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Stilnoct 10mg


Stilnoct 10 mg Tablets

zolpidem tartrate

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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. In this leaflet: 1. What Stilnoct is and what it is used for 2. Before you take Stilnoct 3. How to take Stilnoct 4. Possible side effects 5. How to store Stilnoct 6. Further information What Stilnoct is and what it is used for

The name of your medicine is Stilnoct 10mg Tablets (called Stilnoct in this leaflet). Stilnoct contains a medicine called zolpidem tartrate. This belongs to a group of medicines called hypnotics. It works by acting on your brain to help you sleep.

Stilnoct is used for temporary sleep problems that are causing you severe distress or that are affecting your every day life. This includes sleep problems such as:

Difficulty falling asleep Waking in the middle of the night Waking too early

Stilnoct is not meant to be used every day for long periods of time. Ask your doctor for advice if you are unsure.

Before you take Stilnoct Do not take this medicine and tell your doctor if: You are allergic (hypersensitive) to zolpidem tartrate or any of the other ingredients of Stilnoct (listed in Section 6 below)
Signs of an allergic reaction include: a rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue Your lungs do not work properly (respiratory failure) You have severe liver problems You have a problem where you stop breathing for short periods at night (sleep apnoea) You have a problem that causes severe muscle weakness (myasthenia gravis) You have been told by a doctor that you have a mental illness (psychosis) You are under the age of 18

Do not take this medicine if any of the above applies to you. If you are not sure, talk to your doctor or pharmacist before taking Stilnoct.

Take special care with Stilnoct

Check with your doctor or pharmacist before taking your medicine if:

You have a history of alcohol or drug abuse You have liver problems You have depression or have had another mental illnesses in the past You have recently taken Stilnoct or other similar medicines for more than four weeks You are elderly

If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before taking Stilnoct.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines.

This includes medicines you buy without a prescription, including herbal medicines. This is because Stilnoct can affect the way some other medicines work. Also some medicines can affect the way Stilnoct works.

Tell your doctor if you are taking any of the following medicines:

Stilnoct may increase the effect of the following medicines:

Medicines for some mental health problems (antipsychotics) Medicines for depression such as sertraline Medicines for epilepsy (anticonvulsants) Medicines used in surgery (anaesthetics) Medicines to calm or reduce anxiety or for sleep problems Medicines for hay fever, rashes or other allergies that can make you sleepy (sedative antihistamines) such as chlorphenamine or promethazine Some medicines for moderate to severe pain (narcotic analgesics) such as codeine, methadone, morphine, oxycodone, pethidine or tramadol

The following medicines can increase the chance of you getting side effects when taken with Stilnoct. To make this less likely, your doctor may decide to lower your dose of Stilnoct:

Some antibiotics such as clarithromycin or erythromycin Some medicines for fungal infections such as ketaconazole and itraconazole Ritonavir (a protease inhibitor) - for HIV infections

The following medicines can make Stilnoct work less well:

Some medicines for epilepsy such as carbamazepine, phenobarbital or phenytoin Rifampicin (an antibiotic) - for infections St John’s Wort (a herbal medicine) - for mood swings and depression Taking Stilnoct with food and drink Do not drink alcohol while you are taking Stilnoct.
Alcohol can increase the effects of Stilnoct and make you sleep very deeply so that you do not breathe properly or have difficulty waking Pregnancy and breast-feeding

Talk to your doctor before taking this medicine if you are pregnant, might become pregnant, or think you may be pregnant. Taking Stilnoct during pregnancy may harm your baby.

You should not breast-feed if you are taking Stilnoct. This is because small amounts may pass into mother’s milk.

Ask your doctor or pharmacist for advice before taking any medicine if you are pregnant or breast-feeding.

Driving and using machines

On the day after taking Stilnoct, do not drive or use machinery or tools if you feel sleepy, dizzy or confused. For more information about possible side effects which could affect your driving see section 4 of this leaflet.

Important information about some of the ingredients of Stilnoct

Stilnoct contains:

Lactose. This is a type of sugar. If you have been told by your doctor that you cannot tolerate some sugars (have an intolerance to some sugars), talk to your doctor before taking this medicine How to take Stilnoct

Always take Stilnoct 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 Swallow the tablet whole with a drink of water Take just before bedtime. Make sure you have at least 7-8 hours for sleep after taking this medicine The usual length of treatment is 2 days to 4 weeks Adults

The usual dose is one Stilnoct tablet (10 mg) just before bedtime.

Elderly

The usual dose is half a tablet (5mg) just before bedtime.

Patients with liver problems

The usual starting dose is half a tablet (5mg) just before bedtime. Your doctor may decide to increase this to one tablet (10mg) if it is safe to do so.

Children and Adolescents

Stilnoct should not be used in people under 18 years old.

If you take more Stilnoct than you should

If you take more Stilnoct than you should, tell a doctor or go to a hospital casualty department straight away. Take the medicine pack with you. This is so the doctor knows what you have taken.

Taking too much Stilnoct can be very dangerous.

The following effects may happen:

Feeling drowsy, confused, sleeping deeply and possibly falling into a fatal coma. If you forget to take Stilnoct

Stilnoct must only be taken at bedtime. If you forget to take your tablet at bedtime, then you should not take it at any other time, otherwise you may feel drowsy, dizzy and confused during the day.

Do not take a double dose to make up for a forgotten tablet.

If you stop taking Stilnoct

Keep taking Stilnoct until your doctor tells you to stop.

Do not stop taking Stilnoct suddenly, but tell your doctor if you want to stop. Your doctor will need to lower your dose and stop your tablets over a period of time.

If you stop taking Stilnoct suddenly, your sleep problems may come back and you may get a ‘withdrawal effect’. If this happens you may get some of the effects listed below.

See a doctor straight away if you get any of the following effects:

Feeling anxious, restless, irritable or confused Headache Faster heartbeat or uneven heartbeat (palpitations) Nightmares, seeing or hearing things that are not real (hallucinations) Being more sensitive to light, noise and touch than normal Relaxed grip on reality Feeling distant from your body or feeling ‘puppet-like’ Numbness and tingling in your hands and feet Aching muscles Stomach problems Sleep problems come back worse than before

In rare cases fits (seizures) may also occur.

Stilnoct 10mg Side Effects

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

Stop taking Stilnoct and see a doctor or go to a hospital straight away if: You have an allergic reaction. The signs may include: a rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue Tell your doctor as soon as possible if you have any of the following side effects:

Common (affects less than 1 in 10 people)

Poor memory while taking Stilnoct (amnesia) and strange behaviour during this time. This is more likely to affect you in the few hours after you take this medicine. By having 7-8 hours sleep after taking Stilnoct, this is less likely to cause you a problem. Sleeping problems that get worse after taking this medicine Seeing or hearing things that are not real (hallucinations)

Uncommon (affects less than 1 in 100 people)

Blurred eyesight or ‘seeing double’

Frequency unknown

Being less aware of your environment Falling, especially in the elderly

Sleep-Driving and other strange behaviour

There have been some reports of people doing things while asleep that they do not remember when waking up after taking a sleep medicine.

This includes sleep-driving, sleep walking and having sex. Alcohol and some medicines for depression or anxiety can increase the chance that this serious effect will happen.

Tell your doctor or pharmacist if any of the following side effects get serious or lasts longer than a few days:

Common (affects less than 1 in 10 people)

Diarrhoea Headache Feeling tired or agitated Nightmares

Uncommon (affects less than 1 in 100 people)

Feeling confused or irratable

Frequency unknown

Itching skin or skin rash Weak muscles Feeling restless, aggressive, angry or showing unusual behaviour Thinking things that are not true (delusions) Changes in sex drive (libido) Change in the amount of liver enzymes – shown up in the results of blood tests Changes in the way you walk Stilnoct having less effect than normal

Talk to your doctor or pharmacist if any of the side effects gets serious or lasts longer than a few days, or if you notice any side effects not listed in this leaflet

How to store Stilnoct

Keep this medicine in a safe place where children cannot see or reach it.

Do not use Stilnoct after the expiry date which is stated on the carton or blister after EXP. 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 Stilnoct contains Each tablet of Stilnoct contains 10 mg of the active substance zolpidem tartrate Other ingredients are lactose monohydrate, microcrystalline cellulose, hypromellose, titanium dioxide (E171), sodium starch glycollate, magnesium stearate and macrogol 400. What Stilnoct looks like and contents of the pack

Stilnoct is a white to off-white film-coated oblong (rectangle) shaped tablet with a scored and engraved ‘SN 10’ on one side contained within clear PVC/ foil blisters in cartons containing 4 or 28 tablets.

Not all pack sizes may be marketed

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Sanofi-aventis One Onslow Street Guildford Surrey GU1 4YS Tel:01483 505515 Fax:01483 535432 email:uk-medicalinformation@sanofi-aventis.com

Manufacturer

Sanofi Winthrop Industrie 6, Blvd. De L’Europe 21 800 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 08/2008

© sanofi-aventis, 1993 - 2008

209512


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Isosorbide


In the US, Isosorbide (isosorbide mononitrate systemic) is a member of the drug class miscellaneous uncategorized agents.

US matches:

Isosorbide Isosorbide Dinitrate Isosorbide Dinitrate Extended-Release Isosorbide Dinitrate/Hydralazine Isosorbide Mononitrate Isosorbide Mononitrate Sustained-Release Tablets Isosorbide dinitrate Oral, Sublingual Isosorbide Mononitrate Extended Release Isosorbide Dinitrate/Hydralazine Hydrochloride

UK matches:

Isosorbide Dinitrate Tablets 10mg, 20mgIsosorbide Mononitrate Tablets 10mg, 20mg, 40mg (Actavis UK Ltd)Isosorbide Dinitrate Injection Concentrate BP 1mg/ml (SPC)Isosorbide Dinitrate Tablets BP 10mg (SPC)Isosorbide Dinitrate Tablets BP 20mg (SPC)Isosorbide mononitrate 20mg tablets (SPC)Isosorbide Mononitrate 40mg (SPC)Isosorbide Mononitrate Tablets 40mg (SPC)Ingredient matches for Isosorbide Isosorbide

Isosorbide (BAN, JAN, USAN) is known as Isosorbide in the US.

Isosorbide Mononitrate

Isosorbide Mononitrate is reported as an ingredient of Isosorbide in the following countries:

Bosnia & Herzegowina Cyprus

International Drug Name Search

Glossary

BANBritish Approved NameJANJapanese Accepted NameSPC Summary of Product Characteristics (UK)USANUnited States Adopted Name
Click for further information on drug naming conventions and International Nonproprietary Names.
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Furosemide Tablets 20mg (Actavis UK Ltd)


Furosemide 20mg 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. Index 1 What Furosemide tablets are and what they are used for 2 Before you take 3 How to take 4 Possible side effects 5 How to store 6 Further information What Furosemide tablets are and what they are used for

Furosemide tablets is one of a group of medicines called diuretics (water tablets).

Your doctor has prescribed Furosemide tablets to treat a condition called oedema where there is too much water in your body. This could be due to problems with your heart, kidneys, liver, blood vessels or high blood pressure. Furosemide helps your kidneys to get rid of the extra water that is not needed in your body.

Before you take Do not take Furosemide tablets if you: are allergic (hypersensitive) to furosemide, other sulphonamide related drugs or any of the other ingredients in Furosemide tablets (see section 6) have low blood pressure have severe kidney failure have liver cirrhosis (tiredness, weakness, water retention, feeling or being sick, loss of weight or appetite, yellowing skin or eyes, itch ) have any disorder of body chemicals (this may make you feel weak, apathetic or have muscle spasms) are not producing any urine have digitalis poisoning (feeling or being sick, high levels of potassium in the blood, slow, fast or irregular heart beats). Check with your doctor or pharmacist before taking Furosemide tablets if you have: or have had gout (severe joint pain) prostate trouble or difficulty passing urine low blood volume (hypovolaemia) or may have diabetes. If you are taking insulin, your doctor may need to adjust your insulin dosage.

Your doctor will want to monitor you, and may take blood for testing while you are taking this medicine.

Taking 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. Especially:

drugs to lower blood pressure, such as ACE inhibitors non-steroidal anti-inflammatory drugs (NSAIDs) e.g. ibuprofen or naproxen digoxin for your heart curariform muscle relaxants (eg vercuronium) corticosteroids used to treat allergic reactions laxatives used over a long period of time certain treatments for asthma such as theophylline antibiotics for infections that affect your kidneys or ears (eg cefaclor, colistin, gentamicin, vancomycin) lithium for depression or mania aspirin for pain medicines to control diabetes such as insulin or tablets Pregnancy and breast-feeding

Speak to your doctor before you take Furosemide tablets if you are pregnant, thinking of getting pregnant, or breast-feeding.

Driving and using machines

Do not drive or operate machinery if you feel less alert after taking Furosemide tablets.

Important information about some of the ingredients in Furosemide tablets

Your medicine contains lactose; do not take Furosemide tablets if you have been told by your doctor that you have an intolerance to a sugar called lactose.

How to take

Always take Furosemide tablets exactly as your doctor has told you. If you are not sure, check with your doctor or pharmacist.

Swallow the tablets with a glass of water.

Doses: Adults and children over 12 years:
Water retention: the usual starting dose is 40mg in the morning, then 20mg a day or 40mg on alternate days. Up to 80mg a day may be given.
High blood pressure: 20-40mg twice a day. Elderly: may be reduced in this age group. Children under 12 years: 1-3mg per kg of bodyweight. If you take more than you should

If you take more medicine than your doctor has told you to, contact a doctor or your nearest hospital casualty department immediately and take your Furosemide tablets with you. Symptoms of an overdose include dehydration, changes in the levels of certain chemicals in the blood and low blood pressure.

If you forget to take the tablets

If you forget to take a dose, take another as soon as you remember. Then take your next dose at the normal time. Do not take double the amount to make up for a forgotten dose.

If you stop taking Furosemide tablets

Speak to your doctor before you stop taking Furosemide tablets.

Possible side effects

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

If you have any of the following side effects while taking your medicine tell your doctor immediately or go to hospital straight away: severe allergic reaction which may include a skin rash, itching, dermatitis, peeling skin, sensitivity to sunlight or sun lamps or fever inflammation of blood vessels (vasculitis, which may cause rash, fever and joint or muscle pains) or kidney inflammation, this may change the number of times you pass urine or you may see blood in your urine. You may have a fever, feel drowsy, or notice swelling e.g. of the ankles Tell your doctor or pharmacist if you notice any of the following side effects: Altered balance of fluid or chemicals in the body (e.g. sodium, potassium, chlorine and magnesium) causing a dry mouth, weakness, tiredness or drowsiness, restlessness, fits, muscle pain fatigue or cramps, low blood pressure, difficulty passing water, fast heart rate and feeling and being sick Blood: furosemide can occasionally cause changes in your blood; your doctor will perform regular blood tests to ensure no changes have occurred. The symptoms of these changes include anaemia, leading to tiredness and lethargy; unusual bleeding or bruising, blood slow to clot; ulcers in your throat, mouth or on your skin Metabolism: changes in levels of body chemicals (glucose, fats or calcium) Stomach and intestines: stomach irritation or feeling sick Pancreas: inflammation of the pancreas (pancreatitis) which may cause severe pains in your abdomen or back, nausea, vomiting and fever Muscles and joints: muscle tension Urinary and genital: kidney stones in premature babies Senses: hearing problems or ringing in your ears (tinnitus) Other: generally feeling unwell

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.

How to store

Keep out of the reach and sight of children.

Store below 25°C in a dry place. Protect from light

Do not use Furosemide after the expiry date stated on the label/carton/bottle. 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 Furosemide tablets contain Each tablet contains 20mg of the active substance furosemide (the ingredient that makes the tablets work). The other ingredients are lactose, magnesium stearate, maize starch, stearic acid. What Furosemide tablets look like and contents of the pack

Furosemide tablets are white, uncoated tablets. Pack size is 28.

Marketing Authorisation Holder and Manufacturer Actavis Barnstaple EX32 8NS UK

This leaflet was last revised in September 2008

Actavis Barnstaple EX32 8NS UK

50130006


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Fosinopril Tablets 10mg, 20mg (Actavis UK Ltd)


Fosinopril sodium 10mg and 20mg 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, please 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 on this leaflet, please tell your doctor or pharmacist. In this leaflet 1 What Fosinopril sodium is and what it is used for 2 Before you take Fosinopril sodium tablets 3 How to take Fosinopril sodium tablets 4 Possible side effects 5 How to store Fosinopril sodium tablets 6 Further Information What Fosinopril sodium is and what it is used for

Each tablet contains fosinopril sodium which is used to treat high blood pressure (hypertension) and heart failure.

Fosinopril sodium tablets belong to a group of medicines called ACE inhibitors and make it easier for the heart to pump blood around the body.

Before you take Fosinopril sodium tablets Do not take Fosinopril sodium tablets and tell your doctor if you: are allergic (hypersensitive) to fosinopril sodium, other ACE inhibitors or any of the other ingredients in the tablet. (See Section 6 for further information on the ingredients) or a member of your family have previously had swelling of the legs, arms, face, mucous membranes or tongue and/or throat (angioedema), with or without ACE inhibitor treatment have narrowing of the blood vessels in one or both kidneys are in shock due to heart problems (cardiogenic shock) are pregnant or breastfeeding. Take special care with Fosinopril sodium tablets and tell your doctor if you: have kidney problems are having dialysis are going to undergo treatment for hypersensitivity to bee or wasp stings (hyposensitisation) have problems with your immune system due to some diseases (e.g. scleroderma, lupus erythematosus), white blood cell counts will need to be monitored have high levels of sugar in your blood (diabetes) have narrowing of some blood vessels in the heart or cardiomyopathy (enlarged heart muscle) have become dehydrated from having recently suffered from vomiting or diarrhoea are on a low salt diet are Afro-Caribbean. If you are taking Fosinopril sodium tablets as the only treatment for your high blood pressure, you may have a reduced response to this medicine. This may mean that you may need a higher dose than usually recommended.

Tell your doctor or dentist before undergoing any surgery or dental treatment that you are being treated with Fosinopril, as there is a risk of your blood pressure sinking very low during the anaesthetic.

Taking other medicines

If Fosinopril is taken with certain other medicines your treatment can be affected. Tell your doctor before using other medicines at the same time as Fosinopril. Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

It is especially important for your doctor to know if you are already being treated with any of the following medicines:

other blood pressure lowering medicines including methyldopa, betablockers (e.g. atenolol), calcium antagonists (e.g. verapamil) or diuretics (water tablets) (e.g. furosemide) as it may lead to an increase in the blood pressure lowering effects potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes, as Fosinopril may increase potassium levels. Patient will need their blood potassium levels measured by their doctors painkillers and anti-inflammatory medicines of the NSAID type (e.g. aspirin or indometacin) as they can reduce the effect of Fosinopril antacids (to relieve indigestion) stop the body absorbing Fosinopril. There should be at least 2 hours between taking the antacid and Fosinopril insulin and tablets used in diabetes, as Fosinopril may increase the effect of these especially during the first week of combination treatment lithium (used for manic depression), as Fosinopril may increase the concentration of lithium in the blood immunosuppressants (these reduce the body’s natural defence system) such as azathioprine as using them together may affect some blood counts. Pregnancy and breast feeding

Do not take Fosinopril sodium tablets during pregnancy or if you might become pregnant. There is a risk of injury to the baby. Do not take Fosinopril if you are breast feeding, as Fosinopril passes into breast milk.

Driving and using machines

If you experience dizziness, low blood pressure, light-headedness or vertigo (’spinning sensation), do not drive or use machinery during treatment with Fosinopril.

Important information about some of the ingredients of Fosinopril

Fosinopril contains lactose (see section 6 for further information). If your doctor has told you that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Blood tests

Fosinopril may interfere with the results of some blood tests. Tell your doctor that you are taking Fosinopril sodium tablets.

How to take Fosinopril sodium tablets

Swallow the tablets whole with at least half a glass of water in the morning with or without food. Do not chew or crush the tablets.

Always take Fosinopril exactly as your doctor has told you. If you are not sure check with your doctor or pharmacist.

Adults: The usual dose is 10mg once daily, up to a maximum of 40mg once daily. Fosinopril sodium tablets may be taken alone or in combination with a diuretic (water tablet) or digitalis (digoxin). If you are already taking diuretics, your doctor may tell you to reduce the dose of the diuretic or to stop taking them for several days before beginning treatment with Fosinopril.

Occasionally some people start their treatment in hospital.

Children under 18 years old: Not recommended.

If you take more Fosinopril sodium than you should:

Immediately contact your doctor, the nearest hospital casualty department or the centre for poison information for advice.

If you forget to take Fosinopril sodium

Do not take the missed dose, just carry on with the next one as normal. Do not take a double dose to make up for a forgotten dose.

If you stop taking Fosinopril sodium

Do not stop taking Fosinopril unless your doctor advises you to do so. If you stop taking Fosinopril, your blood pressure may increase.

Possible side effects

Like all medicines, Fosinopril can cause side effects, although not everybody gets them. The following side effects may occur.

Stop taking Fosinopril sodium tablets and contact your doctor immediately if you experience swelling of the face, lips, tongue and/or throat, rash, itching, breathlessness or difficulty swallowing (angioedema).

