist that you are taking Trandolapril capsules. It may affect the anaesthetic or other treatments used.

Contact your doctor and inform him if you are taking any of the above medications. It may be necessary to adjust the dose.

Using Trandolapril capsules with food and drink

You may take Trandolapril capsules with or after food and with drink.

Pregnancy and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine.

Pregnancy

You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking Trandolapril before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Trandolapril. Trandolapril is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.

Breastfeeding

Tell your doctor if you are breast-feeding or about to start breast-feeding. Trandolapril is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely.

Driving and using machines

Trandolapril capsules can make some people feel dizzy or faint especially when they first start to take the capsules. Do not drive, operate machinery or do anything that requires you to be alert for several hours after your first dose, after any increase in the dose or during concurrent use of alcohol.

Wait and see how the capsules affect you.

Important information about some of the ingredients of Trandolapril capsules

This medicine contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

This medicine (in capsules of 0.5 mg, 1 mg and 2 mg) contains sunset yellow (E110). May cause allergic reactions.

How To Use Trandolapril Capsules

Always take Trandolapril capsules exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Swallow your capsules whole without chewing them and take them with a glass of water. Always take them at the same time of day.

The number of capsules that you will need to take will depend on what you are treated for. If you are already taking diuretics your doctor may tell you to reduce the dose of the diuretic or even tell you to stop taking them, before you start to take Trandolapril capsules.

Adults:

High blood pressure (hypertension):

The usual starting dose is 0.5 mg once a day. Your doctor will probably increase this dose to 1-2 mg daily. The maximum dose is 4 mg a day.

Patients with heart failure:

The hospital will initiate your treatment. The usual starting dose is 0.5 mg once a day.

Treatment following a heart attack:

Treatment will normally be started quite as early as the third day after a heart attack, usually at a low dose of 0.5 mg each day. Your doctor will probably increase this dose gradually to a maximum of 4 mg each day.

Dose for adults treated earlier with diuretics (water tablets): -

The diuretic treatment (water tablets) should be discontinued at least 72 hours (3 days) before beginning treatment with Trandolapril capsules, and/or treatment may be started with 0.5 mg once daily. Afterwards the dose will be adjusted when your doctor sees the effect of the treatment.

The elderly:

It is not necessary to reduce the dose if you have normal kidney function. You must start with a low dose, and your doctor will watch your blood pressure and measure your kidney function during treatment.

However, caution is needed if at the same time you are being treated with diuretics (water tablets) or you have reduced heart, liver or kidney function.

Children:

Trandolapril should not be given to children.

Patients with kidney problems:

Your doctor will adjust your dose depending on the results of your laboratory tests (0.5-1 mg daily).

Patients in kidney dialysis: 0.5 mg daily.

Patients with liver problems:

The initial dose is 0.5 mg daily. Afterwards your doctor may adjust your dose as needed.

If you take more Trandolapril capsules than you should

Contact your doctor, hospital or pharmacy, if you have taken too much of this medicine and you feel uncomfortable.

The symptoms of overdose are severely reduced blood pressure, shock (swelling in the mouth and throat which causes difficulty breathing - contact your doctor), slowing down of thought processes (lethargy), slow pulse, disturbances in the salt balance and reduced kidney function.

If you forget to take Trandolapril capsules

Do not take a double dose to make up for a forgotten dose.

If you stop using Trandolapril capsules

It is important that you keep taking the capsules until your doctor tells you to stop. Do not stop just because you feel better. If you stop taking the capsules, your condition may get worse.

If you have any further questions on the use of this product, ask your doctor or pharmacist

Possible Side Effects

Like all medicines, Trandolapril capsules can cause side effects, although not everybody gets them.

Very common side effects (occur in more than 1 out of 10 treated) and common side effects (occur in between 1 and 10 out of 100 treated):

Reduced blood pressure.

Common side effects (occur in between 1 and 10 out of 100 treated):

Dizziness, headache, weakness and cough.

Uncommon side effects (occur in between 1 and 10 out of 1,000 treated):

Noticeable heartbeats. Nausea. Itching and skin rash, feeling sick and/or being sick.

Rare side effects (occur in between 1 and 10 out of 10,000 treated) and very rare side effects (occur in fewer than 1 out of 10,000 treated):

Nervousness, difficulties sleeping, sleepiness moving towards loss of consciousness. Throat irritation, nosebleed. Vomiting, stomach pain, diarrhoea, constipation, indigestion. Fluid retention (oedema), tendency to sweat, nettle rash. Muscle pain. Hot flashes.

