Pheniramine Maleate I/M overdoses in 3 month children
 

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Eye Allergy Relief


pheniramine maleate and naphazoline hydrochloride
Dosage Form: ophthalmic solution
Drug Facts Active ingredients

*Naphazoline HCl (0.02675%)

**Pheniramine Maleate (0.315%)

Purpose

*Redness Reliever

**Antihistamine

Uses Temporarily relieves itching and redness caused by pollen, ragweed, grass, animal hair and dander. Warnings Do not use if you are sensitive to any ingredient in this product if solution changes color or becomes cloudy Ask a doctor before use if you have heart disease high blood pressure trouble urinating due to an enlarged prostate gland narrow angle glaucoma When using this product overuse may cause more eye redness pupils may become enlarged temporarily do not touch tip of container to any surface to avoid contamination you may feel a brief tingling after putting drops in eye replace cap after use remove contact lenses before using Stop use and ask a doctor if you experience eye pain changes in vision redness or irritation of the eye that worsens or lasts more than 72 hours Keep out of reach of children.

If swallowed, get medical help or contact a Poison Control Center right away. Accidental oral ingestion in infants and children may lead to coma and marked reduction in body temperature.

Directions Adults and children 6 years of age and older: Instill 1 or 2 drops in the affected eye(s) up to 4 times daily. Children under 6 years: Ask a doctor Other information Store at 20°-25° C (68°-77° F). Protect from light. Use before expiration date marked on the carton or bottle. Inactive ingredients

Benzalkonium Chloride, Boric Acid, Edetate Disodium, Hypromellose, Purified Water, Sodium Borate and Sodium Chloride.

Questions?

Call 1-800-910-6874

Package/Label Principal Display Panel

NDC 11673-430-15

eye drops allergy relief

itching and redness reliever

eye drops

pheniramine maleate 0.315% and naphazoline hydrochloride 0.02675% ophthalmic solution

[icon- arrow- up&up] sterile

0.5 FL OZ (15 mL)


Eye Allergy Relief 
pheniramine maleate and naphazoline hydrochloride  solution/ drops Product Information Product Type HUMAN OTC DRUG NDC Product Code (Source) 11673-430 Route of Administration OPHTHALMIC DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength NAPHAZOLINE HYDROCHLORIDE (NAPHAZOLINE) NAPHAZOLINE HYDROCHLORIDE 0.2675 mg  in 1 mL PHENIRAMINE MALEATE (PHENIRAMINE) PHENIRAMINE MALEATE 3.15 mg  in 1 mL Inactive Ingredients Ingredient Name Strength BENZALKONIUM CHLORIDE   BORIC ACID   EDETATE SODIUM   HYPROMELLOSE   WATER   SODIUM BORATE   SODIUM CHLORIDE   Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 11673-430-15 1 BOTTLE In 1 CARTON contains a BOTTLE, DROPPER 1 15 mL In 1 BOTTLE, DROPPER This package is contained within the CARTON (11673-430-15)
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA020065 08/31/2010
Labeler - Target Corporation (006961700) Registrant - Bausch & Lomb Incorporated (196603781) Establishment Name Address ID/FEI Operations Bausch & Lomb Incorporated 114406598 MANUFACTURE Establishment Name Address ID/FEI Operations Loba Feinchemie AG 300137478 API MANUFACTURE Revised: 08/2010Target Corporation
More Eye Allergy Relief resources Eye Allergy Relief Dosage Eye Allergy Relief Use in Pregnancy & Breastfeeding Eye Allergy Relief Drug Interactions 0 Reviews for Eye Allergy Relief - Add your own review/rating Naphcon-A MedFacts Consumer Leaflet (Wolters Kluwer) Compare Eye Allergy Relief with other medications Eye Redness/Itching
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Naphazoline/Pheniramine


Pronunciation: naf-AZ-oh-leen/fen-EAR-ay-meen
Generic Name: Naphazoline/Pheniramine
Brand Name: Examples include Naphcon-A and Visine-A
Naphazoline/Pheniramine is used for:

Temporarily relieving itchy, red eyes caused by allergies to things such as pollen, ragweed, grass, or animal hair and dander.