Tell your doctor if you notice any of the following side effects or they get worse:

Common (occurring in less than 1 in 10 patients): dizziness, raise in heart rate, feeling faint on standing up due to reduced blood pressure, low blood pressure, cough, feeling or being sick, diarrhoea, rash, dermatitis, weakness, chest pain (not related to the heart), increase in blood levels of alkaline, bilirubin, LDH and transaminases (as seen in blood tests). Uncommon (occurring in less than 1 in 100 patients): lack of appetite, gout, raised levels of potassium in the blood, depression, confusion, pins & needles, sleepiness, fainting, lack of blood supply to the brain, stroke, tremor, problems with sight, ear ache, vertigo (‘spinning’ sensation), tinnitus (ringing in the ear), palpitations, chest pain (due to angina), heart attack, problems with heart rhythm or heart rate, high blood pressure, shock, reduced blood flow, inflammation of the lungs, difficulty breathing, runny nose, inflamed sinus, constipation, dry mouth, weight gain, changes in taste, flatulence, excessive sweating, itchy rash, muscle pain, kidney failure, problems with sexual function, fever, water retention, sudden death, pain in the upper body. Rare (occurring in less that 1 in 1000 patients): changes in types and numbers of blood cells (you may experience sore throat, recurring infections, nose bleeds, increased bruising), memory and speech problems, flushing, bleeding, asthma or wheezing, nosebleeds, sore throat, hoarseness, damage to small blood vessels, lung infections or fluid on the lungs, stomach pain or bloating, mouth ulcers, swollen tongue, swallowing difficulties, inflammation of the pancreas, inflammation of the liver (causing fatigue, loss of appetite or weight loss, weakness, fever, stomach pains or yellowing of the skin or whites of the eyes), bruising, pain and swelling of the joint, prostate problems, weakness in one arm or leg. Very rare (occurring in less than 1 in 10,000 patients): an infection with symptoms such as fever and serious deterioration of your general condition, or fever with a sore throat/mouth or urinary problems. A blood test may be taken to check possible reduction of white blood cells (agranulocytosis).

If you have any of these side effects, they get worse or you notice any side effects not listed, please tell your doctor or pharmacist.

How to store Fosinopril sodium tablets

Keep out of the reach and sight of children.

Do not store Fosinopril above 25°C. Do not transfer to another container.

Do not use Fosinopril after the expiry date 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 Fosinopril sodium tablets contain The active substance is fosinopril sodium. Each tablet contains either 10mg or 20mg of fosinopril sodium. The other ingredients are lactose monohydrate, croscarmellose sodium, pregelatinised starch (maize), microcrystalline cellulose and glycerol dibehenate. The sodium content is 0.67mg per 10mg tablet and 1.06mg per 20mg tablet. What Fosinopril sodium tablets look like and contents of the pack

Fosinopril sodium tablets are white to off-white, round, uncoated tablets, which come in two strengths.

Each pack contains 28 tablets.

Marketing Authorisation Holder & Manufacturer: Actavis Barnstaple EX32 8NS UK

This leaflet was last revised in: October 2007

Actavis Barnstaple EX32 8NS UK

ACTPL029


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Carbimazole 20mg (Archimedes Pharma UK Ltd)


1. Name Of The Medicinal Product

Carbimazole 20mg tablets

2. Qualitative And Quantitative Composition

Each tablet contains 20mg of carbimazole

For a full list of excipients see section 6.1

3. Pharmaceutical Form

Tablet

Pale pink, uncoated, round, biconvex tablets marked with LINK C20 on one side and a scoreline on the reverse.

4. Clinical Particulars 4.1 Therapeutic Indications

Carbimazole is an anti-thyroid agent. It is indicated in all conditions where reduction of thyroid function is required.

Such conditions are:

1. Hyperthyroidism.

2. Preparation for thyroidectomy in hyperthyroidism.

3. Therapy prior to and post radio-iodine treatment.

4.2 Posology And Method Of Administration

Carbimazole should only be administered if hyperthyroidism has been confirmed by laboratory tests.

Adult:

The initial dose is in the range 20mg to 60mg, taken as two to three divided doses. The dose should be titrated against thyroid function until the patient is euthyroid in order to reduce the risk of over-treatment and resultant hypothyroidism.

Subsequent therapy may then be administered in one of two ways.

Maintenance regimen: Final dosage is usually in the range 5mg to 15mg per day, which may be taken as a single daily dose. Therapy should be continued for at least six months and up to eighteen months. Serial thyroid function monitoring is recommended, together with appropriate dosage modification in order to maintain a euthyroid state.

Blocking-replacement regimen: dosage is maintained at the initial level, i.e. 20mg to 60mg per day, and supplemental L-thyroxine, 50mcg to 150mcg per day, is administered concomitantly, in order to prevent hypothyroidism. Therapy should be continued for at least six months and up to eighteen months. Where a single dosage of less than 20mg is recommended, it is intended that carbimazole 5mg tablets should be taken.

Elderly:

No special dosage regimen is required, but care should be taken to observe the contraindications and warnings as it has been reported that the risk of a fatal outcome to neutrophil dyscrasia may be greater in the elderly (aged 65 or over).

Children:

The usual initial daily dose is 15mg per day adjusted according to response.

4.3 Contraindications

Carbimazole 20mg tablets are contraindicated in patients with a previous history of adverse reactions to carbimazole or to any of the excipients listed in section 6.1 List of Excipients.

Serious, pre-existing haematological conditions, severe hepatic insufficiency.

4.4 Special Warnings And Precautions For Use

As fatal cases of agranulocytosis with carbimazole have been reported and early treatment of agranulocytosis is essential, it is important that patients should always be warned about the onset of sore throats, bruising or bleeding, mouth ulcers, fever, malaise and should be instructed to stop the drug and to seek medical advice immediately.

In such patients white blood cell counts should be performed, particularly where there is any clinical evidence of infection. Following the onset of any signs and symptoms of hepatic disorder (pain in the upper abdomen, anorexia, general pruritus) in patients, the drug should be stopped and liver function tests performed immediately. Early withdrawal of the drug will increase the chance of complete recovery.

Carbimazole tablets should be used with caution in patients with mild-moderate hepatic insufficiency. If abnormal liver function is discovered, the treatment should be stopped. The half-life may be prolonged due to the liver disorder.

Carbimazole should be stopped temporarily at the time of administration of radio-iodine (to avoid thyroid crisis).

Patients unable to comply with the instructions for use or who cannot be monitored regularly should not be treated with Carbimazole.

Regular full blood count checks should be carried out in patients who may be confused or have a poor memory.

Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Precaution should be taken in patients with intrathoracic goitre, which may worsen during initial treatment with Carbimazole. Tracheal obstruction may occur due to intrathoracic goitre.

The use of carbimazole in non-pregnant women of childbearing potential should be based on individual risk/benefit assessment (see section 4.6).

There is a risk of cross-allergy between carbimazole, the active metabolite thiamazole (methimazole) and propylthiouracil.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Little is known about interactions. Particular care is required in case of concurrent administration of medication capable of inducing agranulocytosis. Since carbimazole is a vitamin K antagonist, the effect of anticoagulants could be intensified. The serum levels of theophylline can increase and toxicity may develop if hyperthyroidic patients are treated with antithyroid medications without reducing the theophylline dosage.

4.6 Pregnancy And Lactation

Carbimazole crosses the placenta but, provided the mother's dose is within the standard range and her thyroid status is monitored; there is no evidence of neonatal thyroid abnormalities. Studies have shown that the incidence of congenital malformations is greater in the children of mothers whose hyperthyroidism has remained untreated than in those who have been treated with carbimazole.

However, very rare cases of congenital malformations have been observed following the use of carbimazole or its active metabolite methimazole during pregnancy.

A causal relationship of these malformations, especially choanal atresia and aplasia cutis congenital (congential scalp defects), to transplacental exposure to carbimazole and methimazole cannot be excluded.

Therefore the use of carbimazole in non-pregnant women of childbearing potential should be based on individual risk/benefit assessment (see section 4.4 Special warnings and precautions for use).

Cases of renal, skull, cardiovascular congenital defects, exomphalos, gastrointestinal malformation, umbilical malformation and duodenal atresia have also been reported. Therefore, carbimazole should be used in pregnancy only when propylthiouracil is not suitable.

If carbamazole is used in pregnancy, the dose of carbimazole tablets must be regulated by the patient's clinical condition. The lowest dose possible should be used, and this can often be discontinued three or four weeks before term, in order to reduce the risk of neonatal complications.

The blocking-replacement regimen should not be used during pregnancy since very little thyroxine crosses the placenta in the last trimester.

Carbimazole is excreted in milk and if treatment is continued during lactation the patient should not continue to breast-feed her baby.

4.7 Effects On Ability To Drive And Use Machines

The effect on the ability to drive and use machines is not known.

4.8 Undesirable Effects

Adverse reactions usually occur in the first eight weeks of treatment. The most common minor reactions are nausea, headache, arthralgia, mild gastrointestinal disturbance, skin rashes and pruritus. These reactions are usually self-limiting and may not require withdrawal of the drug.

Blood and lymphatic system disorders

Bone marrow depression including neutropenia, eosinophilia, leucopenia, agranulocytosis has been reported. Fatalities with carbimazole-induced agranulocytosis have been reported.

Rare cases of pancytopenia/aplastic anaemia and isolated thrombocytopenia have also been reported. Additionally, very rare cases of haemolytic anaemia have been reported.

Patients should always be warned about the onset of sore throats, bruising or bleeding, mouth ulcers, fever, malaise and should be instructed to stop the drug and to seek medical advice immediately. In such patients, white blood cell counts should be performed immediately particularly where there is any clinical evidence of infection.

Nervous system disorders

Headache

Gastrointestinal system disorders

Nausea, mild gastrointestinal disturbance.

Loss of sense of taste has been observed.

General disorders and administration site conditions

Fever, Malaise

Hepato-biliary system disorders

Hepatic disorders, including abnormal liver function tests, hepatitis, cholestatic hepatitis, cholestatic jaundice and most commonly jaundice, have been reported; in these cases carbimazole tablets should be withdrawn.

Injury, poisoning and procedural complications

Bruising

Skin and subcutaneous tissue disorders

Skin rashes, pruritus, urticaria. Hair loss has been occasionally reported.

Musculoskeletal system disorders

Isolated cases of myopathy have been reported. Patients experiencing myalgia after the intake of Carbimazole should have their creatine phosphokinase levels monitored.

Hypersensitivity and allergic reaction

Angioedema and multi-system hypersensitivity reactions such as cutaneous vasculitis, liver, lung and renal effects occur.

Vascular Disorders

Bleeding

4.9 Overdose

No symptoms are likely from a single large dose and so no specific treatment is indicated.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

ATC Code: H03B B01 - a thyroid reducing agent.

Carbimazole, a thionamide, is a pro-drug which undergoes rapid and virtually complete metabolism to the active metabolite, thiamazole, also known as Methimazole. The method of action is believed to be inhibition of the organification of iodide and the coupling of iodothyronine residues which in turn suppress the synthesis of thyroid hormones.

5.2 Pharmacokinetic Properties

Carbimazole is rapidly metabolised to thiamazole. The mean peak plasma concentration of thiamazole is reported to occur one hour after a single dose of thiamazole.

After oral ingestion, peak plasma concentrations of thiamazole, the active moiety, occur at 1 to 2 hours. The total volume of distribution of thiamazole is 0.5l/kg. Thiamazole is concentrated in the thyroid gland. This intrathyroidal concentration of thiamazole has the effect of prolonging the activity of carbimazole. However, thiamazole has a shorter half-life in hyperthyroid patients than in normal controls and so more frequent initial doses are required while the hyperthyroidism is active.

Thiamazole is moderately bound to plasma proteins.

Carbimazole has a half-life of 5.3 to 5.4 hours. It is possible that the plasma half-life may also be prolonged by renal or hepatic disease. See Section 4.2. Posology and method of administration.

Thiamazole crosses the placenta and appears in breast milk. The plasma:milk ratio approaches unity.

Over 90% of orally administered carbimazole is excreted in the urine as thiamazole or its metabolites. The remainder appears in faeces. There is 10% enterohepatic circulation.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the Summary of Product Characteristics.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Anhydrous lactose,

Croscarmellose sodium

Iron oxide (red) (E172)

Magnesium stearate

6.2 Incompatibilities

None known

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Do not store above 25°C. Store the blisters in the original package.

6.5 Nature And Contents Of Container

The tablets are supplied in white, opaque 250 micron thermoformed PVC blister packs sealed with 20 micron lacquered aluminium foil containing 28, 56, 100 or 112 tablets (not all pack sizes may be marketed).

The heatseal coating lacquer of the aluminium foil consists of a PVC/PVAC co-polymer and polymethacrylate, with the outer side being a heat resistant lacquer based on polyester.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Archimedes Pharma UK Ltd

250 South Oak Way

Green Park

Reading

Berkshire

RG2 6UG

UK

8. Marketing Authorisation Number(S)

PL 12406/0020

9. Date Of First Authorisation/Renewal Of The Authorisation

08/05/2008

10. Date Of Revision Of The Text

08/05/2008


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Ikorel Tablets


1. Name Of The Medicinal Product

Ikorel 10mg and 20mg Tablet

2. Qualitative And Quantitative Composition

Nicorandil 10mg or 20mg

3. Pharmaceutical Form

Tablet

Off-white, round, with faceted edges, scored on one side and bearing the inscription IK10 (10mg) or IK20 (20mg).

4. Clinical Particulars 4.1 Therapeutic Indications

Ikorel tablets are indicated for the following:

• The prevention and long term treatment of chronic stable angina pectoris

• A reduction in the risk of acute coronary syndromes in patients with chronic stable angina and at least one of the following risk factors:

Previous MI

Previous CABG

CHD on angiography or a positive exercise test together with one of the following: LVH on ECG, left ventricular dysfunction, Age

4.2 Posology And Method Of Administration

Route of administration: oral.

Adults: The recommended starting dose is 10mg nicorandil twice daily, although 5mg twice daily may be employed in patients particularly susceptible to headache. Subsequently the dosage should be titrated upward depending on the clinical response. The usual therapeutic dosage is in the range 10 to 20mg nicorandil twice daily, although up to 30mg twice daily may be employed if necessary.

Elderly:

For elderly patients use of the lowest effective dose is recommended.

Children:A paediatric dosage has not been established and use of nicorandil is not recommended.

4.3 Contraindications

Ikorel is contraindicated in patients with hypersensitivity to nicorandil or any of the excipients.

Nicorandil must not be used in the case of cardiogenic shock, hypotension or left ventricular failure with low filling pressure.

Concurrent use of nicorandil and phosphodiesterase 5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) is contraindicated since it can lead to a serious drop in blood pressure.

4.4 Special Warnings And Precautions For Use

Gastrointestinal ulcerations, skin and mucosal ulceration have been reported with nicorandil. These are refractory to treatment and most only respond to withdrawal of nicorandil treatment. If ulcerations develop, it is recommended to discontinue the nicorandil treatment.

Gastrointestinal perforations in context of concomitant use of nicorandil and corticosteroids have been reported. Caution is advised when concomitant use is considered.

Nicorandil must be used with caution in patients who may have blood volume depletion or in those who present, low systolic blood pressure (e.g below 100 mm Hg), acute pulmonary oedema or acute myocardial infarction with acute left ventricular failure and low filling pressures.

Caution is advised if nicorandil is used in combination with other medicinal products with blood pressure lowering effect (see section 4.5).

The tablets are sensitive to moisture; hence the patients should be advised to keep the tablets in their blister until intake. Besides the nicorandil tablets, each blister contains active substance-free silica gel tablets as desiccant in a separate blister segment which is marked accordingly. The patients should be advised not to take these tablets. Although any accidental intake of this desiccant is usually harmless, it may alter the scheduled intake of the active tablets.

Paediatric patients

Ikorel is not recommended in paediatric patients since its safety and efficacy have not been established in this patient group.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Gastrointestinal perforations in the context of concomitant use of nicorandil and corticosteroids have been reported. Caution is advised when concomitant use is considered.

Concurrent use of nicorandil and phosphodiesterase 5 inhibitors, e.g. sildenafil, tadalfil, vardenafil, is contraindicated, since it can lead to a serious drop in blood pressure.

Therapeutic doses of nicorandil may lower the blood pressure of hypotensive patients. If nicorandil is used concomitantly with antihypertensive agents or other medicinal products with blood-pressure-lowering effect (e.g vasodilators, tricyclic antidepressants, alcohol) the blood-pressure-lowering effect may be increased.

4.6 Pregnancy And Lactation

Pregnancy: Although animal studies have not shown any teratogenic effect of nicorandil, the medicinal product has not been studied in human pregnancy; therefore, Ikorel must only be used in pregnant women if the anticipated benefit outweighs any potential risks.

Lactation: Animal studies have shown that nicorandil is excreted in small amounts into the breast milk. It is not known whether nicorandil is excreted in human milk, therefore Ikorel is not recommended during breastfeeding.

4.7 Effects On Ability To Drive And Use Machines

Blood pressure-lowering effects of nicorandil can reduce the ability to drive or to use machines. This effect can be increased in conjunction with alcohol or other products with blood-pressure-lowering effect (e.g. vasodilators, tricyclic antidepressants). (see section 4.5).

Patients should be warned not to drive or operate machinery until it is established that their performance is unimpaired by nicorandil.

4.8 Undesirable Effects

The following definitions apply to the frequency terminology used hereafter:

Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000).

SOC

FREQUENCY

ADR

     

Nervous system disorders

Very common

Headache,particularly during the first few days of treatment.

 

Common

Dizziness

Cardiac disorders

Common

Increase in heart rate, following the administration of high doses

Vascular disorders

Common

Cutaneous vasodilation with flushing

 

Uncommon

Decrease in blood pressure.

Gastrointestinal disorders

Common

Nausea and vomiting

 

Rare

Gastrointestinal ulcerations such as aphtosis, mouth ulcers, tongue ulcers, intestinal and anal ulcers. These ulcers, if advanced, may develop into perforation, fistula, or abscess formation. (see section 4.4).

     

Hepato-biliary disorders

Very rare

Liver disorders such as hepatitis, cholestasis, or jaundice.

Skin and subcutaneous tissue disorders

Rare

Different types of rash, pruritis.

 

Very rare

Angio-oedema. Skin and muscosal ulcerations (mainly peri-anal ulcerations, genital ulcerations and parastomal ulcerations (see section 4.4).

Musculoskeletal & connective tissue disorders

Rare

Myalgia

General disorders and administration site conditions

Common

Feeling of weakness

Additional Information

In addition, the following events have been reported at a different frequency in the IONA (Impact of Nicorandil in Angina) study which was conducted in subjects at high risk of cardiovascular events only.

Skin and subcutaneous tissue disorders

Uncommon – angio-oedema

Gastrointestinal disorders

Common – rectal bleeding.

Uncommon – mouth ulcers

Very rare – abdominal pain

Musculoskeletal & connective tissue disorders

Uncommon - myalgia

4.9 Overdose

Symptoms

In case of acute overdose, the likely symptomatology may be peripheral vasodilation with a fall in blood pressure and reflex tachycardia.

Management

Monitoring cardiac function and general supportive measures are recommended. If not successful, increase in circulating plasma volume by substitution of fluid is recommended. In life-threatening situations, administration of vasopressors must be considered. There is no experience of massive overdosage in humans, although the LD50 in dogs is in the range 62.5 to 125 mg/kg and in rodents it is in the order of 1200 mg/kg.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other vasodilators used in cardiac disease, ATC code: C01DX16

Nicorandil provides a dual mode of action leading to relaxation of vascular smooth muscle. A potassium channel opening action provides arterial vasodilation, thus reducing afterload, while the nitrate component promotes venous relaxation and a reduction in preload. Nicorandil has a direct effect on coronary arteries without leading to a steal phenomenon. The overall action improves blood flow to post-stenotic regions and the oxygen balance in the myocardium.

A reduction of coronary heart disease complications has been shown in patients suffering from angina pectoris who were treated with nicorandil in the IONA study.

The study was a randomised, double blind, placebo controlled, cardiovascular endpoint study carried out in 5126 patients to determine if Nicorandil could reduce the frequency of coronary events in men and women with chronic stable angina and standard anti anginal treatment at high risk of cardiovascular events defined by either: 1) previous myocardial infarction, or 2) coronary artery bypass grafting , or 3) coronary artery disease confirmed by angiography, or a positive exercise test in the previous two years, together with one of the following: left ventricular hypertrophy on the ECG, left ventricular ejection fraction

The primary endpoint of coronary heart disease (CHD) death, non-fatal myocardial infarction, or unplanned hospital admission for cardiac chest pain, occurred in 13.1% of patients treated with nicorandil compared with 15.5% of patients receiving placebo (hazard ratio 0.83, p=0.014). The rate of acute coronary syndrome (CHD death, non fatal MI or unstable angina) was 6.1% in patients treated with nicorandil compared with 7.6% in patients receiving placebo (hazard ratio 0.79, p=0.028). All cardiovascular events were significantly less in the nicorandil than placebo group 14.7% vs 17.0% (hazard ratio 0.86 p=0.027). The validity of these finding was confirmed by re-analysing the primary endpoint using all cause rather than cardiovascular mortality (nicorandil 14.9% compared with placebo 17.3%, hazard ratio 0.85, p=0.021). The study was not expressly powered to, nor did it detect any statistically significant reduction in any individual component endpoints.

5.2 Pharmacokinetic Properties

Nicorandil is well absorbed with no significant first-pass metabolism. Maximum plasma concentrations are achieved in 30 to 60 minutes and are directly related to the dosage. Metabolism is mainly by denitration of the molecule into the nicotinamide pathway with less than 20% of an administered dose being excreted in the urine. The main phase of elimination has a half-life of about 1 hour. Nicorandil is only slightly bound to plasma proteins.

No clinically relevant modifications in the pharmacokinetic profile have been seen in the elderly or in patients with liver disease or chronic renal failure.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that included in other sections of the SPC.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Maize starch, croscarmellose sodium, stearic acid and mannitol.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

18 months.

Each blister strip should be used within 30 days of opening.

6.4 Special Precautions For Storage

Store in a dry place below 25°C.

6.5 Nature And Contents Of Container

Ikorel tablets 10mg and 20mg are presented in hard tempered aluminium foil/ (Polyamide/aluminium/PVC) blister strips of 10 tablets, in which each tablet is linked to a silica gel capsule dessicant.