Side effects with unknown frequency:

Changes to blood test parameters such as liver enzymes, creatinine and urea. Allergic reaction such as itching and skin rash. Increased levels of potassium in the blood. Bleeding in the brain, muscular paralysis, temporary loss of consciousness. Shortness of breath, bronchitis. Dry mouth, inflammation in the pancreas. Hair loss. Severe skin diseases (including Erythema multiforme and Stevens-Johnson’s syndrome). Fever. Blood disorders such as agranulocytosis (a condition in which there is an insufficient number of white blood cells and therefore infections can occur), leucopenia (reduction in the number of white blood cells), pancytopenia (a reduction of all types of blood cells, including red and white blood cells as well as platelets) and decreased amount of oxygen-carrying protein in the blood (haemoglobin) and haematocrit (the proportion of space red blood cells take up in the blood).

Other side effects that have been reported with ACE inhibitors include kidney problems, severe drops in blood pressure with symptoms such as fainting, chest pain or stroke.

Allergic reactions have been reported very rarely. If you experience any sudden wheeziness, tightness in the chest, difficulty swallowing, swelling of eyelids, face or lips, a skin rash such as red spots or hives (skin lumps) or itching, please talk to your doctor immediately.

If you suffer from any of these side effects or any other side effects not mentioned in this leaflet, please talk to your doctor or pharmacist.

How To Store Trandolapril Capsules Keep out of the reach and sight of children. Store in the original package. Store below 25°C. Do not use after the expiry date which is stated on the carton. The expiry date refers to the last day of that month. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. Further Information What Trandolapril capsules contain The active substance is trandolapril 0.5 mg, 1 mg, 2 mg or 4 mg. The other ingredients are: lactose monohydrate, pregelatinised maize starch, microcrystalline cellulose, dimeticone, magnesium stearate, colloidal anhydrous silica, gelatin, titanium dioxide (E171) and erythrosine (E127). In addition, each strength also contains the following:

0.5 mg: sunset yellow (E110), quinoline yellow (E104)

1 mg: sunset yellow (E110)

2 mg: sunset yellow (E110)

4 mg: red iron oxide (E172) and yellow iron oxide (E172)

What Trandolapril capsules look like and contents of the pack

0.5 mg: light scarlet – rich yellow, size 2 oblong capsules

1 mg: light scarlet – light orange, size 2 oblong capsules

2 mg: light scarlet – light scarlet, size 2 oblong capsules

4 mg: swedish orange – swedish orange, size 2 oblong capsules

Contents:

0.5 mg, 1 mg, 2 mg and 4 mg:

14 and 28 capsules.

Marketing Authorisation Holder Actavis Group PTC ehf Reykjav?kurvegi 76-78 IS-220 Hafnarfj?r?ur Iceland Manufacturers Pharmathen S.A. 6, Dervenakion str. Pallini Attikis 153 51 Greece Pharmathen International S.A. Sapes Industrial Park Block 5 69300 Rodopi Greece

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

Actavis Barnstaple EX32 8NS UK Telephone:01271 311257

This leaflet was last revised in September 2009

If you would like a leaflet with larger text, please contact 01271 311257.

Actavis Barnstaple EX32 8NS UK

PSAPL003


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Avodart


Generic Name: Dutasteride
Class: 5-alpha-Reductase Inhibitors
VA Class: HS900
Chemical Name: 5?,17?)-N-[2,5-bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost-1-ene-17-carboxamide
Molecular Formula: C27H30F6N2O2
CAS Number: 164656-23-9

Special Alerts:

[Posted 06/09/2011] ISSUE: FDA notified healthcare professionals that the Warnings and Precautions section of the labels for the 5-alpha reductase inhibitor (5-ARI) class of drugs has been revised to include new safety information about the increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer).

BACKGROUND: The new safety information is based on FDA’s review of two large, randomized controlled trials––the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. Finasteride (Proscar), dutasteride (Avodart), and dutasteride in combination with tamsulosin (marketed combination product as Jalyn) are approved to improve symptoms of an enlarged prostate gland (benign prostatic hyperplasia or BPH). Proscar and Avodart are also approved to reduce the risk of urinary retention or surgery related to an enlarged prostate. Finasteride (Propecia) is approved to treat male pattern hair loss.