Naphazoline/Pheniramine is a decongestant and antihistamine combination. The antihistamine works by blocking the action of histamine, which helps reduce symptoms such as watery, itchy eyes. The decongestant constricts (narrows) the blood vessels, which reduces eye redness.

Do NOT use Naphazoline/Pheniramine if: you are allergic to any ingredient in Naphazoline/Pheniramine you have taken furazolidone or a monoamine oxidase (MAO) inhibitor (eg, phenelzine) within the last 14 days

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

Before using Naphazoline/Pheniramine:

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

if you are pregnant, planning to become pregnant, or are breast-feeding if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement if you have allergies to medicines, foods, or other substances if you have diabetes, an enlarged prostate, heart disease, high blood pressure, an overactive thyroid, narrow-angle glaucoma, or trouble urinating

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

Furazolidone or MAO inhibitors (eg, phenelzine) because the risk of severe high blood pressure and fast heartbeat may be increased

This may not be a complete list of all interactions that may occur. Ask your health care provider if Naphazoline/Pheniramine may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Naphazoline/Pheniramine:

Use Naphazoline/Pheniramine as directed by your doctor. Check the label on the medicine for exact dosing instructions.

If Naphazoline/Pheniramine contains particles or is discolored, do not use it. Remove contact lenses before using Naphazoline/Pheniramine. To use Naphazoline/Pheniramine, first, wash your hands. Tilt your head back. Using your index finger, pull the lower eyelid away from the eye to form a pouch. Drop the medicine into the pouch and gently close your eyes. Immediately use your finger to apply pressure to the inside corner of the eye for 1 to 2 minutes. Do not blink. Remove excess medicine around your eye with a clean tissue, being careful not to touch your eye. Wash your hands to remove any medicine that may be on them. To prevent germs from contaminating your medicine, do not touch the applicator tip to any surface, including your eye. Keep the container tightly closed. You may feel a brief tingling sensation in your eye and your pupils may become temporarily enlarged when using Naphazoline/Pheniramine. If you miss a dose of Naphazoline/Pheniramine and you are using it regularly, use it as soon as possible. If several hours have passed or if it is nearing time for the next dose, do not double the dose to catch up, unless advised by your health care provider. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Naphazoline/Pheniramine.

Important safety information: If your symptoms do not improve within a few days or if they become worse, check with your doctor. Naphazoline/Pheniramine may be harmful if swallowed. If you may have taken Naphazoline/Pheniramine by mouth, contact your local poison control center or emergency room immediately. Overuse of topical products may worsen your condition. Naphazoline/Pheniramine is not recommended for use in CHILDREN younger than 6 years of age. Safety and effectiveness in this age group have not been confirmed. PREGNANCY and BREAST-FEEDING: If you become pregnant while taking Naphazoline/Pheniramine, discuss with your doctor the benefits and risks of using Naphazoline/Pheniramine during pregnancy. It is unknown if Naphazoline/Pheniramine is excreted in breast milk. If you are or will be breast-feeding while you are using Naphazoline/Pheniramine, check with your doctor or pharmacist to discuss the risks to your baby. Possible side effects of Naphazoline/Pheniramine:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Eye redness; tingling sensation.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blurred vision; changes in vision; eye pain; halos around lights; persistent redness or irritation.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Naphazoline/Pheniramine side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Naphazoline/Pheniramine:

Store Naphazoline/Pheniramine at room temperature, between 59 and 77 degrees F (15 and 25 degrees C). Keep Naphazoline/Pheniramine out of the reach of children and away from pets.