The blister strips are packaged in cartons of 60 tablets.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey, GU1 4YS, UK

8. Marketing Authorisation Number(S)

Ikorel tablets 10mg: PL 04425/0327

Ikorel tablets 20mg: PL 04425/0328

9. Date Of First Authorisation/Renewal Of The Authorisation

24 February 2009

10. Date Of Revision Of The Text

22 February 2011

LEGAL STATUS

POM


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Furosemide 20mg Tablets


1. Name Of The Medicinal Product

Furosemide 20mg Tablets.

2. Qualitative And Quantitative Composition

Each tablet contains 20mg furosemide.

For excipients, see 6.1

3. Pharmaceutical Form

Tablet.

Appearance: A white, circular, flat bevelled edge tablet with 'F' scoreline 20' embossed on one face and plain on the reverse.

4. Clinical Particulars 4.1 Therapeutic Indications

In the treatment of oedema associated with congestive heart failure, cirrhosis of the liver, renal disease including nephrotic syndrome.

In the treatment of peripheral oedema due to mild to moderate hypertension (alone, or in combination with other antihypertensive agents in the treatment of more severe cases).

Management of oliguria due to acute or chronic renal insufficiency.

4.2 Posology And Method Of Administration

Adults: The usual initial daily dose is 40mg. This may require adjustment until the effective dose is achieved. In mild cases 20mg daily or 40mg on alternate days may be sufficient, whereas in cases of resistant oedema daily doses of 80mg and above may be used.

In patients with chronic renal insufficiency, an initial daily dose of 250mg is employed. If a satisfactory diuresis is not produced then the dose may be increased in steps of 250mg at four to six hourly intervals up to a maximum daily dose of 1,500 mg in 24 hours. In exceptional cases up to 2,000 mg in 24 hours may be given.

Children: The oral dose for children ranges from 1-3mg/kg body weight daily, up to a maximum total dose of 40mg per day.

Elderly: The usual adult dose, but caution is advised as furosemide is excreted more slowly in the elderly.

Method of administration: Oral – the tablets should be swallowed with water.

4.3 Contraindications

Furosemide is contra-indicated in the presence of anuria, electrolyte deficiency, precoma associated with hepatic cirrhosis, digitalis intoxication, porphyria and hypersensitivity to furosemide or sulphonamides.

4.4 Special Warnings And Precautions For Use

Where indicated, steps should be taken to correct hypotension or hypovolaemia before commencing therapy. Regular monitoring of fluid and electrolyte balance is recommended.

Use with caution in patients with impaired hepatic or renal function, diabetes mellitus or adrenal disease.

Use with care in elderly patients or those with prostatic hypertrophy or impairment of micturition.

Latent diabetes may become manifest or the insulin requirements of diabetic patients may increase.

Hypotension may occur if ACE inhibitors are added to furosemide therapy. The dose of furosemide should be reduced or the drug stopped before initiating the ACE inhibitor.

Use with caution in patients with a history of gout. Discontinue furosemide if bone marrow depression occurs.

This product contains lactose. Patients with rare herditary 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

Furosemide may enhance the toxicity of cardiac glycosides by electrolyte disturbance particularly potassium and magnesium.

The action of antihypertensive agents such as methyldopa may be enhanced by furosemide. The nephrotoxic effect of cephaloridine and the aminoglycoside antibiotics may be increased by furosemide.

The action of diuretics such as furosemide may be antagonised by certain non-steroidal anti-inflammatory agents.

The renal clearance of lithium is decreased by furosemide, resulting in increased and possibly toxic serum levels. Concomitant administration should be avoided unless plasma levels can be monitored.

Concurrent administration of glucocorticoids may cause sodium retention and exacerbate potassium loss.

Furosemide decreases the effects of some drugs (e.g. antidiabetics and pressor amines) and may potentiate the effects of others (e.g. salicylates, theophylline, and curare type muscle relaxants).

Resultant hypokalaemia may potentiate cardiac toxicity of certain drugs such as antihistamines and antiarrythmics. It may also antagonise the action of antiarrhythmics such as lidocaine, mexiletine and tocainide.

4.6 Pregnancy And Lactation

Furosemide has been given after the first trimester of pregnancy for oedema, hypertension and toxaemia of pregnancy without causing foetal or new-born adverse effects. However, it should only be given during pregnancy if strictly indicated and for short-term treatment.

As it may inhibit lactation and passes into breast milk, furosemide should be used with caution in nursing mothers.

4.7 Effects On Ability To Drive And Use Machines

Reduced mental alertness and rarely dizziness and blurred vision have been reported. Patients so affected should not drive or operate machines.

4.8 Undesirable Effects

Furosemide is generally well tolerated. Fluid and electrolyte imbalance is the most common side effect. Uncommonly nausea, diarrhoea, blurred vision, dizziness, headache, pancreatitis, photosensitivity, vasculitis and interstitial nephritis have occurred very rarely. The incidence of allergic reactions such as skin rashes is very low, but when these occur treatment should be withdrawn.

A transient rise in creatinine may occur as may hypotension and liver dysfunction. Muscle spasm and paraesthesia have also been reported. Hyperuricaemia may be induced and precipitate gout in some patients.

Temporary increase in plasma cholesterol and triglyceride concentrations may occur. Latent diabetes may become manifest and the insulin requirements of diabetic patients may increase.

Bone marrow depression is a rare complication and treatment should be withdrawn. The haemopoeitic status should therefore be regularly monitored.

Calcium depletion may occur and nephrocalcinosis has been reported in premature infants.

Tinnitus and deafness have occurred, usually with large parenteral doses and rapid administration and in renal impairment.

4.9 Overdose

In cases of overdosage there is a danger of dehydration and electrolyte depletion due to excessive diuresis. Treatment should be aimed at fluid replacement and correction of electrolyte imbalance. Gastric lavage may be useful if ingestion is recent.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Furosemide is one of the high ceiling diuretics, a term used to denote a group of diuretics that have a distinctive action on renal tubular function. The peak diuresis is far greater than that observed with other agents.

The main site of action is the thick ascending loop of Henle where they inhibit electrolyte re-absorption. It increases renal blood flow without increasing the filtration rate. Such a change in renal haemodynamics reduces fluid and electrolyte re-absorption in the proximal tubule and may augment the initial diuretic response.

Furosemide is an inhibitor of carbonic anhydrase but this activity is too weak to contribute to a proximal diuresis except when massive doses are employed. Furosemide enhances the excretion of both calcium and magnesium to an extent approximately proportional to the increase in sodium excretion. Unlike the thiazides, high ceiling diuretics do not increase calcium re-absorption in the distal tubule. The calciuric action of these agents is the basis for their use in symptomatic hypercalcaemia.

5.2 Pharmacokinetic Properties

Furosemide is incompletely but fairly rapidly absorbed from the gastrointestinal tract. Bioavailability is about 65%. It has a biphasic half-life in plasma with a terminal elimination phase up to about 2 hours but this is prolonged in neonates, and in patients with hepatic and renal insufficiency.

It is extensively bound to plasma proteins but is rapidly secreted by the organic acid transport system of the proximal tubule. In this manner it gains access to the tubular fluid and eventually to its site of action more distally.

It is mainly excreted in the urine largely unchanged, but also in the form of glucuronide and free amine metabolites. Variable amounts are also excreted in the bile. Furosemide crosses the placental barrier and is excreted in milk. Non renal elimination is considerably increased in renal failure. The clearance of furosemide is not increased by haemodialysis.

5.3 Preclinical Safety Data

Not relevant

6. Pharmaceutical Particulars 6.1 List Of Excipients

Lactose monohydrate

Magnesium stearate (E470b)

Sodium starch glycollate

Maize starch.

Starch paste 15%

6.2 Incompatibilities

Not Applicable

6.3 Shelf Life

Tablet container: 5 Years

Blister: 2 Years

6.4 Special Precautions For Storage

Tablet containers: Do not store above 25°C. Store in the original container. Keep the container tightly closed.

Blister packs: Do not store above 25°C. Store in the original package.

6.5 Nature And Contents Of Container

Tablet container and cap (polypropylene container with low density polyethylene cap)

Pack sizes: 28, 56, 100, 250, 500 and 1000 tablets.

Blister (250 (?m white opaque PVC and 20 (?m hard temper aluminium foil).

Pack sizes: 28 and 56 tablets.

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

Aurobindo Pharma Limited

Ares,

Odyssey Business Park,

West End Road,

South Ruislip HA4 6QD,

United Kingdom

8. Marketing Authorisation Number(S)

PL 20532/0039

9. Date Of First Authorisation/Renewal Of The Authorisation

28/10/2005

10. Date Of Revision Of The Text

30/11/2007


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Gyno-Daktarin 20mg / g Cream


1. Name Of The Medicinal Product

Gyno-Daktarin 20mg/g cream

2. Qualitative And Quantitative Composition

Miconazole nitrate 2% w/w.

(Each gram of cream contains 20mg miconazole nitrate)

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Vaginal cream.

The cream is white and homogeneous.

4. Clinical Particulars 4.1 Therapeutic Indications

For the treatment of mycotic vulvovaginitis and superinfections due to gram-positive bacteria.

4.2 Posology And Method Of Administration

Gyno-Daktarin cream is for vaginal administration.

Recommended dosage

Administer the contents of one applicator (about 5g of cream) once daily deeply into vagina for 10 – 14 days or twice daily for 7 days. For vulvitis the cream should be applied topically twice daily. Continue the course of treatment even after pruritus and leukorrhoea have disappeared or menstruation begins.

4.3 Contraindications

Gyno-Daktarin cream is contraindicated in individuals with a known hypersensitivity to miconazole or another ingredient of the cream.

4.4 Special Warnings And Precautions For Use

Should local sensitisation or an allergic reaction occur, treatment should be discontinued.

Appropriate therapy is indicated when the sexual partner is also infected.

Gyno-Daktarin cream does not stain skin or clothes.

The concurrent use of latex condoms or diaphragms with vaginal anti-infective preparations may decrease the effectiveness of latex contraceptive agents. Therefore Gyno-Daktarin cream should not be used concurrently with a latex condom or latex diaphragm.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Miconazole administered systemically is known to inhibit CYP3A4/2C9. Due to the limited systemic availability after vaginal application, clinically relevant interactions occur very rarely. In patients on oral anticoagulants, such as warfarin, caution should be exercised and anticoagulant effect should be monitored. The effects and side effects of other drugs metabolized by CYP2C9 (e.g.,oral hypoglycemics and phenytoin) and also CYP3A4 (e.g., HMG-CoA reductase inhibitors such as simvastatin and lovastatin and calcium channel blockers such as dihydropyridines and verapamil), when co-administered with miconazole, can be increased and caution should be exercised.

Contact should be avoided between certain latex products such as contraceptive diaphragms or condoms and Gyno-Daktarin cream since the constituents of the cream may damage the latex. (see section 4.4).

4.6 Pregnancy And Lactation

Pregnancy

Although intravaginal absorption is limited, Gyno-Daktarin cream should only be used in the first trimester of pregnancy only if, in the judgement of the physician, the potential benefits outweigh the possible risks.

Lactation

It is not known whether miconazole nitrate is excreted in human milk. Caution should be exercised when using Gyno-Daktarin cream during lactation.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

The safety of GYNO-DAKTARIN was evaluated in a total of 537 women with microbiologically confirmed candidiasis and symptoms (e.g., vulvovaginal itching, burning/irritation), or signs of vulvar erythema, edema, excoriation, or vaginal erythema or edema who participated in 2 single-blind clinical trials. Subjects were treated with miconazole intravaginally, randomly assigned to either a single 1,200 mg capsule, or a 7-day application of 2% vaginal cream. Adverse Drug Reactions (ADRs) reported by

In the table, the frequencies are provided according to the following convention:

Very common

Common

Uncommon

Rare

Very rare <1/10,000, including isolated reports

Table 1. Adverse Drug Reactions Reported by Gyno-Daktarin-treated Subjects in 2 Single Blind Clinical Trials

 

Body System/Organ Class

Frequency Category

Undesirable effects

 

Skin and subcutaneous tissue disorders

 

 

Common

Rash

Uncommon

Rash pruritic, urticaria

Reproductive System and Breast Disorders

 

 

Very common

Genital pruritus female, vaginal burning sensation, vulvovaginal discomfort

 

Common

Dysmenorrhoea

 

A range of additional reactions were reported during the clinical trials, such as: vaginal discharge, vaginal haemorrhage, vaginal pain, headache, dysuria, urinary tract infection, abdominal pain, rosacea, swelling face and nausea. However due to the design of these studies, a definitive causal relationship could not be established.

Table 2.Adverse Drug Reactions Identified During Postmarketing Experience with Gyno-Daktarin by Frequency Category Estimated from Spontaneous Reporting Rates

 

Immune System Disorders

 

Not known

Hypersensitivity including Anaphylactic and Anaphylactoid reactions, Angioedema

Skin and Subcutaneous Tissue Disorders

 

Not known

Pruritis

Reproductive System and Breast Disorders

 

Not known

Vaginal irritation, pelvic cramps

4.9 Overdose

Symptoms

In case of accidental ingestion, no problems are expected.

Treatment

In the event of accidental ingestion of large quantities, an appropriate method of gastric emptying may be used if considered appropriate.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic classification:

(Anti-infectives and antiseptics, excl. combinations with corticosteroids, imidazole derivatives)

ATC code: G01A F04

Miconazole combines a potent antifungal activity against common dermatophytes and yeasts with an antibacterial activity against certain gram-positive bacilli and cocci.

Miconazole inhibits the biosynsthesis of ergosterol in fungi and changes the composition of other lipid components in the membrane, resulting in fungal cell necrosis.

In general, miconazole exerts a very rapid effect on pruritus, a symptom that frequently accompanies dermatophyte and yeast infections.

5.2 Pharmacokinetic Properties

Absorption: Miconazole persists in the vagina for up to 72 hours after a single dose. Systemic absorption of miconazole after intravaginal administration is limited, with a bioavailability of 1 to 2% following intravaginal administration of a 1200 mg dose. Plasma concentrations of miconazole are measurable within 2 hours of administration in some subjects, with maximal levels seen 12 to 24 hours after administration. Plasma concentrations decline slowly thereafter and were still measurable in most subjects 96 hours post-dose. A second dose administered 48 hours later resulted in a plasma profile similar to that of the first dose.

Distribution: Absorbed miconazole is bound to plasma proteins (88.2%) and red blood cells (10.6%).

Metabolism and Excretion: The small amount of miconazole that is absorbed is eliminated predominantly in faeces as both unchanged drug and metabolites over a four-day post-administration period. Smaller amounts of unchanged drug and metabolites also appear in urine. The mean apparent elimination half-life is 57 hours.

5.3 Preclinical Safety Data

No relevant information additional to that contained elsewhere in the Summary of Product Characteristics.

6. Pharmaceutical Particulars 6.1 List Of Excipients

PEG-6, PEG-32 and glycol stearate

Oleoyl macroglycerides

Liquid paraffin

Benzoic acid (E210)

Butylated hydroxyanisole (E320)

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Do not store above 25?C.

6.5 Nature And Contents Of Container

Tube containing 15 g, 40 g or 78 g of cream.

The aluminium tube inner is lined with heat polymerised epoxy-phenol resin with a white polypropylene cap.

The cream is supplied with disposable cardboard vaginal applicators.

*Not all pack sizes are marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Janssen-Cilag Ltd

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8. Marketing Authorisation Number(S)

PL 0242/0015

9. Date Of First Authorisation/Renewal Of The Authorisation

12 December 2008

10. Date Of Revision Of The Text

23rd July 09


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Didronel 200mg Tablets


1. Name Of The Medicinal Product

Didronel 200mg Tablets.

2. Qualitative And Quantitative Composition

Each tablet contains 200mg of Etidronate Disodium, USP.

3. Pharmaceutical Form

White rectangular tablets marked with 'P&G' on one face and '402' on the other.

4. Clinical Particulars 4.1 Therapeutic Indications

Paget's disease of bone:

Effectiveness has been demonstrated primarily in patients with polyostotic Paget's disease with symptoms of pain and with clinically significant elevations of urinary hydroxyproline and serum alkaline phosphatase. In other circumstances in which there is extensive involvement of the skull or the spine with the prospect of irreversible neurological damage, or when a weight-bearing bone may be involved, the use of Didronel may also be considered.

4.2 Posology And Method Of Administration

5mg/kg/day to 20mg/kg/day as detailed below.

Didronel should be given on an empty stomach. It is recommended that patients take the therapy with water, at the mid point of a four hour fast (ie. two hours before and two after food).

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of risedronate on an individual patient basis, particularly after 5 or more years of use.

Adults and Elderly:

The recommended initial dose of Didronel for most patients is 5mg/kg body weight/day, for a period not exceeding six months. Doses above 10mg/kg should be reserved for use when there is an overriding requirement for suppression of increased bone turnover associated with Paget's disease or when the patient requires more prompt reduction of elevated cardiac output. Treatment with doses above 10mg/kg/day should be approached cautiously and should not exceed three months duration. Doses in excess of 20mg/kg/day are not recommended.

Re-treatment should be undertaken only after a drug-free period of at least three months and after it is evident that reactivation of the disease has occurred and biochemical indices of the disease have become substantially re-elevated or approach pretreatment values (approximately twice the upper limit of normal or 75% of pre-treatment value). In no case should duration of treatment exceed the maximum duration of the initial treatment. Premature re-treatment should be avoided. In clinical trials the biochemical improvements obtained during drug therapy have generally persisted for a period of three months to 2 years after drug withdrawal.

Daily Dosage Guide

Body Weight

Required Daily Regimen of 200mg Tablets

     

Kilogrames

Stones

5mg/kg*

10mg/kg*

20mg/kg+

50

8

1

3

5

60

9.5

2

3

6

70

11

2

4

7

80

12.5

2

4

8

90

14

2

5

9

*Course of therapy - 6 months

+Course of therapy - 3 months

Children:

Disorders of bone in children, referred to as juvenile Paget's disease, have been reported rarely. The relationship to adult Paget's disease has not been established. Didronel has not been studied in children for Paget's disease.

4.3 Contraindications

Known hypersensitivity to etidronate disodium or any of the other ingredients in the product (see Section 6.1 List of Excipients). Clinically overt osteomalacia.

4.4 Special Warnings And Precautions For Use

In Pagetic patients the physician should adhere to the recommended dose regimen in order to avoid over- treatment with Didronel. The response to therapy may be of slow onset and may continue even for months after treatment with the drug has been discontinued. Dosage should not be increased prematurely nor should treatment be resumed before there is clear evidence of reactivation of the disease process. Re-treatment should not be initiated until the patient has had at least a three-month drug-free interval.

Etidronate disodium is not metabolized and is excreted intact via the kidney. Due to the lack of clinical experience the treatment of patients with impaired renal function should be undertaken with due caution. The use of etidronate disodium is discouraged in patients with severely impaired kidney function.

Caution should be taken in patients with a history of renal stone formation. In patients with impaired renal function or a history of renal stone formation, serum and urinary calcium should be monitored regularly.

It is recommended that serum phosphate, serum alkaline phosphatase and urinary hydroxyproline be measured before commencing medication and at three month intervals during treatment. If after three months of medication the pre-treatment levels have not been reduced by at least 25%, the patient may be relatively resistant to therapy. If the serum phosphate level is unchanged in the "resistant" patient, consideration should be given to increasing the dose since the absorption of pharmacologically active amounts of Didronel is typically accompanied by a rise in serum phosphate. This rise usually correlates with reductions in the biochemical indices of disease activity. If after three or more months of medication elevations of serum phosphate above the upper limit of normal are not accompanied by clinical or biochemical evidence of reduced activity, resistance of the disease to the action of Didronel is probable and termination of Didronel medication should be considered. Etidronate disodium suppresses bone turnover and may retard mineralisation of osteoid laid down during the bone accretion process. These effects are dose and time dependent. Osteoid, which may accumulate noticeably at doses of 10-20 mg/kg/day, mineralises normally post-therapy. Patients in whom serum phosphate elevations are high and reductions of disease activity are low may be particularly prone to retarded mineralisation of new osteoid. In those cases where 200mg per day (a single tablet) may be excessive, doses may be administered less frequently.

Patients with Paget's disease of bone should maintain an adequate intake of calcium and vitamin D. Patients with low vitamin D and calcium intake may be particularly sensitive to drugs that affect calcium homeostasis and should be closely monitored during Didronel therapy.

Etidronate disodium does not adversely affect serum levels of parathyroid hormone or calcium.

Hyperphosphataemia has been observed in patients receiving etidronate disodium, usually in association with doses of 10-20mg/kg/day. No adverse effects have been traced to this, and it does not constitute grounds for discontinuing therapy. It is apparently due to a drug-related increase in renal tubular reabsorption of phosphate. Serum phosphate levels generally return to normal 2-4 weeks post therapy.

Patients with significant chronic diarrhoeal disease may experience increased frequency of bowel movements and diarrhoea, particularly at higher doses.

Increased or recurrent bone pain at existing Pagetic sites and/or the appearance of pain at sites previously asymptomatic have been reported at a dose of 5mg/kg/day.At higher doses, the incidence rises to approximately 20%. When therapy continues, pain resolves in some patients but persists in others.

Fractures are recognised as a common feature in patients with Paget's disease. There has been no evidence of increased risk of fractures at the recommended dose of 5mg/kg/day for six months. At doses of 20mg/kg/day in excess of three months' duration, mineralisation of newly formed osteoid may be impaired and the risk of fracture may be increased. The risk of fracture may also be greater in patients with extensive and severe disease, a history of multiple fractures, and/or rapidly advancing osteolytic lesions. It is therefore recommended that the drug is discontinued when fractures occur and therapy not reinstated until the fracture healing is complete.