RECOMMENDATION: Prior to initiating therapy with 5-ARIs, perform appropriate evaluation to rule out other urological conditions, including prostate cancer, that might mimic benign prostatic hyperplasia (BPH). See Drug Safety Communication for a Data Summary and additional information. For more information visit the FDA website at: and .

Introduction

Selective inhibitor of steroid 5?-reductase isoenzymes, which are necessary for conversion of testosterone to 5?-dihydrotestosterone (DHT).1 4 9

Uses for Avodart

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Benign Prostatic Hyperplasia (BPH)

Treatment of symptomatic BPH1 to improve symptoms and reduce the risk of acute urinary retention and the need for surgery.1 3 Ineffective in patients who do not have evidence of prostatic enlargement.11

Although drug therapy usually is not as effective as surgical therapy, it may provide adequate symptomatic relief with fewer and less serious adverse effects compared with surgery.11

Steroid 5?-reductase inhibitors may be a useful alternative to surgery in patients with obstructive manifestations who are unwilling to undergo surgical correction of BPH;8 may aid those who may be at increased risk from, but not necessarily candidates for, prostate surgery.4 8 10 Also may be considered in patients who have symptomatic prostatic enlargement but whose symptoms are not bothersome (i.e., do not interfere with activities of daily living) in order to prevent progression of the disease.11

May consider combined therapy with an ?1-adrenergic blocker and 5?-reductase inhibitor for men with bothersome moderate to severe BPH and demonstrable prostatic enlargement.11 Has been more effective than therapy with either drug alone in preventing long-term BPH symptom progression.11 Men at risk for BPH progression are most likely to benefit from combination therapy.11

Avodart Dosage and Administration Administration Oral Administration

Administer orally without regard to meals.1

The capsules should be swallowed whole.1

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Adults Benign Prostatic Hyperplasia Oral

Initially and for maintenance therapy, 0.5 mg once daily.1

While early symptomatic improvement (e.g., within 3 months) may occur, ?6 months of therapy may be necessary to determine clinical benefit.2 Generally, therapy is continued for life.9

Special Populations Hepatic Impairment

No specific dosage recommendations for hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment not required.1

Geriatric Patients

Dosage adjustment not required.1

Cautions for Avodart Contraindications

Known or suspected pregnancy.1 (See Fetal/Neonatal Morbidity and also Pregnancy under Cautions.)

Use in women or children.1

Known hypersensitivity to dutasteride, other 5?-reductase inhibitors, or any ingredient in the formulation.1

Warnings/Precautions Warnings Fetal/Neonatal Morbidity

May cause fetal harm; teratogenicity demonstrated in animals.1 Animal studies indicate adverse effects on embryofetal development of male fetuses exposed to the drug during pregnancy (e.g., abnormalities of the external genitalia, decreased prostatic and seminal vesicular weights, distended preputial glands, nipple development).1

Because of the potential for absorption through the skin and the subsequent potential risk to a male fetus, pregnant women or women who may become pregnant should not handle the capsules.1 2

If contact is made with leaking capsules, wash the affected area immediately with soap and water.1 2

To prevent potential fetal exposure, men receiving the drug should not donate blood during dutasteride therapy and for at least 6 months following discontinuance of the drug.1

Seminal drug concentrations not sufficient to warrant the use of condoms to prevent exposure to dutasteride.10

General Precautions Patient Assessment

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Evaluate candidates for dutasteride therapy for other urologic conditions that might mimic BPH, such as infection,4 prostate 1 4 or bladder cancer,4 stricture disease,4 uncontrolled diabetes mellitus,4 neurogenic bladder,4 or CHF.4 7

Perform digital rectal examinations, as well as other screening tests for prostate cancer, before initiating therapy and periodically thereafter.1 7 8

Monitor patients with a large residual urinary volume and/or severely diminished urinary flow carefully for obstructive uropathy.4 7 Such patients may not be candidates for dutasteride therapy,1 and may require surgery.4 7

Prostate-specific Antigen (PSA)

Decreases PSA concentrations; may interfere with interpretation of serum PSA determinations.1 (See Specific Drugs and Laboratory Tests under Interactions.)

Specific Populations Pregnancy

Category X.1 (See Fetal/Neonatal Morbidity and also Contraindications under Cautions.)