General information: If you have any questions about Naphazoline/Pheniramine, please talk with your doctor, pharmacist, or other health care provider. Naphazoline/Pheniramine is to be used only by the patient for whom it is prescribed. Do not share it with other people. If your symptoms do not improve or if they become worse, check with your doctor. Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Naphazoline/Pheniramine. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012 Database Edition 12.1.1.002 Copyright © 2012 Wolters Kluwer Health, Inc. More Naphazoline/Pheniramine resources Naphazoline/Pheniramine Side Effects (in more detail) Naphazoline/Pheniramine Use in Pregnancy & Breastfeeding Naphazoline/Pheniramine Drug Interactions Naphazoline/Pheniramine Support Group 7 Reviews for Naphazoline/Pheniramine - Add your own review/rating Compare Naphazoline/Pheniramine with other medications Eye Redness/Itching
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Carbinoxamine Maleate/Tannate


Pronunciation: kar-bi-NOX-a-meen
Generic Name: Carbinoxamine Maleate/Tannate
Brand Name: Histex Pd 12
Carbinoxamine Maleate/Tannate is used for:

Treating allergy symptoms such as runny nose, watery/itchy eyes, rash, or hives. It may also be used for other conditions as determined by your doctor.

Carbinoxamine Maleate/Tannate is an antihistamine. It works by blocking the action of histamine, which reduces the symptoms of an allergic reaction.

Do NOT use Carbinoxamine Maleate/Tannate if: you are allergic to any ingredient in Carbinoxamine Maleate/Tannate you are taking sodium oxybate (GHB) or a monoamine oxidase (MAO) inhibitor (eg, phenelzine)

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

Before using Carbinoxamine Maleate/Tannate:

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

if you are pregnant, planning to become pregnant, or are breast-feeding if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement if you have allergies to medicines, foods, or other substances if you have asthma, glaucoma, difficulty urinating, a stomach or bladder blockage, prostate problems, increased pressure in the eye, an underactive thyroid, heart disease, or high blood pressure

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

Barbiturates (eg, phenobarbital), MAO inhibitors (eg, phenelzine), or tricyclic antidepressants (eg, amitriptyline) because side effects of Carbinoxamine Maleate/Tannate may be increased Sodium oxybate (GHB) because side effects, such as an increase in sleep duration and drowsiness leading to unconsciousness or coma, may occur

This may not be a complete list of all interactions that may occur. Ask your health care provider if Carbinoxamine Maleate/Tannate may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Carbinoxamine Maleate/Tannate:

Use Carbinoxamine Maleate/Tannate as directed by your doctor. Check the label on the medicine for exact dosing instructions.

Carbinoxamine Maleate/Tannate may be taken with or without food. Shake well before using. Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure your dose. If you miss a dose of Carbinoxamine Maleate/Tannate and you are taking it regularly, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Carbinoxamine Maleate/Tannate.

Important safety information: Carbinoxamine Maleate/Tannate may cause drowsiness or dizziness. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to Carbinoxamine Maleate/Tannate. Using Carbinoxamine Maleate/Tannate alone, with certain other medicines, or with alcohol may lessen your ability to drive or perform other potentially dangerous tasks. Use Carbinoxamine Maleate/Tannate with caution in the ELDERLY because they may be more sensitive to its effects. Use Carbinoxamine Maleate/Tannate with extreme caution in CHILDREN younger than 9 months of age. Safety and effectiveness in this age group have not been confirmed. PREGNANCY and BREAST-FEEDING: It is unknown if Carbinoxamine Maleate/Tannate can cause harm to the fetus. If you become pregnant while taking Carbinoxamine Maleate/Tannate, discuss with your doctor the benefits and risks of using Carbinoxamine Maleate/Tannate during pregnancy. It is unknown if Carbinoxamine Maleate/Tannate is excreted in breast milk. Do not breast-feed while taking Carbinoxamine Maleate/Tannate. Possible side effects of Carbinoxamine Maleate/Tannate:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Appetite loss; blurred vision; diarrhea; dizziness; drowsiness; dry mouth, nose, or throat; headache; heartburn; nausea; nervousness; thickening of mucus in the nose or throat; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Carbinoxamine Maleate/Tannate side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include double vision; excitement; frequent urination; hallucinations; loss of consciousness; muscle twitching; seizures; tremor; weakness. In children, symptoms may include abnormal eye movement; abnormal tongue movement; agitation; bizarre behavior; confusion; difficulty urinating; excitation; flushed face; irritability; loss of consciousness; loss of coordination; restlessness; seizures; slurred speech; tiredness; trembling; twitching.