Patients with predominantly lytic lesions should be monitored radiographically and biochemically to permit termination of etidronate disodium in those patients unresponsive to treatment.The incidence of osteogenic sarcoma is known to be increased in Paget's disease. Pagetic lesions, with or without therapy, may appear by X-ray to progress markedly, possibly with some loss of definition of periosteal margins. Such lesions should be evaluated carefully to differentiate these from osteogenic sarcoma.

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving bisphosphonates.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patient with concominant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

While on treatment, these patients should avod invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces risk of osteonecrosis of the jaw.

Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.

During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Food in the stomach or upper portions of the small intestine, particularly materials with a high calcium content such as milk, may reduce absorption of etidronate disodium. Vitamins with mineral supplements such as iron, calcium supplements, laxatives containing magnesium, or antacids containing calcium or aluminium should not be taken within two hours of dosing etidronate disodium.

The diagnostic utility of bone-imaging agents may be impaired by current or recent etidronate use.

There have been isolated reports of patients experiencing changes in their prothrombin times when etidronate was added to warfarin therapy. The majority of these reports concerned variable elevations in prothrombin times without clinically significant sequelae. Although the relevance of these reports and any mechanism of coagulation alterations is unclear, patients on warfarin should have their prothrombin time monitored.

4.6 Pregnancy And Lactation

The safety of this medicinal product for use in human pregnancy has not been established. Reproductive studies have shown skeletal abnormalities in rats. It is therefore recommended that Didronel should not be used in women of childbearing potential unless adequate contraceptive measures are taken.

It is not known whether this drug passes into breast milk. It should therefore not be used during lactation period.

4.7 Effects On Ability To Drive And Use Machines

Etidronate disodium does not interfere with the ability to drive or use machines.

4.8 Undesirable Effects

Gastro-intestinal

The most common effects reported are diarrhoea and nausea. Reports of exacerbation of peptic ulcer with complications in a few patients.

Dermatological/hypersensitivity

Hypersensitivity reactions, including angio-oedema/urticaria, rash and/or pruritus, have been reported rarely.

Nervous System

Paresthesia, peripheral neuropathy , confusion, have been reported rarely.

Haematological

In patients receiving etidronate disodium, there have been rare reports of leucopenia, agranulocytosis and pancytopenia.

Musculoskeletal and connective tissue disorders

osteonecrosis of the jaw (see section 4.4 special warnings and precautions of use)

Other

Less common effects believed to be related to therapy include arthropathies (arthralgia and arthritis), and rarely burning of the tongue, alopecia, erythema multiforme and exacerbation of asthma.

During post-marketing experience the following reactions have been reported (frequency rare):

Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction).

4.9 Overdose

Overdose would manifest as the signs and symptoms of hypocalcaemia. Treatment should involve cessation of therapy and correction of hypocalcaemia with administration of Ca2+ intravenously.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Etidronate acts primarily on bone. It can inhibit the formation, growth and dissolution of hydroxyapatite crystals and amorphous precursors by chemisorption to calcium phosphate surfaces. Inhibition of crystal resorption occurs at lower doses than are required for the inhibition of crystal growth. Both effects increase as dose increases.

5.2 Pharmacokinetic Properties

Etidronate is not metabolised. Absorption averages about 1% of an oral dose of 5mg/kg body weight/day. This increases to about 1.5% at 10mg/kg/day and 6% at 20mg/kg/day. Most of the drug is cleared from the blood within 6 hours. Within 24 hours about half of the absorbed dose is excreted in the urine. The remainder is chemically absorbed to bone, especially to areas of elevated osteogenesis, and is slowly eliminated. Unabsorbed drug is excreted in the faeces.

5.3 Preclinical Safety Data

In long term studies in mice and rats, there was no evidence of carcinogenicity with etidronate disodium. All in vitro and in vivo assays conducted to assess the mutagenic potential of etidronate disodium have been negative.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Starch, magnesium stearate and microcrystalline cellulose.

6.2 Incompatibilities

See section 4.5 Interactions with other medicaments and other forms of interaction.

6.3 Shelf Life

Four years.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

Supplied in high density polypropylene bottles or blister packs of 60 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Warner Chilcott UK Limited

Old Belfast Road,

Millbrook,

Larne,

County Antrim,

BT40 2SH

8. Marketing Authorisation Number(S)

PL 10947/0018

9. Date Of First Authorisation/Renewal Of The Authorisation

26th November 1987

10. Date Of Revision Of The Text

September 2011


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Ismelin ampoules 10mg / ml


1. Name Of The Medicinal Product

Ismelin®ampoules l0mg/ml

2. Qualitative And Quantitative Composition

Guanethidine monosulphate Ph.Eur. 10mg/ml

3. Pharmaceutical Form

A colourless solution in a clear glass l ml ampoule, for intramuscular administration.

4. Clinical Particulars 4.1 Therapeutic Indications

Control of hypertensive crises, and to obtain more rapid blood pressure control.

4.2 Posology And Method Of Administration

Adults:

Ismelin should be given by intramuscular injection. One injection of 10 to 20mg will generally cause a fall in blood pressure within 30 minutes which reaches a maximum in one to two hours and is maintained for four to six hours. If a further dose of 10 to 20mg is deemed necessary, then three hours should be allowed to elapse between doses.

In hypertensive patients with moderate renal insufficiency, the intervals between dosing should be extended or the dosage reduced to avoid accumulation as the drug is renally excreted. (For patients with renal failure, see Section 4.3, "Contra

Children: not recommended.

Elderly: Clinical evidence would indicate that no special dosage regime is necessary, but concurrent coronary or cerebral insufficiency should be taken into account.

4.3 Contraindications

Cases of phaeochromocytoma and patients previously treated with monoamine oxidase inhibitors (see Section 4.5, "Interactions with other medicaments and other forms of interaction"); in such cases, Ismelin may lead to the release of large quantities of catecholamines, which may cause a hypertensive crisis.

Patients with known hypersensitivity to guanethidine and related derivatives. Heart failure due to causes other than hypertension. Renal failure (creatinine clearance 10 to 40ml/min).

4.4 Special Warnings And Precautions For Use

Heat and physical exertion may increase the antihypertensive effect of Ismelin.

Ismelin should be used with caution in patients with moderate renal insufficiency (creatinine clearance 41 to 65ml/min), or with coronary and/or cerebral arteriosclerosis; abrupt lowering of blood pressure should be avoided. Caution should be exercised in asthmatic patients or in patients with a history of gastro

The concurrent administration of guanethidine and ?

When patients have to undergo surgery, it is recommended that treatment with Ismelin be withdrawn a few days before the operation. To avoid excessive bradycardia during anaesthesia, it is advisable to premedicate with larger than usual doses of atropine.

After prolonged treatment with Ismelin, latent heart failure may develop. This is due to salt and water retention, and mild negative inotropic and chronotropic effects. Concomitant administration of diuretics can readily correct this condition.

If patients develop fever, the dose of Ismelin should be lowered.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Monoamine oxidase inhibitors should be withdrawn at least fourteen days before starting treatment with Ismelin (See Section 4.3, "Contra

Concurrent administration of Ismelin with anti

The anti-hypertensive action of Ismelin may be enhanced by other anti-hypertensive agents such as reserpine, methyldopa, vasodilators (especially minoxidil), calcium antagonists, ?

The anti-hypertensive action of Ismelin may be reduced by chlorpromazine, phenothiazine derivatives, tricyclic antidepressants and related anti-psychotic drugs, and oral contraceptives. Consequently if larger doses of Ismelin are prescribed, care must be taken upon the withdrawal of any of the drugs listed, as severe hypotension may ensue if the dose of Ismelin is not adjusted in advance.

After prolonged treatment with Ismelin, it may be necessary to adjust the dosage of insulin or oral anti

Patients on Ismelin may become hypersensitive to adrenaline, amphetamines or other sympathomimetic agents. Therefore caution should be exercised when taking or using preparations containing these drugs.

4.6 Pregnancy And Lactation

No foetal toxicity or fertility studies have been carried out in animals. Therefore the drug should only be used if there is no safer alternative. However, in particular, it should not be used during the first trimester of pregnancy nor within at least two weeks prior to the birth or during labour since it may induce paralytic ileus in the newborn infant.

In mothers receiving Ismelin in therapeutic doses, the active substance passes into the breast milk, but in quantities so small that no undesirable effects on the infant are to be expected.

4.7 Effects On Ability To Drive And Use Machines

Patients should be warned of the potential hazards of driving or operating machinery if they experience side effects such as dizziness, blurred vision or drowsiness.

4.8 Undesirable Effects

Side effects are often an indication of excessive dosage. The following effects may occur:

Central nervous system: Particularly at the start of treatment: dizziness, tiredness, lethargy, paraesthesia and headache. Occasional: blurred vision and depression. Rare: myalgia and muscular tremor.

Cardiovascular system: Postural hypotension (which may be associated with cerebral or myocardial ischaemia in severe cases) especially when getting up in the morning or after physical exertion, sick

Gastro Diarrhoea and gaseous distension. Occasional: vomiting, nausea and dry mouth. Rare: swelling of parotid glands.

Respiratory tract: Nasal congestion. Rare: asthma.

Urogenital system: Raised BUN levels or uraemia in patients with latent or manifest renal failure, and ejaculation disturbances.

Skin and hair: Occasional: dermatitis. Rare: hair loss.

Blood: Isolated reports of anaemia, leucopenia, and/or thrombocytopenia.

4.9 Overdose

Symptoms: may include postural hypotension which may cause syncope, sinus bradycardia (although tachycardia has been observed), tiredness, dizziness, blurring of vision, muscular weakness, nausea, vomiting, severe diarrhoea and oliguria.

Treatment: Postural hypotension may be overcome by keeping the patient recumbent, or by instituting fluid and electrolyte replacement, and if necessary, by cautious administration of pressor agents (see Section 4.5, "Interactions with other medicaments and other forms of interaction"). Sinus bradycardia can be treated with atropine, and diarrhoea with an anticholinergic agent.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Ismelin is a peripheral sympathetic blocking drug which lowers blood pressure by depleting and inhibiting reformation of noradrenaline in postganglionic nerve endings. Guanethidine, being highly polar, does not cross the blood

5.2 Pharmacokinetic Properties

Guanethidine may be excreted more slowly in those patients with moderate to severely compromised renal function, therefore the potential for accumulation of the drug will be higher.

5.3 Preclinical Safety Data

There are no pre

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium chloride, sulphuric acid and water for injections.

6.2 Incompatibilities

None known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

Clear glass type I, l ml ampoules containing l0mg/ml: Boxes of 5.

6.6 Special Precautions For Disposal And Other Handling

None

Administrative Data 7. Marketing Authorisation Holder

Amdipharm Plc

Regency House

Miles Gray Road

Basildon

Essex SS14 3AF

United Kingdom

8. Marketing Authorisation Number(S)

PL 20072/0027

9. Date Of First Authorisation/Renewal Of The Authorisation

18th April 2005

10. Date Of Revision Of The Text Legal Status

POM


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Amiloride Tablets BP 5mg


1. Name Of The Medicinal Product

AMILORIDE TABLETS BP 5mg

2. Qualitative And Quantitative Composition

Each tablet contains Amiloride Hydrochloride BP equivalent to 5mg anhydrous amiloride hydrochloride.

3. Pharmaceutical Form

Yellow uncoated tablets.

4. Clinical Particulars 4.1 Therapeutic Indications

Potassium-conserving agent; diuretic. Although amiloride may be used alone, its principal indication is as concurrent therapy with thiazides or more potent diuretics to conserve potassium during periods of vigorous diuresis and during long-term maintenance therapy. It is indicated for use in:

1) Congestive heart failure.

2) Hypertension.

3) Hepatic cirrhosis with ascites.

4.2 Posology And Method Of Administration

Monotherapy: Initially 10mg which may be given as a single or divided dose. This may be increased if necessary to a maximum of 20mg daily. When diuresis has been achieved, the dosage may be reduced by 5mg increments to the least amount required.

In conjunction with other diuretic therapy: When amiloride is used with a diuretic which is given on an intermittent basis, it should be given at the same time as the diuretic.

Congestive heart failure: Initially 5-10mg daily, together with the usual dosage of the diuretic concurrently employed. Where diuresis is not achieved dosage of both agents may be increased if necessary, however, the maximum dose for amiloride is 20mg a day. Once diuresis is achieved, reduction in dosage of both agents may be attempted for maintenance therapy. The dosage of both drugs is determined by diuresis and the level of plasma potassium.

Hypertension: 5-10mg daily, together with the usual antihypertensive dosage of the thiazide concurrently employed. It is not usually necessary to exceed 10mg of amiloride daily; in any event, not more than 20mg a day should be given.

Hepatic cirrhosis with ascites: When used in conjunction with another diuretic, treatment should be commenced with a small amiloride dose of 5mg, plus a low dosage of the other diuretic agent. If necessary, dosage of both agents may gradually be increased until there is effective diuresis. The maximum dose for amiloride is 20mg daily. Maintenance doses may be lower than those required to initiate diuresis; reduction in the daily dosage should therefore be attempted when the patient's weight is stabilised.

Elderly: Dosage in the elderly should be carefully adjusted according to renal function, blood electrolytes and diuretic response. The elderly are more susceptible to electrolyte imbalance and more likely to experience hyperkalaemia since renal reserve may be reduced.

Children: The use of amiloride in children is contraindicated.

For oral administration.

4.3 Contraindications

Hyperkalaemia (plasma potassium over 5.5mmol/l); other potassium-conserving agents or potassium supplements; anuria, acute renal failure, severe progressive renal disease, diabetic nephropathy; known sensitivity to amiloride; use in children as safety has not been established.

4.4 Special Warnings And Precautions For Use

Diabetes mellitus: To minimise the risk of hyperkalaemia in known or suspected diabetic patients, the status of renal function should be determined before initiating therapy. Amiloride should be discontinued for at least three days before a glucose-tolerance test.

Metabolic or respiratory acidosis: Potassium-conserving therapy should be initiated only with caution in severely ill patients in whom metabolic or respiratory acidosis may occur, eg patients with cardiopulmonary disease of decompensated diabetes. Shifts in acid-base balance alter the balance of extracellular-intracellular potassium, and the development of acidosis may be associated with rapid increase in plasma potassium.

Hyperkalaemia: This has been observed in some patients receiving amiloride, alone or with other diuretics. These patients should be observed carefully for clinical, laboratory, and ECG evidence of hyperkalaemia. Some deaths have been reported in this group of patients. Hyperkalaemia has been noted particularly in the elderly and in hospital patients with hepatic cirrhosis or cardiac oedema who have known renal involvement, who were seriously ill, or were undergoing vigorous diuretic therapy.

Neither potassium-conserving agents nor a diet rich in potassium should be used with amiloride except in severe and/or refractory cases of hypokalaemia. If the combination is used, plasma potassium levels must be continuously monitored.

Treatment of hyperkalaemia: If hyperkalaemia occurs, amiloride should be discontinued immediately and, if necessary, active measures taken to reduce the plasma potassium level.

Impaired renal function: Patients with blood urea over 10mmol/l, serum creatinine over 130µmol/l, or with diabetes mellitus require careful monitoring of serum electrolytes and blood urea levels. In renal impairment, use of a potassium-conserving agent may result in rapid development of hyperkalaemia.

Electrolyte imbalance and blood urea increases: Hyponatraemia and hypochloraemia may occur when amiloride is used with other diuretics. Reversible increases in blood urea levels have been reported accompanying vigorous diuresis, especially when diuretics were used in seriously ill patients, such as those with hepatic cirrhosis with ascites and metabolic alkalosis, or those with resistant oedema. Careful monitoring of serum electrolytes and blood urea levels should therefore be carried out when amiloride is given with oral diuretics to such patients.

Cirrhotic patients: Oral diuretic therapy is more frequently accompanied by side-effects in patients with hepatic cirrhosis with or without ascites, because these patients are intolerant of acute shifts in electrolyte balance, and because they often already have hypokalaemia as a result of associated aldosteronism.

Reports suggest that patients with pre-existing severe liver disease treated with diuretics, including amiloride hydrochloride, may experience hepatic encephalopathy, manifested by tremors, confusion and coma, and increased jaundice.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Lithium should not generally be given with diuretics because they reduce it renal clearance and add a high risk of lithium toxicity.

When combined with thiazide diuretics, amiloride can act synergistically with chlorpropamide to increase the risk of hyponatraemia.

When amiloride is administered concurrently with an angiotensin-converting enzyme inhibitor, NSAIDs or ciclosporin the risk of hyperkalaemia may be increased. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.In patients receiving amiloride with NSAIDs or ciclosporin the risk of nephrotoxcity may also be increased.

4.6 Pregnancy And Lactation

Amiloride is not recommended for use during pregnancy due to limited clinical experience. The potential benefits must be weighed against the possible hazard to the foetus if administered to a woman of childbearing age.

The routine use of diuretics in otherwise healthy pregnant women with or without mild oedema is not indicated because they may be associated with hypovolaemia, increased blood viscosity and decreased placental perfusion. Foetal and neonatal jaundice, foetal bone depression and thrombocytopenia have also been described.

It is not known whether amiloride is excreted in human milk. Therefore, due to the risk that it may take this route of excretion, and possibly cause serious adverse reactions to the nursing infant, the mother should either stop breast-feeding or cease taking the drug.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Amiloride is usually well tolerated, although minor side-effects are reported relatively frequently. Apart from hyperkalaemia, significant adverse reactions have been infrequently reported. Nausea/anorexia, abdominal pain, flatulence and mild skin rash are probably due to amiloride; but other side-effects are generally associated with diuresis or with the underlying disease being treated.

Body as a whole: Headache, weakness, fatigue, back pain, chest pain, neck/shoulder ache, pain in the extremities.

Cardiovascular: Angina pectoris, orthostatic hypotension, arrhythmias, palpitation, one patient with partial heart block developed complete heart block.

Digestive: Anorexia, nausea, vomiting, diarrhoea, constipation, abdominal pain, GI bleeding, jaundice, thirst, dyspepsia, flatulence.

Metabolic: Elevated plasma potassium levels above 5.5mmol/l, hyponatraemia.

Musculoskeletal: Muscle cramps, joint pain.Serum uric acid levels may rise during treatment with amiloride and acute attacks of gout may be precipitated.

Nervous: Dizziness, vertigo, paraesthesia, tremors, encephalopathy.

Psychiatric: nervousness, mental confusion, insomnia, decreased libido, depression, somnolence.

Respiratory: Cough, dyspnoea.

Special senses: Nasal congestion, visual disturbances, increased intra-ocular pressure, tinnitus.

Urogenital: Impotence, polyuria, dysuria, bladder spasms, frequency of micturition.

Reactions in which no causal relationship could be established were activation of probable pre-existing peptic ulcer, aplastic anaemia, neutropenia and abnormal liver function tests. In a few cirrhotic patients, jaundice associated with the underlying disease has deepened, but the drug relationship is unknown.

4.9 Overdose

No data are available; it is not known whether the drug is dialysable. No specific antidote is available.

The most likely signs and symptoms are dehydration and electrolyte imbalance which should be treated by established methods. Therapy should be discontinued and the patient closely observed. Emesis should be induced or gastric lavage performed if ingestion is recent. Treatment is symptomatic and supportive. If hyperkalaemia occurs, active measures should be taken to reduce plasma potassium levels.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Amiloride hydrochloride is a diuretic.

5.2 Pharmacokinetic Properties

Amiloride is incompletely absorbed from the gastrointestinal tract. Peak serum concentrations are achieved about 3-4 hours after administration by mouth. It is excreted unchanged in the urine. Amiloride has been estimated to have a serum half-life of about 6 hours.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Also contains: lactose, magnesium stearate, maize starch, E172, E460.

6.2 Incompatibilities

None known.

6.3 Shelf Life

Shelf-life

Three years from the date of manufacture.

Shelf-life after dilution/reconstitution

Not applicable.

Shelf-life after first opening

Not applicable.

6.4 Special Precautions For Storage

Store below 25°C in a dry place.

Protect from light.

6.5 Nature And Contents Of Container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene tablet containers with and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass bottles with screw caps and polyfoam wad or cotton wool.

The product may also be supplied in blister packs in cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-7g/M? PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 28s, 30s, 56s, 60s, 84s, 90s, 100s, 112s, 120s, 168s, 180s, 250s, 500s, 1000s

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material.

Maximum size of bulk packs: 50,000.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data 7. Marketing Authorisation Holder

Name or style and permanent address of registered place of business of the holder of the Marketing Authorisation:

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

8. Marketing Authorisation Number(S)

PL 0142/0210

9. Date Of First Authorisation/Renewal Of The Authorisation

August 1986; August 1991

10. Date Of Revision Of The Text

May 2007


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Isosorbide mononitrate 20mg tablets (Aurobindo Pharma Ltd)


1. Name Of The Medicinal Product

Monomil 20 mg Tablets

Carmil 20 mg Tablets

Isosorbide Mononitrate 20 mg tablets.

2. Qualitative And Quantitative Composition

Isosorbide-5-mononitrate Ph. Eur. 20 mg/tablet.

3. Pharmaceutical Form

Tablets

White to off-white, round flat tablets with 'I15' embossing on one side.

4.1 Therapeutic Indications

For the prophylaxis of angina pectoris

As adjunctive therapy in congestive heart failure not responding to cardiac glycosides or diuretics.

4.2 Posology And Method Of Administration

Adults: One tablet to be taken asymmetrically (to allow a nitrate low period) two or three times a day. For patients not already receiving prophylactic nitrate therapy it is recommended that the initial dose of isosorbide mononitrate be 20mg twice a day. The dosage may be increased to 120mg per day. The lowest effective dose should be used.

Children: The safety and efficacy of Isosorbide Mononitrate 20mg tablets in children has not been established.

Elderly: There is no evidence to suggest that an adjustment of the dosage is necessary.