Lactation

Not known whether dutasteride is distributed into milk, but use of the drug is contraindicated in women.1 10

Pediatric Use

Safety and efficacy not established, but the drug is not indicated for use in children.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger men.1

Hepatic Impairment

Not studied in patients with hepatic impairment.1 Increased exposure to the drug is probable.1 Use with caution.1

Common Adverse Effects

Impotence, decreased libido, ejaculation disorder, gynecomastia (breast tenderness, enlargement).1

Interactions for Avodart

Metabolized by CYP isoenzymes 3A4 and 3A5 to active metabolites; not metabolized by CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1.1

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction with inhibitors of CYP3A4 (decreased clearance and increased serum concentrations of dutasteride).1

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Amlodipine

Pharmacokinetic interaction unlikely1

Cholestyramine

Pharmacokinetic or pharmacodynamic interaction unlikely1

Cimetidine

Decreased clearance and increased serum concentrations of dutasteride1

Use concomitantly with care

Ciprofloxacin

Decreased clearance and increased serum concentrations of dutasteride1

Use concomitantly with care1

Digoxin

Pharmacokinetic or pharmacodynamic interaction unlikely1

Diltiazem

Decreased clearance and increased serum concentrations of dutasteride1

Not considered clinically important1

Ketoconazole

Decreased clearance and increased serum concentrations of dutasteride1

Use concomitantly with care1

Ritonavir

Decreased clearance and increased serum concentrations of dutasteride1

Tamsulosin

Pharmacokinetic or pharmacodynamic interaction unlikely1

Terazosin

Pharmacokinetic or pharmacodynamic interaction unlikely1

Test for PSA

50% decrease in serum PSA concentration after ?6 months of treatment1 3 6 9 10

No substantial change in ratio of free to total PSA (percentage of free PSA)1

Establish a new baseline PSA 3–6 months after initiation of treatment1

For clinical interpretation of isolated PSA values in men receiving dutasteride for ?6 months, double the reported value for PSA for comparison with normal values in men not receiving the drug1 3

No adjustment of reported value of ratio appears to be necessary1

Troleandomycin

Decreased clearance and increased serum concentrations of dutasteride1

Verapamil

Decreased clearance and increased serum concentrations of dutasteride1

Not considered clinically important1

Warfarin

Pharmacokinetic or pharmacodynamic interaction unlikely1

Avodart Pharmacokinetics Absorption Bioavailability

Absolute bioavailability is approximately 60%.1

Onset

Reduces serum and prostatic 5?-dihydroxytestosterone (DHT) concentrations maximally within 1–2 weeks of initiation of therapy.1

Duration

Serum drug concentrations are detectable for up to 4–6 months following discontinuance of therapy.1

Food

Decreases peak serum concentrations.1 Not considered clinically important.1

Distribution Extent

Widely distributed; volume of distribution is 300–500 L.1

Distributes into semen.1

Plasma Protein Binding

Highly bound to albumin (99%) and ?-1 acid glycoprotein (96.6%).1

Elimination Metabolism

Metabolized by CYP3A4 and CYP3A5 to active metabolites.1

Elimination Route

Excreted in the feces (45%) and urine (<1%) mainly as metabolites; approximately 55% remained unaccounted.1

Half-life

Terminal half-life is approximately 5 weeks at steady state.1

Special Populations

In patients with hepatic impairment, pharmacokinetics not studied.1 Metabolized extensively in the liver, and increased exposure to the drug is probable in hepatic impairment.1

In adolescents (<18 years of age), pharmacokinetics not studied.1

In patients with renal impairment, pharmacokinetics not studied; however, <0.1% of a dose is excreted in urine in healthy individuals.1

In women, pharmacokinetics not studied; use contraindicated.1

Effects of race on pharmacokinetics not studied.1

Stability Storage Oral Capsules

25°C (may be exposed to 15–30°C).1

ActionsActions

Competitive inhibitor of both the type 1 and type 2 isoenzymes of steroid 5?-reductase.1 9 These enzymes convert testosterone to DHT.1 9

Reduces serum and prostatic DHT concentrations substantially.1 DHT appears to be the principal androgen responsible for initial development and subsequent enlargement of the prostate gland.1 9

Increases serum testosterone (generally remaining within the normal range) and prostatic testosterone concentrations.1 3 9

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Importance of obtaining and reading patient information on dutasteride before initiation of therapy and with each new prescription refill.1

Importance of advising pregnant women or women who may become pregnant to avoid handling the drug.1 (See Pregnancy under Cautions.)

Advise patients that a decrease in the volume of ejaculate may occur but that this does not appear to interfere with normal sexual function.1

Advise patients of the small possibility of impotence and decreased libido.1 10

Advise patients of possibility of developing enlarged or tender breasts.1

Advise patients of possibility of allergic reactions (e.g., rash, pruritus, urticaria, swelling of lips or face).1

Advise patients that ?6 months of therapy may be required before improvement in BPH symptoms occurs.2

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Dutasteride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, liquid-filled

0.5 mg

Avodart

GlaxoSmithKline

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 07/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Avodart 0.5MG Capsules (GLAXO SMITH KLINE): 30/$129.98 or 90/$354.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions June 09, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. GlaxoSmithKline. Avodart (dutasteride) soft gelatin capsules prescribing information. Research Triangle Park, NC; 2005 May.

2. GlaxoSmithKline. Avodart (dutasteride) soft gelatin capsules patient information. Research Triangle Park, NC; Undated. Available at: . Accessed 2006 Aug 15.

3. Roehrborn CG, Boyle P, Nickel JC et al. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology. 2002 60:434-41.

4. Dull P, Reagan RW, Bahnson RR. Managing benign prostatic hyperplasia. Am Fam Physician. 2002; 66:77-84, 87-8. [IDIS 483339] [PubMed 12126034]

5. Roehrborn CG, McConnell JD, Lieber M et al. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retenion and need for surgery in men with clinical benign prostatic hyperplasia. PLESS study group. Urology. 1999; 53:473-80. [PubMed 10096369]

6. Potts JM. Prospective identification of National Institutes of Health category IV prostatitis in men with elevated prostate specific antigen. J Urol. 2000; 164:1550-3. [IDIS 455479] [PubMed 11025702]

7. de la Rossette JJ, Alivizatos G, Madersbacher S et al. EAU guidelines on benign prostatic hyperplasia (BPH). Eur Urol. 2001; 40:256-63. [PubMed 11684840]

8. Agency for Health Care Policy and Research. Benign prostatic hyperplasia: diagnosis and treatment. J Am Geriatric Soc. 1998; 46:1163-5.

9. Anon. Dutasteride (avodart) for benign prostatic hyperplasia. Med Lett Drugs Ther. 2002; 44:109-10. [PubMed 12500154]

10. GlaxoSmithKline. Research Triangle Park, NC: Personal communication.

11. American Urological Association. Guideline on the management of benign prostatic hyperplasia (BPH)(2003/updated 2006). Available at: . Accessed 2006 Aug 10.

More Avodart resources Avodart Side Effects (in more detail) Avodart Use in Pregnancy & Breastfeeding Drug Images Avodart Drug Interactions Avodart Support Group 14 Reviews for Avodart - Add your own review/rating Avodart Prescribing Information (FDA) Avodart Consumer Overview Avodart Advanced Consumer (Micromedex) - Includes Dosage Information Avodart MedFacts Consumer Leaflet (Wolters Kluwer) Dutasteride Professional Patient Advice (Wolters Kluwer) Compare Avodart with other medications Benign Prostatic Hyperplasia
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aliskiren and amlodipine


Generic Name: aliskiren and amlodipine (AL is KYE ren and am LOE de peen)
Brand Names: Tekamlo

What is this drug?

Aliskiren is an anti-hypertensive (blood pressure lowering) medication. It works by decreasing substances in the body that narrow blood vessels and raise blood pressure.

Amlodipine is in a group of drugs called calcium channel blockers. Amlodipine relaxes (widens) blood vessels and improves blood flow.

The combination of aliskiren and amlodipine is used to treat high blood pressure (hypertension).

Aliskiren and amlodipine may also be used for purposes not listed in this medication guide.

What is the most important information I should know about this drug? Do not use aliskiren and amlodipine if you are pregnant. It could harm the unborn baby. Stop using this medication and tell your doctor right away if you become pregnant. You should not take this medication if you are allergic to aliskiren or amlodipine, or if you are also using cyclosporine (Gengraf, Neoral, Sandimmune) or itraconazole (Sporanox).