Treatment with Isosorbide mononitrate tablets, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually (see section 4.4)

4.3 Contraindications

Isosorbide mononitrate tablets should not be used in cases of acute myocardial infarction with low filling pressures, acute circulatory failure (shock, vascular collapse), or very low blood pressure, hypertrophic obstructive cardiomyopathy (HOCM), constrictive pericarditis, cardiac tamponade, low cardiac filling pressures, aortic/mitral valve stenosis and diseases associated with a raised intra-cranial pressure e.g. following a head trauma and including cerebral haemorrhage.

This product should not be given to patients with a known sensitivity to isosorbide mononitrate, the listed ingredients or other nitrates.

Isosorbide mononitrate Tablets should not be used in patients with marked anaemia, severe hypotension, closed angle glaucoma or hypovolaemia.

Phosphodiesterase type-5 inhibitors (e.g. sildenafil, tadalafil and vardenafil) have been shown to potentiate the hypotensive effects of nitrates, and their co-administration with nitrates or nitric oxide donors is therefore contraindicated (see section 4.5)

4.4 Special Warnings And Precautions For Use

Isosorbide mononitrate Tablets should be used with caution in patients who have recent history of myocardial infarction, or who are suffering from hypothyroidism, hypothermia, malnutrition and severe liver or renal disease.

Symptoms of circulatory collapse may arise after first dose, particularly in patients with labile circulation.

This product may give rise to postural hypotension and syncope in some patients. Severe postural hypotension with light-headedness and dizziness is frequently observed after the consumption of alcohol.

Hypotension induced by nitrates may be accompanied by paradoxical bradycardia and increased angina.

Isosorbide mononitrate Tablets contain lactose and therefore should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

In the event of an acute angina attack, a sublingual treatment such as a GTN spray or tablet should be used instead of Isosorbide mononitrate Tablets.

If the tablets are not taken as indicated (see section 4.2), tolerance to the medication could develop. The lowest effective dose should be used.

Treatment with Isosorbide mononitrate, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually (see section 4.2)

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concurrent administration of drugs with blood pressure lowering properties, e.g. beta-blockers, calcium channel blockers, vasodilators, alprostadil, aldesleukin, angiotensin II receptor antagonists etc. and/or alcohol may potentiate the hypotensive effects of Isosorbide mononitrate Tablets. This may occur with neuroleptics and tricyclic antidepressants.

Any blood pressure lowering effect of Isosorbide mononitrate tablets will be increased if used together with phosphodiesterase type-5- inhibitors, which are used for erectile dysfunction (see special warning and contraindications). This may lead to life threatening cardiovascular complications. Patients who are on Isosorbide mononitrate therapy therefore must not use phosphodiesterase type-5 inhibitors.

Reports suggest that concomitant administration of Isosorbide mononitrate tablets may increase the blood levels of dihydroergotamine and its hypertensive effects.

4.6 Pregnancy And Lactation

There is inadequate evidence of safety in human pregnancy and lactation and use during pregnancy and lactation is not recommended unless considered essential by the patient's physician.

4.7 Effects On Ability To Drive And Use Machines

Dizziness, tiredness or blurred vision might occur at the start of the treatment. The patient should therefore be advised that if affected, they should not drive or operate machinery. This effect may be increased by alcohol.

4.8 Undesirable Effects

A very common (>10% of patients) adverse reaction to Isosorbide mononitrate Tablets is throbbing headache. The incidence of headache diminishes gradually with time and continued use.

At the start of therapy or when the dosage is increased, hypotension and/or light-headedness in the upright position are commonly observed (i.e. in 1-10% of patients). These symptoms may be associated with dizziness, drowsiness, reflex tachycardia and a feeling of weakness.

Infrequently (i.e. in less than 1% patients) nausea, vomiting, flushing and allergic skin reactions (e. g. rash) may occur sometimes severely. In single cases exfoliative dermatitis may occur.

Severe hypotensive responses have been reported for organic nitrates and include nausea, vomiting, restlessness pallor and excessive perspiration. Uncommonly collapse may occur (sometimes accompanied by bradyarrhythmia and syncope). Uncommonly severe hypotension may lead to enhanced angina symptoms.

A few reports of heartburn most likely due to a nitrate induced sphincter relaxation have been reported.

Tachycardia and paroxysmal bradycardia have been reported.

4.9 Overdose

Symptoms and signs: Headache, hypotension, nausea, vomiting, sweating, tachycardia, vertigo, restlessness, warm flushed skin, blurred vision and syncope. A rise in intracranial pressure with confusion and neurological deficits can sometimes occur. Methaemoglobinaemia (cyanosis, hypoxaemia, restlessness, respiratory depression, convulsions, cardiac arrhythmias, circulatory failure, raised intracranial pressure) occurs rarely.

Management:

Consider oral activated charcoal if ingestion of a potentially toxic amount has occurred within 1 hour. Observe for at least 12 hours after the overdose. Monitor blood pressure and pulse. Correct hypotension by raising the foot of the bed and /or by expanding the intravascular volume. Other measures as indicated by the patient's clinical condition. If severe hypotension persists despite the above measures consider use of inotropes.

If methaemoglobinaemia (symptoms or >30% methaemoglobin), IV administration of methylene blue 1-2mg/kg body-weight. If therapy fails with second dose after 1 hour or contraindicated, consider red blood cell concentrates or exchange transfusion. In case of cerebral convulsions, diazepam or clonazepam IV, or if therapy fails, phenobarbital, phenytoin or propofol anaesthesia.

5.1 Pharmacodynamic Properties

ATC code: C01D A14 Vasodilatator used in cardiac diseases

Isosorbide mononitrate is an organic nitrate, which, in common with other cardioactive nitrates, is a vasodilator. It produces decreased left and right ventricular end-diastolic pressures to a greater extent than the decrease in systemic arterial pressure, thereby reducing afterload and especially the preload of the heart.

Isosorbide mononitrate influences the oxygen supply to ischaemic myocardium by causing the redistribution of blood flow along collateral channels and from epicardial to endocardial regions by selective dilation of large epicardial vessels.

It reduces the requirements of the myocardium for oxygen by increasing venous capacitance, causing a pooling of blood in peripheral veins, thereby reducing ventricular volume and heart wall distension.

5.2 Pharmacokinetic Properties

Isosorbide 5—mononitrate is rapidly absorbed and peak plasma levels occur approx. 1 hour following oral dosing.

Isosorbide-5-mononitrate is completely bioavailable after oral doses and is not subject to pre-systemic elimination processes.

Isosorbide-5-mononitrate is eliminated from the plasma with a half-life of about 5.1 hours. It is metabolised to Isosrbide-5-mn-2-glucoronide, which has a half-life of approximately 2.5 hours. As well as being excreted unchanged in the urine.

After multiple oral dosing plasma concentrations are similar to those that can be predicted from single dose kinetic parameters.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, oncogenicity and toxicity to reproduction.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Microcrystalline cellulose Ph. Eur., Lactose Monohydrate Ph. Eur., Colloidal Anhydrous Silica Ph. Eur., Maize starch Ph. Eur., Talc Ph. Eur., and Magnesium stearate Ph. Eur.

6.2 Incompatibilities

None known.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Do not store above 25?C.

6.5 Nature And Contents Of Container

PVC/Aluminium foil blisters on a cardboard carton.

Each sheet of blisters contains 10 tablets and there are six sheets of ten tablets per carton (60's pack).

Each strip of blister contains 14 tablets and there are four such strips per carton (56's pack).

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Milpharm Limited,

Ares,

Odyssey Business Park,

West End Road,

South Ruislip HA4 6QD,

United Kingdom

8. Marketing Authorisation Number(S)

PL 16363/0001

9. Date Of First Authorisation/Renewal Of The Authorisation

21st September 1998

10. Date Of Revision Of The Text

16/10/2007


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Gentamicin Paediatric 20mg / 2ml Solution for Injection


1. Name Of The Medicinal Product

Cidomycin Paediatric Injectable 20mg/2ml

or

Gentamicin Paediatric 20mg/2ml Solution for Injection.

2. Qualitative And Quantitative Composition

Each vial (2ml) contains Gentamicin Sulphate Ph Eur equivalent to 20mg Gentamicin base.

For excipients, see section 6.1.

3. Pharmaceutical Form

Solution for Injection.

Clear, colourless solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Gentamicin is an aminoglycoside antibiotic with broad-spectrum bactericidal activity. It is usually active against most strains of the following organisms: escherichia coli, klebsiella spp., Proteus spp. (indole positive and indole negative), pseudomonas aeruginosa, staphylococci, enterobacer spp., Citrobacter spp. and providencia spp.

Indications : gentamicin injection and gentamicin paediatric injection are indicated in bacteraemia, septicaemia, urinary tract infections, chest infections, severe neonatal infections and other serious systemic infections due to susceptible organisms.

Consideration should be given to official local guidance on the appropriate use of antibacterial agents.

4.2 Posology And Method Of Administration

Adults:

Serious infections: if renal function is not impaired, 5mg/kg daily in divided doses at six or eight hourly intervals. The total daily dose may be subsequently increased or decreased as clinically indicated.

Systemic infections: if renal function is not impaired, 3-5 mg/kg/day in divided doses according to severity of infection, adjusting according to clinical response and body weight.

Urinary tract infections: as 'systemic infections'. Or, if renal function is not impaired, 160mg once daily may be used.

Paediatric Patients

The daily dose recommended in children (aged 1 year and above) and adolescents with normal renal function, is 3-6 mg/kg body weight per day as 1 (preferred) up to 2 single doses.

The daily dose in infants after the first month of life is 4.5-7.5 mg/kg body weight per day as 1 (preferred) up to 2 single doses.

The daily dose in newborns is 4-7 mg/kg body weight per day. Due to the longer half-life, newborns are given the required daily dose in 1 single dose.

Elderly:

There is some evidence that elderly patients may be more susceptible to aminoglycoside toxicity whether secondary to previous eighth nerve impairment or borderline renal dysfunction.

Accordingly, therapy should be closely monitored by frequent determination of gentamicin serum levels, assessment of renal function and signs of toxicity.

Renal impairment

Gentamicin is excreted by simple glomerular filtration. In impaired renal function, the recommended daily dose has to be decreased and adjusted to the renal function.

Nomograms are available for the calculation of the dose, which depends on the patient's age, weight, and renal function

The following table may be useful when treating adults.

Blood Urea

Creatine clearance

Dose and frequency of administration

 

(mg/100ml)

(mmol/I)

(GFR) (ml/min)

 

<40

6-7

>70

80mg* 8 hourly

40-100

6-17

30-70

80mg* 12 hourly

100-200

17-34

10-30

80mg* daily

>200

>34

5-10

80mg* every 48 hours

Twice weekly intermittent haemodialysis

<5

80mg* after dialysis

 

*60mg if body weight <60kg. Frequency of dosage in hours may also be approximated as serum creatine (mg%) x eight or in SI units, as serum creatine (?mol/l) divided by 11. If these dosage guides are used peak serum levels must be measured. Peak levels of genamicin occur approximately one hour after intramuscular injectable and intravenous injectable. Trough levels are measured just prior to the next injectable. Assay of peak serum levels gives confirmation of adequacy of dosage and also serves to detect levels above 10mg/l, at which the possibility of ototoxicity should be considered. One hour concentrations of gentamicin should not exceed 10mg/l (but should reach 4mg/l), while the pre-dose trough concentration should be less than 2mg/l

The recommended dose and precautions for intramuscular and intravenous administration are identical. Gentamicin when given intravenously should be injected directly into a vein or into the drip set tubing over no less than three minutes. If administered by infusion, this should be over no longer than 20 minutes and in no greater volume of fluid than 100ml.

Monitoring advice:

Serum concentration monitoring of gentamicin is recommended, especially in elderly, in newborns and in patients with impaired renal function. Samples are taken at the end of a dosing interval (trough level). Trough levels should not exceed 2 µg/ml administering gentamicin twice daily and 1 µg/ml for a once daily dose.

4.3 Contraindications

Hypersensitivity; maysthenia gravis.

4.4 Special Warnings And Precautions For Use

To avoid adverse events, continuous monitoring (before, during and after) of renal function (serum creatinin, creatinin clearance), control of function of vestibule and cochlea as well as hepatic and laboratory parameters is recommended.

Ototoxicity has been recorded following the use of gentamicin. Groups at special risk include patients with impaired renal function, infants and possibly the elderly. Consequently, renal, auditory and vestibular functions should be monitored in these patients and serum levels determinedso as to avoid peak concentrations above 10mg/l and troughs above 2mg/l. As there is some evidence that risk of both ototixicity and nephrotoxicity is related to the level of total exposure, duration of therapy should be the shortest possible compatible with clinical recovery. In some patients with impaired renal function there has been a transient rise in blood-urea-nitrogen which has usually reverted to normal during or following cessation of therapy. It is important to adjust the frequency of dosage according to the degree of renal function.

Gentamicin should only be used in pregnancy if considered essential by the physician (see section 4.6 Pregnancy and Lactation.)

Gentamicin should be used with care in conditions characterised by muscular weakness.

In cases of significant obesity gentamicin serum concentrations should be closely monitored and a reduction in dose should be considered.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concurrent administration of gentamicin and other potentially ototoxic or nephrotoxic drugs should be avoided. Potent diuretics such as etacrynic acid and furosemide are believed to enhance the risk of otoxicity whilst amphotericin b, cis-platinum and ciclosporin are potential enhancers of nephrotoxicity.

Any potential nephrotoxicity of cephalosporins , and in particular cephaloridine, may also be increased in the presence of gentamicin. Consequently, if this combination is used monitoring of kidney function is advised.

Neuromuscular blockade and respiratory paralysis have been reported from administration of aminoglycosides to patients who have received curare-type muscle relaxants during anaesthesia.

Indometacin possibly increases plasma concentrations of gentamicin in neonates.

Concurrent use with oral anticoagulants may increase the hypothrombinanaemic effect.

Concurrent use of bisphosphonates may increase the risk of hypocalcaemia.

Concurrent use of the Botulinum Toxin and gentamicin may increase the risk of toxicity due to enhanced neuromuscular block.

Antagonism of effect may occur with concomitant administration of gentamicin with either neostigmine or pyridostigmine.

4.6 Pregnancy And Lactation

There are no proven cases of intrauterine damage caused by gentamicin. However, in common with most drugs known to cross the placenta , usage in pregnancy should only be considered in life-threatening situations where the expected benefits outweigh possible risks. In the absence of gastro-intestinal inflammation, the amount of gentamcin ingested from the milk is unlikely to result in significant blood levels in breast-fed infants

4.7 Effects On Ability To Drive And Use Machines

Not known.

4.8 Undesirable Effects

Side-effects include vestibular damage or hearing loss, particularly after exposure to ototoxic drugs or in the presence of renal dysfunction. Nephrotoxicity (usually reversible) and occasionally acute renal failure, hypersensitivity, anaemia, blood dycrasias, purpura, stomatitis, convulsions and effects on liver function occur occasionally.

Rarely hypomagnesia on prolonged therapy and antibiotic–associated colitis have been reported.

Nausea, vomiting and rash have also been reported.

Central neurotoxicity, including encephalopathy, confusion, lethargy, mental depression and hallucinations, has been reported in association with gentamicin therapy but this is extremely rare.

4.9 Overdose

Haemodialysis and peritoneal dialysis will aid removal from the blood but the former is probably more efficient. Calcium salts given intravenously have been used to counter the neuromuscular blockade caused by gentamicin.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Gentamicin is a mixture of antibiotic substances produced by the growth of micromonospora purpurea. It is bactericidal with greater antibacterial activity than streptomycin, neomycin or kanamycin.

Gentamicin exerts a number of effects on cells of susceptible bacteria. It affects the integrity of the plasma membrane and the metabolism of RNA, but its most important effects is inhibition of protein synthesis at the level of the 30s ribosomal subunit.

5.2 Pharmacokinetic Properties

Gentamicin is not readily absorbed from the gastro-intestinal tract. Gentamicin is 70-85% bound to plasma albumin following administration and is excreted 90% unchanged in urine. The half-life for its elimination in normal patients is 2 to 3 hours.

• Effective plasma concentration is 4-8?g/ml.

• The volume of distribution (VD) is 0.31kg.

• The elimination rate constant is:

1. 0.02hr-1 for anuric patients*

2. 0.30hr-1 normal

* Therefore in those with anuria care must be exercised following the initial dose, any subsequent administration being reduced in-line with plasma concentrations of gentamicin.

Paediatric patients, premature infants and neonates

Distribution

The distribution volume of gentamicin is about equivalent to the volume of extracellular water. In the newborn water makes up 70 to 75% of bodyweight, compared with 50 to 55% in adults. The extracellular water compartment is larger (40% of body weight compared with 25% of body weight in adults). Therefore, the volume of distribution of gentamicin per kg bodyweight is affected and decreases with increasing age from 0.5 to 0.7 L/kg for a premature newborn to 0.25 L/kg for an adolescent. The larger volume of distribution per kg bodyweight means that for adequate peak blood concentration a higher dose per kg bodyweight needs to be administered.

Elimination

Gentamicin is not metabolized in the body but is excreted unchanged in microbiologically active form predominantly via the kidneys. In patients with normal renal function the elimination half life is about 2 to 3 hours. In neonates elimination rate is reduced due to immature renal function.

Elimination half life averages approximately 8 hours in neonates at a gestational age of 26 to 34 weeks compared with about 6.7 hours in neonates at a gestational age of 35 to 37 weeks.

Correspondingly, clearance values increase from about 0.05 L/h in neonates at a gestational age of 27 to 0.2 L/h in neonates at a gestational age of 40 weeks.

5.3 Preclinical Safety Data

Not applicable

6. Pharmaceutical Particulars 6.1 List Of Excipients

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Disodium Edetate

2M Sodium Hydroxide

1M Sulphuric Acid

Water for Injections

6.2 Incompatibilities

In general, gentamicin injection should not be mixed. In particular the following are incompatible in mixed solution with gentamicin injection: penicillins, cephalosporins, erythromycin, heparins, sodium bicarbonate. * Dilution in the body will obviate the danger of physical and chemical incompatibility and enable gentamicin to be given concurrently with the drugs listed above either as a bolus injection into the drip tubing, with adequate flushing, or at separate sites. In the case of carbenicillin, administration should only be at a separate site.

* Carbon Dioxide may be liberated on addition of the two solutions. Normally this will dissolve in the solution but under some circumstances small bubbles may form.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not Store above 25°C. Do not refrigerate or freeze.

6.5 Nature And Contents Of Container

Cidomycin Paediatric Injectable is supplied in vials.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

Trading as: Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS

8. Marketing Authorisation Number(S)

PL 17780/0507

9. Date Of First Authorisation/Renewal Of The Authorisation

10/03/2010

10. Date Of Revision Of The Text

01/09/2010


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Sominex Tablets (Actavis UK Ltd)


Sominex

(promethazine hydrochloride)

Important information about Sominex This medicine is used as a night time sleep aid for short term use. It can be taken by people over 16 years. Do not take If you are under 16 years old. If you are pregnant. See section 2. Do not drink alcohol when taking this medicine. Do not use for longer than 7 days.
See section 3.

Now read the rest of the leaflet before you use this medicine. It includes other information which might be especially important for you.

Keep this leaflet. You may need to read it again. Ask your pharmacist if you need any more information or advice. 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. What the medicine is for

Sominex tablets contain promethazine hydrochloride, an antihistamine, which has a sedative effect. The medicine is used as a night time sleep aid, to correct temporary disturbances of sleep pattern where there is difficulty in going to sleep or staying asleep, caused for example by alteration of normal routine.

Before you use this medicine Do not use the medicine if you have An allergy to any of the ingredients listed in section 6. An allergy to Phenothiazine drugs (used to treat mental illness, severe nausea/vomiting or vertigo, e.g. chlorpromazine, pericyazine). Concussion, light headedness, drowsiness, dizziness or a recent head injury. Taken MAOIs (monoamine oxidase inhibitors) for depression within the last two weeks. This medicine is for short term sleeping problems. It should not be used for more than 7 days without talking to the doctor. Do not drink alcohol when taking Sominex. Talk to your doctor or pharmacist if you have Asthma. Breathing problems or bronchitis. Epilepsy. Difficulty passing urine. Glaucoma (raised pressure inside the eyeball). Prostate trouble. Kidney or liver problems. Heart problems. A blocked intestine. Talk to your doctor or pharmacist if you are taking Other medicines which make you drowsy (e.g. sedatives or relaxants). MAOIs (monoamine oxidase inhibitors) for depression. Medicines which may give you a dry mouth or blurred vision (e.g. atropine or antidepressants). Pregnancy tests based on urine samples, as they may give false positive or negative results if used when taking this medicine. Pregnant or breastfeeding

Ask your doctor or pharmacist for advice before using this medicine if you are pregnant, might be pregnant or are breastfeeding.

Sominex should not be used in pregnancy unless the doctor has told you to do so.

Driving and using machines

These tablets will cause drowsiness and you should not drive or operate machinery until the effects have worn off.

Important information about some of the ingredients This product 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. How to use this medicine

Take this medicine by mouth

Adults, the elderly and children over 16 Take one tablet at bedtime. It may be taken up to one hour after going to bed when you can’t go to sleep. Do not use this medicine for more than 7 days in a row. If natural sleep does not return within 7 days or you have repeated bouts of sleeplessness talk to your doctor. Children under 16 years

Do not give to children under 16 unless your doctor tells you to.

If you take too many

If you accidentally take too many tablets, see a doctor straight away. Take the pack with you to show which medicine you have swallowed.

Possible side effects

Like all medicines, Sominex can have side effects, although these don’t affect everyone.