Before you take aliskiren and amlodipine, tell your doctor if you have kidney or liver disease, congestive heart failure, coronary artery disease, an electrolyte imbalance (such as low potassium or magnesium), if you are on a low-salt diet, or if you have ever had an allergic reaction to a blood pressure medication.

Keep using this medicine as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life. What should I discuss with my health care provider before taking this drug? You should not take this medication if you are allergic to aliskiren or amlodipine, or if you are also using cyclosporine (Gengraf, Neoral, Sandimmune) or itraconazole (Sporanox).

To make sure you can safely take aliskiren and amlodipine, tell your doctor if you have any of these other conditions:

kidney disease (or if you are on dialysis);

liver disease;

congestive heart failure;

coronary artery disease (hardened arteries);

an electrolyte imbalance (such as low levels of potassium or magnesium in your blood);

if you are on a low-salt diet; or

if you have ever had an allergic reaction to a blood pressure medication, such as benazepril (Lotensin), candesartan (Atacand), enalapril (Vasotec), lisinopril (Prinivil, Zestril), losartan (Cozaar, Hyzaar), olmesartan (Benicar, Azor), quinapril (Accupril), ramipril (Altace), telmisartan (Micardis, Twynsta), valsartan (Diovan, Exforge), and others.

FDA pregnancy category D. Do not use aliskiren and amlodipine if you are pregnant. Stop using this medication and tell your doctor right away if you become pregnant. Aliskiren and amlodipine can cause injury or death to the unborn baby if you take the medicine during your second or third trimester. Use effective birth control while taking aliskiren and amlodipine. It is not known whether this medication passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are taking aliskiren and amlodipine. How should I take this drug?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Your chest pain may become worse when you first start taking amlodipine or when your dose is increased. Call your doctor if your chest pain is severe or ongoing.

Aliskiren and amlodipine may be taken with or without food, but take it the same way each time.

Your blood pressure will need to be checked often. Visit your doctor regularly.

Conditions that may cause very low blood pressure include: vomiting, diarrhea, heavy sweating, heart disease, dialysis, a low-salt diet, or taking diuretics (water pills). Tell your doctor if you have a prolonged illness that causes diarrhea or vomiting.

Keep using this medicine as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life. Store at room temperature away from moisture and heat.

See also: Aliskiren and amlodipine dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include rapid heartbeats, severe dizziness, warmth or tingly feeling, and fainting.

What should I avoid while taking this drug?

Avoid taking this medication with foods that are high in fat, which can make it harder for your body to absorb aliskiren.

This drug side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

swelling in your hands, ankles, or feet;

feeling like you might pass out; or

chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling.

Less serious side effects may include:

diarrhea;

stomach pain, upset stomach; or

cough.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Aliskiren and amlodipine Dosing Information

Usual Adult Dose for Hypertension:

Initial or add-on therapy: 150 mg/5 mg orally once a day. Titrate as needed up to a maximum of 300 mg/10 mg.
The blood pressure lowering effect is largely attained within 1 to 2 weeks.
Maximum dose: 300 mg/10 mg

What other drugs will affect this drug?

Tell your doctor about all other heart or blood pressure medications you are taking.

Tell your doctor about all other medicines you use, especially:

atorvastatin (Lipitor, Caduet), simvastatin (Zocor, Simcor, Vytorin, Juvisync);

antifungal medication such as fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), or voriconazole (Vfend);

a potassium supplement such as K-Dur, Klor-Con;

salt substitutes that contain potassium; or

a diuretic (water pill).

This list is not complete and other drugs may interact with aliskiren and amlodipine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More aliskiren and amlodipine resources Aliskiren and amlodipine Side Effects (in more detail) Aliskiren and amlodipine Dosage Aliskiren and amlodipine Use in Pregnancy & Breastfeeding Aliskiren and amlodipine Drug Interactions Aliskiren and amlodipine Support Group 0 Reviews for Aliskiren and amlodipine - Add your own review/rating Compare aliskiren and amlodipine with other medications High Blood Pressure Where can I get more information? Your pharmacist can provide more information about aliskiren and amlodipine.

See also: aliskiren and amlodipine side effects (in more detail)


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Lozol


Generic Name: indapamide (in DAP a mide)
Brand Names: Lozol

What is Lozol (indapamide)?

Indapamide is a thiazide diuretic (water pill) that helps prevent your body from absorbing too much salt, which can cause fluid retention.