Important side effects

If you think you have any of the following side effects or symptoms, stop using this medicine immediately and see a doctor as soon as possible

Allergic reactions which cause difficulty in breathing, swelling of the mouth or skin, vomiting or stomach pain. Jaundice (yellowing of the skin and eyes). Palpitations or abnormal heart rhythm. Low blood pressure (dizziness and lightheadedness). Blurred or reduced vision or pain in the eye. Anaemia or listlessness and lack of energy. Other possible side effects Drowsiness. Dizziness. Headache. Clumsiness. Shaking and trembling. Stomach upsets. Dry mouth. Difficulty in passing urine. Restlessness. Disorientation. Sensitivity to sunlight.

If you notice these or any other side effect not included above, stop use and tell your doctor or pharmacist. They will tell you what to do.

Elderly people may be more susceptible to the side effects or confusion when taking this medicine.

Storing this medicine There are no special conditions for storing this medicine. Keep it out of the reach and sight of children. Do not use after the expiry date shown on the carton. The expiry date refers to the last day of that month. Medicine should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of any unused medicine. These measures will help to protect the environment. Further information What is in this medicine

The active ingredient per tablet is: promethazine hydrochloride 20mg

The other ingredients are: lactose, maize starch, croscarmellose sodium, magnesium stearate.

What the medicine looks like

Sominex tablets are white flat tablets with bevelled edges and are embossed ‘S’ on one side.

They are supplied in blister packs of 8 and 16 tablets.

Marketing authorisation holder Actavis Group PTC ehf Reykjav?kurvegi 76-78 220 Hafnarfjordur Iceland Manufacturer Custom Pharmaceuticals Ltd. Conway Street Hove East Sussex BN3 3LW

This leaflet was revised in October 2008

Sominex is a trade mark of Actavis Group PTC ehf.

CUSPL003

PM/20/311


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Nexium Tablets 20mg


1. Name Of The Medicinal Product

NEXIUM® 20 mg Tablets

2. Qualitative And Quantitative Composition

Each tablet contains: 20mg esomeprazole (as magnesium trihydrate).

For excipients see 6.1.

3. Pharmaceutical Form

Gastro-resistant tablet

20 mg: A light pink, oblong, biconvex, film-coated tablet engraved 20 mg on one side and

4. Clinical Particulars 4.1 Therapeutic Indications

NEXIUM tablets are indicated for:

Gastroesophageal Reflux Disease (GERD)

• treatment of erosive reflux esophagitis

• long-term management of patients with healed esophagitis to prevent relapse

• symptomatic treatment of gastroesophageal reflux disease (GERD)

In combination with an appropriate antibacterial therapeutic regimen for the eradication of Helicobacter pylori and

• healing of Helicobacter pylori associated duodenal ulcer and

• prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcers.

4.2 Posology And Method Of Administration

The tablets should be swallowed whole with liquid. The tablets should not be chewed or crushed.

Gastroesophageal Reflux Disease (GERD)

• treatment of erosive reflux esophagitis

40 mg once daily for 4 weeks.

An additional 4 weeks treatment is recommended for patients in whom esophagitis has not healed or who have persistent symptoms.

• long-term management of patients with healed esophagitis to prevent relapse

20 mg once daily.

• symptomatic treatment of gastroesophageal reflux disease (GERD)

20 mg once daily in patients without esophagitis. If symptom control has not been achieved after four weeks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using an on-demand regimen taking 20 mg once daily, when needed.

In combination with an appropriate antibacterial therapeutic regimen for the eradication of Helicobacter pylori and

• healing of Helicobacter pylori associated duodenal ulcer and

• prevention of relapse of peptic ulcers in patients with Helicobacter pylori associated ulcers.

20 mg NEXIUM with 1 g amoxicillin and 500 mg clarithromycin, all twice daily for 7 days.

Children

NEXIUM should not be used in children since no data is available.

Impaired renal function

Dose adjustment is not required in patients with impaired renal function. Due to limited experience in patients with severe renal insufficiency, such patients should be treated with caution. (See Section 5.2).

Impaired hepatic function

Dose adjustment is not required in patients with mild to moderate liver impairment. For patients with severe liver impairment, a maximum dose of 20 mg NEXIUM should not be exceeded. (See section 5.2).

Elderly

Dose adjustment is not required in the elderly.

4.3 Contraindications

Known hypersensitivity to esomeprazole, substituted benzimidazoles or any other constituents of the formulation.

4.4 Special Warnings And Precautions For Use

In the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with NEXIUM may alleviate symptoms and delay diagnosis.

Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.

Patients on on-demand treatment should be instructed to contact their physician if their symptoms change in character. When prescribing esomeprazole for on-demand therapy, the implications for interactions with other pharmaceuticals, due to fluctuating plasma concentrations of esomeprazole should be considered. See section 4.5

When prescribing esomeprazole for eradication of Helicobacter pylori possible drug interactions for all components in the triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4 and hence contraindications and interactions for clarithromycin should be considered when the triple therapy is used in patients concurrently taking other drugs metabolised via CYP3A4 such as cisapride.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects of esomeprazole on the pharmacokinetics of other drugs

The decreased intragastric acidity during treatment with esomeprazole, might increase or decrease the absorption of drugs if the mechanism of absorption is influenced by gastric acidity. In common with the use of other inhibitors of acid secretion or antacids, the absorption of ketoconazole and itraconazole can decrease during treatment with esomeprazole.

Esomeprazole inhibits CYP2C19, the major esomeprazole metabolising enzyme. Thus, when esomeprazole is combined with drugs metabolised by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin etc., the plasma concentrations of these drugs may be increased and a dose reduction could be needed. This should be considered especially when prescribing esomeprazole for on-demand therapy. Concomitant administration of 30 mg esomeprazole resulted in a 45% decrease in clearance of the CYP2C19 substrate diazepam. Concomitant administration of 40 mg esomeprazole resulted in a 13% increase in trough plasma levels of phenytoin in epileptic patients. It is recommended to monitor the plasma concentrations of phenytoin when treatment with esomeprazole is introduced or withdrawn.

In healthy volunteers, concomitant administration of 40 mg esomeprazole resulted in a 32% increase in area under the plasma concentration-time curve (AUC) and a 31% prolongation of elimination half-life(t1/2) but no significant increase in peak plasma levels of cisapride. The slightly prolonged QTc interval observed after administration of cisapride alone, was not further prolonged when cisapride was given in combination with esomeprazole (see also section 4.4).

Esomeprazole has been shown to have no clinically relevant effects on the pharmacokinetics of amoxicillin, quinidine or warfarin.

Effects of other drugs on the pharmacokinetics of esomeprazole

Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant administration of esomeprazole and a CYP3A4 inhibitor, clarithromycin (500 mg b.i.d.), resulted in a doubling of the exposure (AUC) to esomeprazole. Dose adjustment of esomeprazole is not required.

4.6 Pregnancy And Lactation

For esomeprazole no clinical data on exposed pregnancies are available. Animal studies with esomeprazole do not indicate direct or indirect harmful effects with respect to embryonal/fetal development. Animal studies with the racemic mixture do not indicate direct or indirect harmful effects with respect to pregnancy, parturition or postnatal development. Caution should be exercised when prescribing to pregnant women.

It is not known whether esomeprazole is excreted in human breast milk. No studies in lactating women have been performed. Therefore NEXIUM should not be used during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

No effects have been observed.

4.8 Undesirable Effects

The following adverse drug reactions have been identified or suspected in the clinical trials programme for esomeprazole. None was found to be dose-related.

Common

Headache, abdominal pain, diarrhoea, flatulence, nausea/vomiting, constipation.

(>1/100, <1/10)

 

 

 

 

 

Uncommon

Dermatitis, pruritus, urticaria, dizziness, dry mouth

(>1/1000, <1/100)

 

 

The following adverse drug reactions have been observed for the racemate (omeprazole) and may occur with esomeprazole:

Central and peripheral nervous system

Paraesthesia, somnolence, insomnia, vertigo. Reversible mental confusion, agitation, aggression, depression and hallucinations, predominantly in severely ill patients.

Endocrine

Gynaecomastia.

Gastrointestinal

Stomatitis and gastrointestinal candidiasis.

Haematological

Leukopenia, thrombocytopenia, agranulocytosis and pancytopenia.

Hepatic

Increased liver enzymes, encephalopathy in patients with pre-existing severe liver disease; hepatitis with or without jaundice, hepatic failure.

Musculoskeletal

Arthralgia, muscular weakness and myalgia.

Skin

Rash, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), alopecia.

Other

Malaise. Hypersensitivity reactions e.g. angioedema, fever, bronchospasm, interstitial nephritis and anaphylactic shock. Increased sweating, peripheral oedema, blurred vision, taste disturbance and hyponatraemia.

4.9 Overdose

There is no experience to date with deliberate overdose. Data are limited but single doses of 80 mg esomeprazole were uneventful. No specific antidote is known. Esomeprazole is extensively plasma protein bound and is therefore not readily dialyzable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

ATC Code: A02B C05

Esomeprazole is the S-isomer of omeprazole and reduces gastric acid secretion through a specific targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. Both the R- and S-isomer of omeprazole have similar pharmacodynamic activity.

Site and mechanism of action

Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H+K+-ATPase – the acid pump and inhibits both basal and stimulated acid secretion.

Effect on gastric acid secretion

After oral dosing with esomeprazole 20 mg and 40 mg the onset of effect occurs within one hour. After repeated administration with 20 mg esomeprazole once daily for five days, mean peak acid output after pentagastrin stimulation is decreased 90% when measured 6 – 7 hours after dosing on day five.

After five days of oral dosing with 20 mg and 40 mg of esomeprazole, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours, respectively over 24 hours in symptomatic GERD patients. The proportion of patients maintaining an intragastric pH above 4 for at least 8, 12 and 16 hours respectively were for esomeprazole 20 mg 76%, 54% and 24%. Corresponding proportions for esomeprazole 40 mg were 97%, 92% and 56%.

Using AUC as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown.

Therapeutic effects of acid inhibition

Healing of reflux esophagitis with esomeprazole 40 mg occurs in approximately 78% of patients after four weeks, and in 93% after eight weeks.

One week treatment with esomeprazole 20 mg b.i.d. and appropriate antibiotics, results in successful eradication of H. pylori in approximately 90% of patients.

After eradication treatment for one week there is no need for subsequent monotherapy with antisecretory drugs for effective ulcer healing and symptom resolution in uncomplicated duodenal ulcers.

Other effects related to acid inhibition

During treatment with antisecretory drugs serum gastrin increases in response to the decreased acid secretion.

An increased number of ECL cells possibly related to the increased serum gastrin levels, have been observed in some patients during long-term treatment with esomeprazole.

During long-term treatment with antisecretory drugs gastric glandular cysts have been reported to occur at a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.

5.2 Pharmacokinetic Properties

Absorption and distribution

Esomeprazole is acid labile and is administered orally as enteric-coated granules. In vivo conversion to the R-isomer is negligible. Absorption of esomeprazole is rapid, with peak plasma levels occurring approximately 1-2 hours after dose. The absolute bioavailability is 64% after a single dose of 40mg and increases to 89% after repeated once-daily administration. For 20mg esomeprazole the corresponding values are 50% and 68%, respectively. The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 L/kg body weight. Esomeprazole is 97% plasma protein bound.

Food intake both delays and decreases the absorption of esomeprazole although this has no significant influence on the effect of esomeprazole on intragastric acidity.

Metabolism and excretion

Esomeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxy- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma.

The parameters below reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive metabolisers.

Total plasma clearance is about 17 L/h after a single dose and about 9 L/h after repeated administration. The plasma elimination half-life is about 1.3 hours after repeated once-daily dosing. The area under the plasma concentration-time curve increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a non-linear dose-AUC relationship after repeated administration. This time - and dose-dependency is due to a decrease of first pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulphone metabolite. Esomeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration.

The major metabolites of esomeprazole have no effect on gastric acid secretion. Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the faeces. Less than 1% of the parent drug is found in urine.

Special patient populations

Approximately 1-2% of the population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of esomeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60%. These findings have no implications for the posology of esomeprazole.

The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years of age).

Following a single dose of 40mg esomeprazole the mean area under the plasma concentration-time curve is approximately 30% higher in females than in males. No gender difference is seen after repeated once-daily administration. These findings have no implications for the posology of esomeprazole.

The metabolism of esomeprazole in patients with mild to moderate liver dysfunction may be impaired. The metabolic rate is decreased in patients with severe liver dysfunction resulting in a doubling of the area under the plasma concentration-time curve of esomeprazole. Therefore, a maximum of 20mg should not be exceeded in patients with severe dysfunction. Esomeprazole or its major metabolites do not show any tendency to accumulate with once-daily dosing.

No studies have been performed in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.

5.3 Preclinical Safety Data

Preclinical bridging studies reveal no particular hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction. Carcinogenicity studies in the rat with the racemic mixture have shown gastric ECL-cell hyperplasia and carcinoids. These gastric effects in the rat are the result of sustained, pronounced hypergastrinaemia secondary to reduced production of gastric acid and are observed after long-term treatment in the rat with inhibitors of gastric acid secretion.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Glycerol monostearate 40-55, hydroxypropyl cellulose, hypromellose, iron oxide (reddish-brown, yellow) (E 172), magnesium stearate, methacrylic acid ethyl acrylate copolymer (1:1) dispersion 30 per cent, cellulose microcrystalline, synthetic paraffin, macrogol 6000, polysorbate 80, crospovidone, sodium stearyl fumarate, sugar spheres (sucrose and maize starch), talc, titanium dioxide (E 171), triethyl citrate.

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Keep the container tightly closed (bottle). Store in the original package (blister).

6.5 Nature And Contents Of Container

- Polyethylene bottle with a tamper proof, polypropylene screw cap equipped with a desiccant capsule.

- Aluminium blister package.

20 mg, 40 mg: Bottles of 2, 5, 7, 14, 15, 28, 30, 56, 60, 100, 140(5x28) tablets.

20 mg, 40 mg: Blister packs in wallet and/or carton of 3, 7, 7x1, 14, 15, 25x1, 28, 30, 50x1, 56, 60, 90, 98, 100x1, 140 tablets

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

AstraZeneca UK Limited

Kings Langley

Hertfordshire

WD4 8DH

United Kingdom

8. Marketing Authorisation Number(S)

PL 17901/0068

9. Date Of First Authorisation/Renewal Of The Authorisation

27th July 2000

10. Date Of Revision Of The Text

July 2000


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Diurexan 20mg Tablets


Diurexan 20 mg tablets

Xipamide

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. In this leaflet: 1. What Diurexan is for 2. Before you take Diurexan 3. How to take Diurexan 4. Possible side effects 5. How to store Diurexan 6. Further information What Diurexan is for

Diurexan belongs to the group of medicines known as diuretics. Diuretics are often referred to as water tablets.

Diurexan removes excess water from the body by increasing how often you urinate. It is used to treat high blood pressure (hypertension) and too much fluid in the body (oedema), often caused by heart failure or problems with your liver or kidneys.

Before you use Diurexan Do not take Diurexan if: You are allergic to Xipamide You are allergic to any of the other ingredients of Diurexan (listed in section 6) You have low levels of salts in your blood sometimes caused by severe vomiting or diarrhoea You have liver disease that is causing you to become unconscious You have severe kidney disease You have untreated Addison’s disease – a condition in which your adrenal glands do not produce sufficient levels of natural steroid in the blood You are less than 4 months’ pregnant.

If any of the above applies to you, talk to your doctor or pharmacist.

Check with your doctor before taking Diurexan if: You have gout or have too much uric acid in your urine You have diabetes You have kidney or liver disease You have an enlarged prostate gland or trouble urinating You suffer with coronary or cerebral arteriosclerosis (narrowing of the arteries in the heart or brain) Your body produces too much aldosterone, a hormone which controls salt and water balance (hyperaldosteronism) You have diarrhoea You are malnourished (a severe lack of food) You are being sick You are over 65 years of age. Tell your doctor if you are taking any of the following medicines: Medicines for high blood pressure Medicines called cardiac glycosides such as digoxin for heart problems Insulin or tablets for diabetes Lithium.

Taking these Diurexan at the same time as these medicines may lead to your doctor adjusting the dose you require.

Also tell your doctor if you are taking:

Steroids used to treat many conditions including asthma, arthritis, eczema and dermatitis ACTH which is mainly used to test if your pituitary gland is working properly Carbenoxolone used to treat stomach ulcers and inflammation of the oesophagus Amphotericin used to treat fungal and bacterial infections Laxatives.

These medicines may cause the level of potassium in your blood to fall when used at the same time as Diurexan.

Tell your doctor or pharmacist if you are taking any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

If you are pregnant, trying to become pregnant or breastfeeding ask your doctor or pharmacist for advice before taking Diurexan.

How to take Diurexan

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

Important:

Your doctor will choose the dose that is right for you. Your dose will be shown clearly on the label that your pharmacist puts on your medicine. If it does not, or you are not sure, ask your doctor or pharmacist.

For high blood pressure:

The usual dose is one tablet per day, taken early in the morning.

For excessive fluid retention:

The usual starting dose is two tablets per day, taken early in the morning.

Once your doctor has seen how the medicine is working, they may change your dose. They may reduce it to one tablet per day. If the medicine is not having much effect, your doctor may increase your dose to 3 or 4 tablets per day.

Medical check-ups

Taking Diurexan for a long time can cause you to lose potassium from your blood. Your doctor will check for this and may prescribe you extra potassium especially if you are elderly or getting little potassium in your diet.

If you take more Diurexan than you should

If you accidentally take too much Diurexan immediately go to the nearest hospital casaulty department or your doctor. An overdose may cause the loss of too much fluid from your body.

This can cause hypotension, making you feel faint and change the make-up of your blood.

You may have your stomach washed out and an infusion into your vein to replace lost fluids.

If you forget to take Diurexan

Do not take a double dose to make up for a missed dose. Simply take your dose as planned.

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

Possible side effects

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

These may include:

Slight dizziness Effects on your stomach or intestine such as stomach pain, constipation and diarrhoea Low potassium and sodium levels in blood (hypokalaemia and hyponatraemia respectively) which may cause headaches, muscle cramps and weakness.

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.

How to store Diurexan

Keep out of the reach and sight of children.

Do not use Diurexan 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. Return any medicine you no longer need to your pharmacist.

Further information What Diurexan contains

The active substance is xipamide. Each tablet contains 20 mg of xipamide.

The other ingredients are maize starch, mannitol, cellulose powder, colloidal silicon dioxide, magnesium stearate and purified water.

What Diurexan looks like

Diurexan tablets are white and round with a notch on one side and an "A" on the other. They are about 6 mm in diameter. They come in blister strips strips of 14 tablets with 10 blister strips in a box.

Marketing Authorisation Holder is: Meda Pharmaceuticals Ltd Skyway House Parsonage Road Takeley Bishop’s Stortford CM22 6PU United Kingdom Manufacturer is: Sidefarma, S.A. Rua da Guin?, n? 26 2689-514 Prior Velho PORTUGAL

This leaflet was last updated on September 2008

If this leaflet is difficult to see or read and you would like it in a different format, please contact

Meda Pharmaceuticals Skyway House Parsonage Road Takeley Bishop’s Stortford CM22 6PU United Kingdom
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Cardene 20mg and 30mg capsules


UK

Cardene 20 mg and 30 mg capsules

Nicardipine hydrochloride

Please read this leaflet carefully before you start to take your medicine.

If you have any questions or are not sure about anything, ask your doctor or pharmacist.

What is Cardene?

Cardene contains the active ingredient nicardipine hydrochloride which belongs to the class of drugs called calcium channel blockers. These cause relaxation of the smooth muscle of the blood vessels causing these vessels to widen or dilate.

Cardene capsules come in two strengths. Each capsule contains either 20 mg or 30 mg of nicardipine hydrochloride.

The 20 mg capsule is coloured blue and white. The 30 mg capsule is coloured blue and pale blue.

They also contain the additional ingredients: starch, magnesium stearate, gelatin, indigotine E132, titanium dioxide El71.

Both strengths of capsules are available in packs of 56.

The Product Licence holder is

Astellas Pharma Limited Lovett House Lovett Road Staines Middx TW18 3AZ UK

This medicine is made by

Farmasierra, S.A. Carretera de Ir?n Km. 26,200 San Sebasti?n de los Reyes 28700 Madrid Spain

The site where batch release takes place is

Astellas Pharma Europe BV Hogemaat 2 Meppel The Netherlands What is Cardene used for?

Your medicine is used for the treatment of mild to moderate high blood pressure (hypertension) and to help prevent attacks of chest pain diagnosed by your doctor as chronic stable angina. Chronic stable angina is a pattern of attacks of chest pain that are predictable and reproducible under certain conditions such as after exercise, stress or in cold weather. They are short in duration and can be relieved by rest or certain drugs.

When must Cardene not be used? If you are allergic to nicardipine or other dihydropyridines, or any of the ingredients Cardene contains. If you have had a recent heart attack (ie. within the last month), or a condition called advanced aortic stenosis which is narrowing of your aortic heart valve. If your chest pain is diagnosed by your doctor as unstable angina. For example, if the pattern of attacks of chest pain changes and occur without exertion, you should contact your doctor immediately. If you need immediate relief of chest pain in a sudden or acute angina attack. This situation should be treated with a different class of medicine. to try to prevent the occurrence of future heart attacks (if you have already had at least one heart attack). Cardene is not recommended for patients under the age of 18. When should you be extra careful when using/while taking Cardene?