Indapamide treats fluid retention (edema) in people with congestive heart failure. This medication is also used to treat high blood pressure (hypertension).

Indapamide may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about Lozol (indapamide)? Do not use this medication if you have severe kidney disease or are unable to urinate, if you have severe liver disease, or if you have low potassium levels in your blood (hypokalemia).

Before using this medication, tell your doctor if you have liver disease, kidney disease, gout, lupus, diabetes, or an allergy to sulfa drugs.

Avoid becoming overheated or dehydrated during exercise and in hot weather. Follow your doctor's instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

If you are being treated for high blood pressure, keep using this medication even if you feel fine. High blood pressure often has no symptoms.

What should I discuss with my doctor before taking Lozol (indapamide)? Do not use this medication if you have: severe kidney disease or are unable to urinate; severe liver disease; or

low potassium levels in your blood (hypokalemia).

If you have any of these other conditions, you may need a dose adjustment or special tests to safely take indapamide:

kidney disease; liver disease;

gout;

lupus;

diabetes; or

an allergy to sulfa drugs.

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether indapamide passes into breast milk or if it could cause harm to a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. How should I take Lozol (indapamide)?

Take this medication exactly as it was prescribed for you. Do not take the medication in larger amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label.

To be sure this medication is not causing harmful effects, your blood will need to be tested on a regular basis. Do not miss any scheduled appointments.

Your blood and urine may both be tested if you have been vomiting or are dehydrated.

If you are being treated for high blood pressure, keep using this medication even if you feel fine. High blood pressure often has no symptoms.

Store the tablets at room temperature away from heat, light, and moisture.

See also: Lozol dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose? Seek emergency medical attention if you think you have used too much of this medicine.

Overdose symptoms of a indapamide overdose may include nausea, weakness, dizziness, dry mouth, thirst, and muscle pain or weakness.

What should I avoid while taking Lozol (indapamide)?

Avoid becoming overheated or dehydrated during exercise and in hot weather. Follow your doctor's instructions about the type and amount of liquids you should drink. In some cases, drinking too much liquid can be as unsafe as not drinking enough.

Lozol (indapamide) side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have a serious side effect such as:

dry mouth, thirst, nausea, vomiting;

feeling weak, drowsy, restless, or light-headed;

fast or uneven heartbeat; or

muscle pain or weakness.

Less serious side effects may include:

dizziness;

headache; or

mild skin rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Lozol (indapamide)?

Before taking this medication, tell your doctor if you are using any of the following drugs:

lithium;

baclofen (Lioresal);

other blood pressure medications;

steroids (prednisone and others);

insulin or diabetes medicine taken by mouth;

salicylates such as aspirin, Disalcid, Doan's Pills, Dolobid, Salflex, Tricosal, and others;

an ACE inhibitor such as benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril), ramipril (Altace), and others;

NSAIDs (non-steroidal anti-inflammatory drugs) such as aspirin, ibuprofen (Motrin, Advil), diclofenac (Voltaren), indomethacin, naproxen (Aleve, Naprosyn), piroxicam (Feldene), and others; or

amiodarone (Cordarone, Pacerone), chloroquine (Arelan), cisapride (Propulsid), clarithromycin (Biaxin), disopyramide (Norpace), dofetilide (Tikosyn), droperidol (Inapsine), erythromycin (Erythrocin, E.E.S), haloperidol (Haldol), pentamidine (NebuPent, Pentam), pimozide (Orap), procainamide (Procan), quinidine (Cardioquin, Quinaglute), sotalol (Betapace), or thioridazine (Mellaril).

This list is not complete and there may be other drugs that can interact with indapamide. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

More Lozol resources Lozol Side Effects (in more detail) Lozol Dosage Lozol Use in Pregnancy & Breastfeeding Drug Images Lozol Drug Interactions Lozol Support Group 0 Reviews for Lozol - Add your own review/rating Lozol Prescribing Information (FDA) Lozol MedFacts Consumer Leaflet (Wolters Kluwer) Lozol Monograph (AHFS DI) Lozol Advanced Consumer (Micromedex) - Includes Dosage Information Indapamide Prescribing Information (FDA) Indapamide Professional Patient Advice (Wolters Kluwer) Compare Lozol with other medications Edema High Blood Pressure Where can I get more information? Your pharmacist can provide more information about indapamide.

See also: Lozol side effects (in more detail)


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