Make sure your doctor knows if you:

have a heart, liver or kidney condition, or have had a stroke. are taking other medicines including those not prescribed by your doctor. This is extremely important, as using more than one medicine at the same time can strengthen or weaken the effect of either Cardene or other medicines. Examples of such effects have been reported for Cardene when also taking digoxin, cimetidine, cyclosporin and other blood pressure lowering drugs amongst other medicines. Rifampicin or grapefruit juice should not be taken with Cardene, since they could also interact and alter the effects of Cardene. are about to undergo an operation. You must tell the doctors in the hospital that you are taking Cardene. if you experience sudden dizziness, light-headedness or palpitations on treatment with Cardene, let your doctor know. Sometimes Cardene can cause too great a fall in blood pressure which, if not dealt with, could damage your heart or brain. May Cardene be used during pregnancy or while breast feeding? You should NOT take these capsules if you are pregnant. You must tell your doctor if you are pregnant, if you think you are pregnant or if you intend to become pregnant. You should NOT breast feed if you are taking these capsules. How should Cardene be taken? Always take your medicine exactly as your doctor tells you to and do not stop treatment unless he/she tells you to do so: The usual dose is 20-30 mg, every 8 hours. Your doctor may vary this according to your symptoms and blood pressure. The label will tell you how much to take and how often. If you are not sure, ask your doctor or pharmacist. Capsules should be swallowed with a glass of water, preferably at the same time each day. (NB. Do not use grapefruit juice). If you forget to take a dose, take another dose as soon as you remember provided there are at least 3 hours between doses. If this is not possible, do not take the missed dose. Do not take two doses together. Do not change the prescribed dose of your medicine yourself. If you think the effect of your medicine is too weak or too strong, talk to your doctor If you take too many capsules or someone else accidentally takes your medicine, contact your doctor, pharmacist or nearest hospital straight away. What are the possible unwanted effects of Cardene?

This medicine sometimes causes side-effects. These are usually mild and tend to pass with time, but if they trouble you consult your doctor.

Common side effects are:

Headache, ankle swelling (oedema), heat sensation, facial flushing, sensation of fast heart beats (palpitations), nausea, dizziness.

In some patients Cardene may cause an attack of angina (chest pain) shortly after first starting to take the capsules. If this happens to you, do not take any further doses and contact your doctor. In addition a few patients experience an increase in the severity or frequency of chest pain during treatment with Cardene. If this happens to you, you must inform your doctor as soon as possible.

Other less frequent side-effects include heart complaints, drowsiness, sleeplessness, ringing in the ears, pins and needles, psychological upset, itching, rashes, diffculty in passing urine or an increase in passing urine, shortness of breath, stomach upsets, and rarely, depression, increase in bruising and impotence.

If you are concerned about these or any other unwanted effects talk to your doctor.

How should Cardene be stored? Keep this medicine out of the reach and sight of children. Do not store above 25 °C. This medicine must not be used after the date (EXP) printed on the pack. Return any left over medicine to your pharmacist. Only keep it if your doctor tells you to. REMEMBER this medicine is for you. Only a doctor can prescribe it for you. Never give it to others. It may harm them even if their symptoms are the same as yours. Further information:

You can get more information on Cardene from your doctor or pharmacist.

Date of last review

July 2005

118143

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Kolanticon Gel


1. Name Of The Medicinal Product

Kolanticon Gel

2. Qualitative And Quantitative Composition

Kolanticon Gel is a white viscous suspension containing 2.5mg dicycloverine hydrochloride, 200mg aluminium hydroxide, 100mg light magnesium oxide, 20mg simethicone per 5ml.

3. Pharmaceutical Form

Suspension for oral administration.

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment and prophylaxis of symptoms of peptic ulcer and functional dyspepsia especially in patients in whom gastric distress results from hyperacidity, smooth muscle spasm, including irritable bowel syndrome (IBS), and flatulence. Also indicated for symptomatic relief in oesophagitis, hiatus hernia, gastritis and iatrogenic gastritis.

4.2 Posology And Method Of Administration

Two to four 5ml spoonfuls every four hours as required.

4.3 Contraindications

Known idiosyncrasy to any of the ingredients. Should not be used in patients with prostatic enlargement, glaucoma, obstructive uropathy, obstructive disease of the gastro-intestinal tract, paralytic ileus and intestinal atony, severe ulcerative colitis, and myasthenia gravis.

4.4 Special Warnings And Precautions For Use

In the presence of renal insufficiency magnesium salts may cause central nervous system depression. Aluminium hydroxide in the presence of low phosphorous diets may cause phosphorous deficiency. Aluminium hydroxide may reduce absorption of tetrayclines when given concomitantly. Use with care in patients with hiatus hernia associated with reflux oesophagitis because anticholinergic drugs may aggravate this condition.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Antacids may interfere with the absorption of tetracyclines, ACE inhibitors, digoxin, rifampicin, ketoconazole, penicillamine, ciprofloxacin (and other quinolones), anticoagulants and biphosphonates, if given concurrently. Because of the large number of possible interactions they should not be given at the same time as any other drugs.

4.6 Pregnancy And Lactation

Epidemiological studies in pregnant women with products containing dicycloverine hydrochloride (at doses up to 40mg/day) have not shown that dicycloverine increases the risk of foetal abnormalities if administered during the first trimester of pregnancy. Reproduction studies have been performed in rats and rabbits at doses of up to 100 times the maximum recommended dose (based on 60mg per day for an adult person) and have revealed no evidence of impaired fertility or harm to the foetus due to dicycloverine.

For aluminium hydroxide, magnesium oxide and simethicone no clinical data on exposed pregnancies are available.

Caution should be exercised when prescribing to pregnant women.

Since the risk of teratogenicity cannot be excluded with absolute certainty for any product, the drug should be used during pregnancy only if clearly needed.

It is not known whether dicycloverine is secreted into human milk. Because many drugs are excreted in human milk, caution should be exercised when dicycloverine is administered to a nursing woman.

4.7 Effects On Ability To Drive And Use Machines

None known

4.8 Undesirable Effects

In particularly sensitive patients dicycloverine hydrochloride may cause atropine-like

side-effects such as dry mouth, blurred vision, urinary retention or constipation.

4.9 Overdose

Signs and symptoms of dicycloverine hydrochloride overdose include: headache, nausea and vomiting, blurred vision, dilated pupils, hot dry skin, dizziness, vertigo, dryness of mouth, difficulty in swallowing and CNS stimulation.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Dicycloverine hydrochloride:

anticholinergic agent used as an antispasmodic; also has direct antispasmodic activity.

Aluminium hydroxide dried gel, magnesium hydroxide are antacids.

 

Simethicone:

antiflatulent

5.2 Pharmacokinetic Properties

Dicycloverine hydrochloride:

Dicycloverine hydrochloride when given orally was rapidly and completely absorbed and the drug and/or its metabolites were found in the urine (dominant route of elimination) within 1 hour after drug ingestion. Plasma half-life of 4-6 hours was found for dicycloverine and/or its metabolites.

Antacids:

Act by local action in the stomach by neutralising stomach acid and are largely unabsorbed.

5.3 Preclinical Safety Data

None applicable.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Kolanticon Gel contains magnesium sulphate, methylcellulose 450, benzyl alcohol, sodium lauryl sulphate, saccharin sodium, alcohol 95%, methylparaben, propylparaben, butylparaben., citric acid, oil of cinnamon, oil of peppermint, oil of spearmint, oil of cedar leaf, oil of nutmeg, menthol and eucalyptol.

6.2 Incompatibilities

None known

6.3 Shelf Life

36 Months

6.4 Special Precautions For Storage

Store below 25°C

6.5 Nature And Contents Of Container

Amber glass bottles of 200 and 500ml

6.6 Special Precautions For Disposal And Other Handling

Shake well before use.

Administrative Data 7. Marketing Authorisation Holder

Peckforton Pharmaceuticals Ltd,

Crewe Hall,

Crewe,

Cheshire,

CW1 6UL.

United Kingdom

8. Marketing Authorisation Number(S)

PL 15760/0004

9. Date Of First Authorisation/Renewal Of The Authorisation

15 October 1999

10. Date Of Revision Of The Text

June 2007

11. Legal Category

P


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Xigris 20mg powder for solution for infusion, 5mg powder for solution for infusion


1. Name Of The Medicinal Product

Xigris* 5mg powder for solution for infusion.

Xigris 20mg powder for solution for infusion.

2. Qualitative And Quantitative Composition

Xigris 5mg: Each vial contains 5mg of Drotrecogin alfa (activated).

After reconstitution with 2.5ml of Water for Injection each ml contains 2mg of Drotrecogin alfa (activated).

Excipient: Each vial contains approximately 17mg sodium.

Xigris 20mg: Each vial contains 20mg of drotrecogin alfa (activated).

After reconstitution with 10ml of Water for Injection, each ml contains 2mg of Drotrecogin alfa (activated).

Excipient: Each vial contains approximately 68mg sodium.

Drotrecogin alfa (activated) is a recombinant version of the endogenous activated Protein C and is produced by genetic engineering from an established human cell line.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder for solution for infusion. Xigris is supplied as a lyophilised, white to off-white powder.

4. Clinical Particulars 4.1 Therapeutic Indications

Xigris is indicated for the treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care. The use of Xigris should be considered mainly in situations when therapy can be started within 24 hours after the onset of organ failure (for further information see section 5.1).

4.2 Posology And Method Of Administration

Xigris should be used by experienced doctors in institutions skilled in the care of patients with severe sepsis.

Treatment should be started within 48 hours, and preferably within 24 hours, of onset of the first documented sepsis-induced organ dysfunction (see section 5.1).

The recommended dose of Xigris is 24?g/kg/hr (based on actual body weight) given as a continuous intravenous infusion for a total duration of 96 hours. It is recommended that Xigris be infused with an infusion pump to accurately control the infusion rate. If the infusion is interrupted for any reason, Xigris should be restarted at the 24?g/kg/hr infusion rate and continued to complete the full recommended 96 hours of dosing administration. Dose escalation or bolus doses of Xigris are not necessary to account for the interruption in the infusion.

No dose adjustments are required in adult patients with severe sepsis with regard to age, gender, hepatic function (as measured by transaminase levels), renal function, obesity or co-administration of prophylactic heparin. The pharmacokinetics of drotrecogin alfa (activated) have not been studied in patients with severe sepsis and pre-existing end-stage renal disease and chronic hepatic disease.

Paediatrics: Data from a placebo-controlled clinical trial, which was stopped for futility after 477 patients 0 to 17 years old had received the study treatment, did not establish efficacy of Xigris in paediatric patients and showed a higher rate of central nervous system bleeding in the Xigris versus placebo group. Xigris is contraindicated in children below the age of 18 (see sections 4.3 and 5.1).

4.3 Contraindications

Hypersensitivity to the active substance, to any of the excipients, or to bovine thrombin (a trace residue from the manufacturing process).

Drotrecogin alfa (activated) is contraindicated in children below the age of 18 years (see section 5.1).

Because drotrecogin alfa (activated) may increase the risk of bleeding, Xigris is contraindicated in the following situations:

• Active internal bleeding.

• Patients with intracranial pathology; neoplasm or evidence of cerebral herniation.

• Concurrent heparin therapy

• Known bleeding diathesis except for acute coagulopathy related to sepsis.

• Chronic severe hepatic disease.

• Platelet count <30,000 x 106 /l, even if the platelet count is increased after transfusions.

• Patients at increased risk for bleeding (for example):

a) Any major surgery, defined as surgery that requires general or spinal anaesthesia, performed within the 12-hour period immediately preceding drug infusion, or any postoperative patient who demonstrates evidence of active bleeding, or any patient with planned or anticipated surgery during the drug infusion period.

b) History of severe head trauma that required hospitalisation, intracranial or intraspinal surgery, or haemorrhagic stroke within the previous 3 months, or any history of intracerebral arteriovenous malformation, cerebral aneurysm, or central nervous system mass lesion; patients with an epidural catheter or who are anticipated to receive an epidural catheter during drug infusion.

c) History of congenital bleeding diatheses.

d) Gastro-intestinal bleeding within the last 6 weeks that has required medical intervention unless definitive surgery has been performed.

e) Trauma patients at increased risk of bleeding.

 

4.4 Special Warnings And Precautions For Use

No further study has confirmed the efficacy results of the single pivotal trial.

Patients With Single Organ Dysfunction and Recent Surgery

Xigris is not approved for the treatment of patients with single organ dysfunction and should not be used in this particular subgroup of patients, especially if they had recent surgery (within 30 days). In each of two randomised, placebo-controlled trials, PROWESS and ADDRESS (see section 5.1), 28-day and in-hospital mortality were higher in patients treated with drotrecogin alfa (activated) compared to placebo for the sub-population of patients with single organ dysfunction and recent surgery (n = 98 in PROWESS and n = 636 in ADDRESS).

Bleeding

Drotrecogin alfa (activated) increases the risk of bleeding. In the following conditions, the risks of the administration of Xigris should be weighed against the anticipated benefits:

• Recent administration (within 3 days) of thrombolytic therapy.

• Recent administration (within 7 days) of oral anticoagulants.

• Recent administration (within 7 days) of aspirin or other platelet inhibitors.

• Recent (within 3 months) ischaemic stroke.

• Any other condition in which the physician considers significant bleeding is likely.

For procedures with an inherent bleeding risk, discontinue Xigris for 2 hours prior to the start of the procedure. Xigris may be restarted 12 hours after major invasive procedures or surgery if adequate haemostasis has been achieved. The incidence of serious bleeding events with Xigris was higher in patients with recent (within 30 days) surgery than in “medical” patients without surgery (see section 4.8). Bleeding risk should be taken into account when considering the risk benefit for individual patients. Xigris may be restarted immediately after uncomplicated less invasive procedures if adequate haemostasis has been achieved.

As a component of routine care, measures of haemostasis (e.g., activated partial thromboplastin time [APTT], prothrombin time [PT], and platelet count) should be obtained during the infusion of Xigris. If sequential tests of haemostasis indicate an uncontrolled or worsening coagulopathy that significantly increases the risk of bleeding, the benefits of continuing the infusion must be weighed against the potential increased risk of bleeding for that patient.

Laboratory Tests

Drotrecogin alfa (activated) has minimal effect on the PT. Prolongation of the APTT in patients with severe sepsis receiving Xigris may be due to the underlying coagulopathy, the pharmacodynamic effect of drotrecogin alfa (activated), and/or the effect of other concurrent medicinal products. The pharmacodynamic effect of drotrecogin alfa (activated) on the APTT assay is dependent on the reagent and instrument used to perform the assay and the time that elapses between sample acquisition and assay performance. Drotrecogin alfa (activated) that is present in a blood or plasma sample drawn from a patient who is being infused with the drug will be gradually neutralised by endogenous plasma protease inhibitors present in the sample. Virtually no measurable activity of drotrecogin alfa (activated) is present 2 hours after obtaining the blood sample. Due to these biological and analytical variables, the APTT should not be used to assess the pharmacodynamic effect of drotrecogin alfa (activated). In addition, approximately 2 hours after terminating the infusion of the drug, there is virtually no measurable activity of drotrecogin alfa (activated) remaining in the circulation of the patient; blood samples drawn for APTT determination after this point are no longer affected by the drug. The interpretation of sequential determinations of the PT and/or APTT should take these variables into consideration.

Because drotrecogin alfa (activated) may affect the APTT assays, drotrecogin alfa (activated) present in plasma samples may interfere with one-stage coagulation assays based on the APTT (such as Factor VIII, IX, and XI assays). Drotrecogin alfa (activated) present in plasma samples does not interfere with one-stage factor assays based on the PT (such as Factor II, V, VII and X assays).

If sequential measures of coagulopathy (including platelet count) indicate severe or worsening coagulopathy, the risk of continuing the infusion should be weighed against the expected benefit.

Immunogenicity

In adult patients in severe sepsis clinical studies, the frequency of anti-human Activated Protein C IgA/IgG/IgM antibodies or neutralising antibodies is low and is similar between drotrecogin alfa (activated) and placebo-treated patients tested. In patients developing antibodies, adverse events were not more frequent in drotrecogin alfa (activated) than in placebo patients. There was no evidence that the antibodies detected represented a specific immune response to drotrecogin alfa (activated) therapy.

There have been no clinical trials in severe sepsis specifically studying drotrecogin alfa (activated) re-administration. However, a small number of patients in severe sepsis controlled clinical trials received a prior course of drotrecogin alfa (activated). No hypersensitivity reactions were reported in these patients. Samples available were subsequently tested and all were negative for anti-human Activated Protein C antibody.

No anti-activated Protein C antibody formation was detected in healthy subjects, even after repeat administration.

However, the possibility of allergic reactions to constituents of the preparation cannot be completely excluded in certain predisposed patients. If allergic or anaphylactic reactions occur, treatment should be discontinued immediately and appropriate therapy initiated. If Xigris is readministered to patients, caution should be employed.

Xigris 5mg: This medicinal product contains approximately 17mg sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

Xigris 20mg: This medicinal product contains approximately 68mg sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Caution should be employed when Xigris is used with other drugs that affect haemostasis (see sections 4.3 and 4.4), including Protein C, thrombolytics (e.g., streptokinase, tPA, rPA and urokinase), oral anticoagulants (e.g., warfarin), hirudins, antithrombin, aspirin and other anti-platelets agents, e.g., non-steroidal anti-inflammatory drugs, ticlopidine and clopidogrel, glycoprotein IIb/IIIa antagonists (such as abciximab, eptifibatide, tirofiban) and prostacyclins, such as iloprost.

Co-administration of Low-dose Heparin for Prophylaxis of Venous Thrombotic Events (VTE)

Low-dose heparin for VTE prophylaxis may be co-administered with drotrecogin alfa (activated). In a randomised study of heparin versus placebo (XPRESS) in 1,935 adult severe sepsis patients, all treated with drotrecogin alfa (activated), prophylactic heparin did not adversely affect mortality (heparin 28.3% versus placebo 31.9% in the overall ITT population, and heparin 30.3% versus placebo 26.9% in patients with multiple organ dysfunction treated within 24 hours of their first sepsis-induced organ dysfunction (n=890)). In the subgroup of 885 patients who were already receiving prophylactic heparin at study entry, mortality was 26.9% in the group randomised to continue heparin versus 35.6% in the group whose randomisation (to placebo) led to the discontinuation of heparin. However, the reasons for this difference are unknown and could be related to other factors. Additionally, there was no increased risk of serious bleeding, including central nervous system (CNS) bleeding. Prophylactic heparin increased the risk of non-serious bleeding (see section 4.8). There was no statistical difference in the rates of VTE between study arms.

4.6 Pregnancy And Lactation

Animal studies with respect to effects on pregnancy, embryonal/foetal development, parturition, and post-natal development have not been conducted with Xigris. Therefore, the potential risk for humans is unknown. Xigris should not be used during pregnancy unless clearly necessary.

It is not known whether Xigris is excreted in human milk or if there is a potential effect on the breast-fed infant. Therefore, the patient should not breast-feed whilst treated with Xigris.

4.7 Effects On Ability To Drive And Use Machines

Not relevant.

4.8 Undesirable Effects

Xigris increases the risk of bleeding.

The Phase 3 international, multi-centre, randomised, double-blind, placebo-controlled clinical trial (PROWESS) involved 850 drotrecogin alfa (activated)-treated and 840 placebo-treated patients. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 24.9% and 17.7%, respectively. In both treatment groups, the majority of bleeding events were ecchymosis or gastro-intestinal tract bleeding. The difference in the incidence of serious bleeding events between the two treatment groups occurred primarily during study drug administration.

A total of 2,378 adult patients with severe sepsis received drotrecogin alfa (activated) in a Phase 3b, international, single-arm, open-label clinical trial (ENHANCE).

The incidence of serious bleeding events in the PROWESS and ENHANCE studies is provided below. In these studies, serious bleeding events included any intracranial haemorrhage, any life-threatening or fatal bleed, any bleeding event requiring the administration of

A Phase 3b, international, multi-centre, randomised, double-blind, placebo-controlled clinical trial (ADDRESS) of adult severe sepsis patients at low risk of death involved 1,317 drotrecogin alfa (activated)-treated and 1,293 placebo-treated patients. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 10.9% and 6.4%, respectively (P <0.001). Bleeding events included serious bleeding events, bleeding events assessed as possibly study drug related by the investigator, bleeding events associated with the need for a red blood cell transfusion, and bleeding events that led to permanent discontinuation of the study drug. In the ADDRESS trial, serious bleeding events included any fatal bleed, any life-threatening bleed, any CNS bleed, or any bleeding event assessed as serious by the investigator.

Serious Bleeding Events During the Infusion Period

The following table lists the percentage of patients in PROWESS and ENHANCE experiencing serious bleeding events by site of haemorrhage during the study drug infusion period (defined as the duration of infusion plus the next full calendar day following the end of the infusion).

Site of Haemorrhage

Drotrecogin Alfa

(Activated)

[PROWESS]

n = 850

Placebo

[PROWESS]

n = 840

Drotrecogin Alfa

(Activated)

[ENHANCE]

n = 2,378

Gastro-intestinal

5 (0.6%)

4 (0.5%)

19 (0.8%)

Intra-abdominal

2 (0.2%)

3 (0.4%)

18 (0.8%)

Intra-thoracic

4 (0.5%)

0

11 (0.5%)

Retroperitoneal

3 (0.4%)

0

4 (0.2%)

Central nervous system (CNS)1

2 (0.2%)

0

15 (0.6%)

Genito-urinary

2 (0.2%)

0

0

Skin/soft tissue

1 (0.1%)

0

16 (0.7%)

Nasopharyngeal

0

0

4 (0.2%)

Joint/bone

0

0

1 (0.04%)

Site unknown2

1 (0.1%)

1 (0.1%)

6 (0.3%)

Total

20 (2.4%)

8 (1.0%)

853 (3.6%)

 

1 CNS bleeding is defined as any bleed in the central nervous system, including the following types of haemorrhage: petechial, parenchymal, subarachnoid, subdural, and stroke with haemorrhagic transformation.

2 Patients requiring the administration of

3 In ENHANCE, six patients experienced multiple serious bleeding events during the study drug infusion period (94 events observed in 85 patients).

     

During the infusion period in PROWESS and ENHANCE, the incidence of serious bleeding events with Xigris was numerically higher in patients with recent (within 30 days) surgery than in patients without surgery (PROWESS: 3.3% versus 2.0%; ENHANCE: 5.0% versus 3.1% respectively. Placebo rates in PROWESS 0.4% versus 1.2% respectively).

In ADDRESS, the percentage of treated patients experiencing a serious bleeding event by site of haemorrhage was similar to that observed in PROWESS. The incidence of serious bleeding events during infusion (defined as study day 0 through study day 6) was 31 (2.4%) and 15 (1.2%) in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively (P = 0.02). The incidence of CNS bleeds during infusion was 4 (0.3%) and 3 (0.2%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. Recent surgery (within 30 days prior to study entry) was associated with a numerically higher risk of serious bleeding during infusion in both the Xigris-treated and the placebo-treated patients (Xigris: 3.6% in patients with recent surgery versus 1.6% in patients without recent surgery; placebo: 1.6% versus 0.9%, respectively).

In XPRESS, a randomised study of prophylactic heparin versus placebo in adult severe sepsis patients, all treated with drotrecogin alfa (activated), serious bleeding rates were consistent with those observed in previous studies over the treatment period of 0-6 days, and prophylactic heparin did not increase the risk of serious bleeding compared to placebo (2.3% versus 2.5%, respectively), including CNS bleeding (0.3% on both arms). However, prophylactic heparin increased the risk of non-serious bleeding compared with placebo (8.7% versus 5.7%, respectively; P = 0.0116).

Serious Bleeding Events During the 28-Day Study Period

In PROWESS, the incidence of serious bleeding events during the 28-day study period was 3.5% and 2.0% in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. The incidence of CNS bleeds during the 28-day study period was 0.2% and 0.1% for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively. The risk of CNS bleeding may increase with severe coagulopathy and severe thrombocytopenia (see sections 4.3 and 4.4).

In the open-label ENHANCE study, the incidence of serious bleeding events during the 28-day study period was 6.5%, and the incidence of CNS bleeds during the 28-day study period was 1.5%.

In the placebo-controlled ADDRESS study, the incidence of serious bleeding events during the 28-day study period was 51 (3.9%) and 28 (2.2%) in drotrecogin alfa (activated)-treated and placebo-treated patients, respectively (P = 0.01). The incidence of CNS bleeds during the 28-day study period was 6 (0.5%) and 5 (0.4%) for drotrecogin alfa (activated)-treated and placebo-treated patients, respectively.

In XPRESS, serious bleeding rates were consistent with those observed in previous studies during the 28-day study period (days 0-28). Prophylactic heparin did not increase the risk of serious bleeding compared to placebo (3.9% versus 5.2%, respectively), including CNS bleeding (1.0% versus 0.7%, respectively).

In the Phase 1 studies, adverse events with a frequency of

4.9 Overdose

In clinical trials and in post-marketing experience there have been reports of accidental overdosing. In the majority of cases, no reactions have been observed. For the other reports, the observed events were consistent with known undesirable effects of the drug (see section 4.8), effects of the drug on laboratory tests (see section 4.4), or consequences of the underlying condition of sepsis.

There is no known antidote for drotrecogin alfa (activated). In case of overdose, immediately stop the infusion (see section 5.2).

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antithrombotic agents, enzymes. ATC code: B01AD10.

This medicinal product has been authorised under “Exceptional Circumstances”. This means that for scientific reasons it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMEA) will review any new information which may become available every year, and this SPC will be updated as necessary.

Mechanism of Action

Xigris is a recombinant version of the natural plasma-derived Activated Protein C, from which it differs only by unique oligosaccharides in the carbohydrate portion of the molecule. Activated Protein C is a crucial coagulation regulator. It limits thrombin formation by inactivating Factors Va and VIIIa, thereby providing negative feedback regulation of coagulation. Excessive coagulation activation in the microcirculatory bed plays a significant part in the pathophysiology of severe sepsis. Furthermore, Activated Protein C is an important modulator of the systemic response to infection and has antithrombotic and profibrinolytic properties. Xigris has similar properties to those of endogenous human Activated Protein C.

Pharmacodynamic Effects

In placebo-controlled clinical trials in patients with severe sepsis, Xigris exerted an antithrombotic effect by limiting thrombin generation and improved sepsis-associated coagulopathy, as shown by a more rapid improvement in markers of coagulation and fibrinolysis. Xigris caused a more rapid decline in thrombotic markers, such as D-dimer, prothrombin F1.2, and thrombin-antithrombin levels, and a more rapid increase in Protein C and antithrombin levels. Xigris also restored endogenous fibrinolytic potential, as evidenced by a more rapid trend toward normalisation in plasminogen levels and a more rapid decline in plasminogen activator inhibitor-1 levels. Additionally, patients with severe sepsis treated with Xigris had a more rapid decline in interleukin-6 levels, a global marker of inflammation, consistent with a reduction in the inflammatory response.

Clinical Efficacy

Xigris was studied in one Phase 3, international, multi-centre, randomised, double-blind, placebo-controlled trial (PROWESS) in 1,690 patients with severe sepsis. Severe sepsis is defined as sepsis associated with acute organ dysfunction. Patients meeting the clinical diagnosis of severe sepsis had: a) known or suspected infection; b) clinical evidence of systemic response to infection, including fever or hypothermia, leucopenia or leucocytosis, tachycardia and tachypnoea; and c) acute organ dysfunction. Organ dysfunction was defined as shock, hypotension or the need for vasopressor support despite adequate fluid resuscitation, relative hypoxemia (ratio of partial pressure of oxygen in arterial blood in mmHg to the percentage of oxygen in the inspired air expressed as a decimal [PaO2/FiO2 ratio] <250), oliguria despite adequate fluid resuscitation, marked reduction in blood platelet counts, and/or elevated lactic acid concentrations.

Exclusion criteria encompassed patients at high risk of bleeding (see sections 4.3 and 4.4), patients who were not expected to survive for 28 days due to a pre-existing, non-sepsis related medical condition, HIV positive patients whose most recent CD4 count was 3, patients on chronic dialysis, and patients who had undergone bone marrow, lung, liver, pancreas, or small bowel transplantation, and patients with acute clinical pancreatitis without a proven source of infection.

In the PROWESS trial, treatment was initiated within 48 hours of onset of the first sepsis-induced organ dysfunction. The median duration of organ dysfunction prior to treatment was 18 hours. Patients were given a 96-hour constant rate infusion of Xigris at 24?g/kg/hr (n = 850) or placebo (n = 840). Xigris was added to best standard care. Best standard care includes adequate antibiotics, source control and supportive treatment (fluids, inotropes, vasopressors and support of failing organs, as required).

Patients treated with Xigris experienced improved 28-day survival compared to those treated with placebo. At 28 days, the overall mortality rates were 24.7% for the Xigris-treated group and 30.8% for the placebo-treated group (P = 0.005).

Significant absolute death reduction was limited to the subgroup of patients with greater disease severity, i.e., baseline APACHE II score

A consistent treatment effect on mortality with Xigris administration was observed across patient subgroups defined by age, gender, and infection type.

PROWESS Follow-Up Study

Survival status was assessed in a follow-up study of PROWESS survivors. In-hospital and 3-month survival status was reported for 98% and 94% of the 1,690 PROWESS subjects, respectively. In the overall population, the in-hospital mortality was significantly lower in patients on Xigris than in patients on placebo (29.4% versus 34.6%; P = 0.023). Survival through 3 months was also better in the Xigris group compared to placebo (log rank P = 0.048). These data confirmed that the benefit of Xigris is limited to the more severely affected sepsis patients, such as patients with multiple organ failure and shock.

Further Clinical Experience

In a Phase 3b, international, single-arm, open-label clinical trial (ENHANCE), 2,378 adult patients with severe sepsis received drotrecogin alfa (activated). The entry criteria were similar to those employed in PROWESS. Patients received drotrecogin alfa (activated) within 48 hours of onset of the first sepsis-induced organ dysfunction. The median duration of organ dysfunction prior to treatment was 25 hours. At 28 days, the mortality rate in the Phase 3b study was 25.3%. The mortality rate was lower for patients treated within 24 hours of organ dysfunction compared to those treated after 24 hours, even after adjustment for differences in disease severity.

A total of 2,640 adult patients with severe sepsis who were at low risk of death (e.g., patients with APACHE II <25 or with only one sepsis-induced organ failure) were enrolled in a randomised, double-blind, placebo-controlled trial (ADDRESS). The trial was stopped for futility after an interim analysis.

No benefit of drotrecogin alfa (activated) was observed in the subgroup of 872 patients at low risk of death with multiple organ dysfunction, so ADDRESS did not confirm the efficacy results of the PROWESS study.

In the multiple organ dysfunction subgroup of ADDRESS the 28-day placebo mortality was 21.9%, similar to the single organ dysfunction subgroup of PROWESS (21.2%), confirming the lack of efficacy in patients with severe sepsis who are at low risk of death.

Paediatric Patients

Xigris is contraindicated in children below the age of 18 years (see also sections 4.2 and 4.3).

Data from a placebo-controlled clinical trial (RESOLVE) did not establish efficacy of Xigris in paediatric patients suffering from severe sepsis, acute infection, systemic inflammation and respiratory and cardiovascular organ dysfunction. This trial was stopped for futility after 477 patients had received the study drug (out of 600 patients intended). A planned interim analysis (with 400 patients enrolled) showed a low likelihood of demonstrating a significant difference in the primary endpoint of “Composite Time to Complete Organ Failure Resolution” (CTCOFR score of 9.8 versus 9.7 mean days over 14 days). There was also no difference in 28-day mortality (17.1% versus 17.3% in the Xigris and placebo groups, respectively).

Investigators attributed 2 deaths in the Xigris group and 5 deaths in the placebo group to bleeding events. There was a higher rate of central nervous system (CNS) bleeding in the drotrecogin alfa (activated) versus the placebo group. Over the infusion period (study days 0-6) the number of patients experiencing CNS bleeding was 5 versus 1 (2.1% versus 0.4%) for the overall population (drotrecogin alfa (activated) versus placebo), with 4 of the 5 events in the drotrecogin alfa (activated) group occurring in patients

In placebo controlled clinical trials, the treatment effect was most evident at sites enrolling larger numbers of patients.

5.2 Pharmacokinetic Properties

Drotrecogin alfa (activated) and endogenous human Activated Protein C are inactivated in plasma by endogenous protease inhibitors, but the mechanism by which they are cleared from plasma is unknown. Plasma concentrations of endogenous Activated Protein C in healthy subjects and patients with severe sepsis are usually below detection limits (<5ng/ml) and do not significantly influence the pharmacokinetic properties of drotrecogin alfa (activated).

In healthy subjects, greater than 90% of the steady-state condition is attained within 2 hours following the start of a constant-rate intravenous infusion of Xigris. Following the completion of an infusion, the decline in plasma drotrecogin alfa (activated) concentrations is biphasic and is comprised of a rapid initial phase (t?? = 13 minutes) and a slower second phase (t?? = 1.6 hours). The short half-life of 13 minutes accounts for approximately 80% of the area under the plasma concentration curve and governs the initial rapid accrual of plasma drotrecogin alfa (activated) concentrations towards the steady-state. Plasma drotrecogin alfa (activated) steady-state concentrations are proportional to the infusion rate over a range of infusion rates from 12?g/kg/hr to 48?g/kg/hr. The mean steady-state plasma concentration of drotrecogin alfa (activated) in healthy subjects receiving 24?g/kg/hr is 72ng/ml.

In patients with severe sepsis, infusion of drotrecogin alfa (activated) from 12?g/kg/hr to 30?g/kg/hr rapidly produced steady-state plasma concentrations that were proportional to infusion rates. In the Phase 3 trial, the pharmacokinetics of drotrecogin alfa (activated) were evaluated in 342 patients with severe sepsis administered a 96-hour continuous infusion at 24µg/kg/hr. The pharmacokinetics of drotrecogin alfa (activated) were characterised by attainment of steady-state plasma concentration within 2 hours following the start of the infusion. In the majority of patients, measurements of Activated Protein C beyond 2 hours after termination of the infusion were below the quantifiable limit, suggesting rapid elimination of drotrecogin alfa (activated) from the systemic circulation. The plasma clearance of drotrecogin alfa (activated) is approximately 41.8 l/hr in sepsis patients as compared with 28.1 l/hr in healthy subjects.

In patients with severe sepsis, the plasma clearance of drotrecogin alfa (activated) was significantly decreased by renal impairment and hepatic dysfunction, but the magnitude of the differences in clearance (<30%) does not warrant any dosage adjustment.

5.3 Preclinical Safety Data

Changes observed in monkeys at, or in small excess of, the maximum human exposure during repeated dose studies were all related to the pharmacological effect of Xigris and include, beside the expected prolongation of APTT, decreases in haemoglobin, erythrocytes and haematocrit and increases in reticulocyte count and PT.

Drotrecogin alfa (activated) was not mutagenic in an in vivo micronucleus study in mice or in an in vitro chromosomal aberration study in human peripheral blood lymphocytes with or without rat liver metabolic activation.

Carcinogenicity studies and animal reproduction studies have not been conducted with Xigris. However, with respect to the latter, the potential risk for humans being unknown, Xigris should not be used during pregnancy unless clearly necessary (see section 4.6).

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sucrose

Sodium chloride

Sodium citrate

Citric acid

Hydrochloric acid

Sodium hydroxide

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

3 years.

After reconstitution, immediate use is recommended. However, the reconstituted solution in the vial may be held for up to 3 hours at room temperature (15?C- 30?C). After preparation, the intravenous infusion solution can be used at room temperature (15?C- 30?C) for a period up to 14 hours.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C-8°C). Keep the vial in the outer carton in order to protect it from light.

6.5 Nature And Contents Of Container

Powder in Type I glass vial. Pack of 1 vial.

6.6 Special Precautions For Disposal And Other Handling

1.

Use appropriate aseptic technique during the preparation of Xigris for intravenous administration.

2.

Calculate the dose and the number of Xigris vials needed.

 

 

Xigris 5mg: Each Xigris vial contains 5mg of drotrecogin alfa (activated).

 

 

Xigris 20mg: Each Xigris vial contains 20mg of drotrecogin alfa (activated).

 

 

The vial contains an excess of drotrecogin alfa (activated) to facilitate delivery of the label amount.

3.

Xigris 5mg: Prior to administration, 5mg vials of Xigris must be reconstituted with 2.5ml of sterile water for injection, resulting in a solution with a concentration of approximately 2mg/ml drotrecogin alfa (activated).

 

 

Xigris 20mg: Prior to administration, 20mg vials of Xigris must be reconstituted with 10ml of sterile water for injection, resulting in a solution with a concentration of approximately 2mg/ml drotrecogin alfa (activated).

 

 

Slowly add the sterile water for injection to the vial and avoid inverting or shaking the vial. Gently swirl each vial until the powder is completely dissolved.

4.

The solution of reconstituted Xigris must be further diluted with sterile 0.9% sodium chloride injection to a final concentration of between 100?g/ml and 200?g/ml. Slowly withdraw the appropriate amount of reconstituted drotrecogin alfa (activated) solution from the vial. Add the reconstituted drotrecogin alfa (activated) into a prepared infusion bag of sterile 0.9% sodium chloride injection. When adding the reconstituted drotrecogin alfa (activated) into the infusion bag, direct the stream to the side of the bag to minimise the agitation of the solution. Gently invert the infusion bag to obtain a homogeneous solution. Do not transport the infusion bag between locations using mechanical delivery systems.

5.

After reconstitution, immediate use is recommended. However, the reconstituted solution in the vial may be held for up to 3 hours at room temperature (15 to 30?C).

 

 

After preparation, the intravenous infusion solution can be used at room temperature (15 to 30?C) for a period up to 14 hours.

6.

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration.

7.

It is recommended that Xigris be infused with an infusion pump to accurately control the infusion rate. The solution of reconstituted Xigris should be diluted into an infusion bag containing sterile 0.9% sodium chloride injection to a final concentration of between 100µg/ml and 200µg/ml.

8.

When administering drotrecogin alfa (activated) at low flow rates (less than approximately 5ml/hr), the infusion set must be primed for approximately 15 minutes at a flow rate of approximately 5ml/hr.

9.

Xigris should be administered via a dedicated intravenous line or a dedicated lumen of a multi-lumen central venous catheter. The ONLY other solutions that can be administered through the same line are 0.9% sodium chloride injection, lactated Ringer's injection, dextrose, or dextrose and saline mixtures.

10.

Avoid exposing drotrecogin alfa (activated) solutions to heat and/or direct sunlight. No incompatibilities have been observed between drotrecogin alfa (activated) and glass infusion bottles or infusion bags made of polyvinylchloride, polyethylene, polypropylene, or polyolefin. The use of other types of infusion sets could have a negative impact on the amount and potency of drotrecogin alfa (activated) administered.

11.

Care should be taken to administer Xigris at the appropriate rate, calculated based on kg of bodyweight and infused for the correct duration. It is recommended that the bag be labelled accordingly.

7. Marketing Authorisation Holder

Eli Lilly Nederland BV, Grootslag 1-5, 3991 RA Houten, The Netherlands.

8. Marketing Authorisation Number(S)

5mg vial:

EU/1/02/225/001

20mg vial:

EU/1/02/225/002

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation:

22 August 2002

Date of latest renewal:


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Daktarin Aktiv Cream (McNeil Products Ltd)


1. Name Of The Medicinal Product

Daktarin Aktiv Cream

2. Qualitative And Quantitative Composition

Miconazole nitrate 2.0% w/w

(Each gram of cream contains 20mg of miconazole nitrate)

For excipients, see Section 6.1

3. Pharmaceutical Form

Cream

White homogeneous cream

4. Clinical Particulars 4.1 Therapeutic Indications

For the treatment of athlete's foot.

4.2 Posology And Method Of Administration

For all ages.

Apply the cream twice daily to the lesions. Treatment should be prolonged for 10 days after all lesions have disappeared to prevent relapse.

Method of administration: Cutaneous application.

4.3 Contraindications

Daktarin Aktiv Cream is contraindicated in individuals with a known hypersensitivity to miconazole or another ingredient in this product.

4.4 Special Warnings And Precautions For Use

Daktarin Aktiv Cream must not come into contact with the eyes.

If a reaction suggesting sensitivity or irritation should occur, the treatment should be discontinued.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Miconazole administered systemically is known to inhibit CYP3A4/2C9. Due to the limited systemic availability after topical application, clinically relevant interactions are rare. However, in patients on oral anticoagulants, such as warfarin, caution should be exercised and anticoagulant effect should be monitored.

4.6 Pregnancy And Lactation

Pregnancy

In animals, miconazole nitrate has shown no teratogenic effects but is foetotoxic at high oral doses. Only small amounts of miconazole nitrate are absorbed following topical administration. However, as with other imidazoles, miconazole nitrate should be used with caution during pregnancy.

Lactation

Topically applied miconazole is minimally absorbed into the systemic circulation, and it is not known whether miconazole is excreted in human breast milk. Caution should be exercised when using topically applied miconazole products during lactation.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Adverse drug reactions from spontaneous reports during the worldwide postmarketing experience with Daktarin that meet threshold criteria are included. The adverse drug reactions are ranked by frequency, using the following convention:

Very common > 1/10

Common > 1/100 and < 1/10

Uncommon > 1/1,000 and < 1/100

Rare > 1/10,000, < 1/1,000

Very rare < 1/10,000, including isolated reports

The frequencies provided below reflect reporting rates for adverse drug reactions from spontaneous reports, and do not represent more precise estimates of incidence that might be obtained in clinical or epidemiological studies.

Immune system disorders

Very rare: anaphylactic reaction, hypersensitivity, angioneurotic edema.

Skin and subcutaneous tissue disorders

Very rare: urticaria, contact dermatitis, rash, erythema, pruritus, skin burning sensation.

General disorders and administration site conditions

Rare: application site reactions, including application site irritation.

4.9 Overdose

Symptoms

Cutaneous use: Excessive use can result in skin irritation, which usually disappears after discontinuation of therapy.

Treatment

Daktarin Aktiv Cream is intended for cutaneous use, not for oral use. If accidental ingestion of large quantities of the product occurs, an appropriate method of gastric emptying may be used if considered necessary.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic classification: (Antifungals for dermatological/topical use; imidazole derivative) ATC code: D01A C02.

Miconazole is an imidazole antifungal agent and may act by interfering with the permeability of the fungal cell membrane. It possesses a wide antifungal spectrum and has some antibacterial activity.

5.2 Pharmacokinetic Properties

Absorption: There is little absorption through skin or mucous membranes when miconazole nitrate is applied topically.

Distribution: Absorbed miconazole is bound to plasma proteins (88.2%) and red blood cells (10.6%).

Metabolism and Excretion: The small amount of miconazole that is absorbed is eliminated predominantly in faeces as both unchanged drug and metabolites.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of local irritation, single and repeated dose toxicity, genotoxicity, and toxicity to reproduction.

6. Pharmaceutical Particulars 6.1 List Of Excipients

PEG-6, PEG 32 and glycol stearate

Oleoyl macroglycerides

Liquid paraffin

Benzoic acid (E210)

Butylated hydroxyanisole (E320)

Purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Aluminium tube lined with epoxyphenol resin. Cap made of white polypropylene for the 15, 30 and 70g sizes. Cap for 5g size made of high density polyethylene.

Daktarin Aktiv Cream may be supplied in packs of 5, 15, 30 and 70g.

*Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

McNeil Products Limited

Foundation Park

Roxborough Way

Maidenhead

Berkshire

SL6 3UG

United Kingdom

8. Marketing Authorisation Number(S)

PL 15513/0304

9. Date Of First Authorisation/Renewal Of The Authorisation

01 July 2008

10. Date Of Revision Of The Text

10 July 2008


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