Proper storage of Carbinoxamine Maleate/Tannate:

Store Carbinoxamine Maleate/Tannate between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Carbinoxamine Maleate/Tannate out of the reach of children and away from pets.

General information: If you have any questions about Carbinoxamine Maleate/Tannate, please talk with your doctor, pharmacist, or other health care provider. Carbinoxamine Maleate/Tannate is to be used only by the patient for whom it is prescribed. Do not share it with other people. If your symptoms do not improve or if they become worse, check with your doctor. Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Carbinoxamine Maleate/Tannate. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012 Database Edition 12.1.1.002 Copyright © 2012 Wolters Kluwer Health, Inc. More Carbinoxamine Maleate/Tannate resources Carbinoxamine Maleate/Tannate Side Effects (in more detail) Carbinoxamine Maleate/Tannate Use in Pregnancy & Breastfeeding Drug Images Carbinoxamine Maleate/Tannate Drug Interactions Carbinoxamine Maleate/Tannate Support Group 2 Reviews for Carbinoxamine Maleate/Tannate - Add your own review/rating Compare Carbinoxamine Maleate/Tannate with other medications Allergic Reactions Allergic Urticaria Conjunctivitis, Allergic Dermatographism Hay Fever Vasomotor Rhinitis
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Imot Ofteno


Imot Ofteno may be available in the countries listed below.

Ingredient matches for Imot Ofteno Timolol

Timolol is reported as an ingredient of Imot Ofteno in the following countries:

Peru

Timolol maleate (a derivative of Timolol) is reported as an ingredient of Imot Ofteno in the following countries:

Colombia Costa Rica Dominican Republic El Salvador Guatemala Honduras Mexico Nicaragua Panama

International Drug Name Search


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Boots Bite & Sting Relief 2 Years Plus Antihistamine Cream


Boots Bite & Sting Relief 2 Years Plus Antihistamine Cream

(Mepyramine Maleate)

From 2 years

Relieves pain, itching and swelling

20 g e

Read all of this carton for full instructions.

What this medicine is for

A soothing antihistamine cream for the relief of pain, itching and swelling caused by insect bites and stings, and nettle stings.

Before you use this medicine X Do not use: If you are allergic to any of the ingredients or other antihistamines If you have eczema or other skin conditions If you are pregnant or breastfeeding, unless your doctor tells you to On broken skin, sunburnt skin or on large areas of skin

Cetostearyl alcohol and lanolin may cause skin reactions (e.g. contact dermatitis).

How to use this medicine

Check the tube seal is not broken before first use. If it is, do not use the cream. Pierce tube seal with end of cap.

Apply to the skin only.

Adults and children of 2 years and over:

Smooth a very small amount on the affected area. Use the cream 2 or 3 times a day, for a maximum of 3 days.

Do not use on children under 2 years.

If a rash develops, or the condition gets worse, stop using the cream.

If symptoms do not go away talk to your doctor.

! If anyone accidentally swallows some:

Talk to a doctor straight away.

Possible side effects

Most people will not have problems.

If you get these side effects stop using the cream and see a doctor.

Allergic reaction (e.g. skin rash, red or itchy skin, worsening of the condition you are treating)

If you notice any side effect not listed here, please tell your pharmacist or doctor.

How to store this medicine

Do not store above 25°C.

Keep all medicines out of the sight and reach of children.

Use by the date on the end flap of the carton.

Active ingredient

This cream contains Mepyramine Maleate 2% w/w.

Also contains: purified water, cetostearyl alcohol, white soft paraffin, liquid paraffin, cetomacrogol 1000, anhydrous hypoallergenic lanolin, sorbitan sesquioleate, sodium citrate, citric acid monohydrate.

PL 00014/0440

Text prepared 2/07

Manufactured by the Marketing Authorisation holder The Boots Company PLC Nottingham NG2 3AA

If you need more advice ask your pharmacist.

BTC14991 vD 15-06-07


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Wasp-Eze Spray


1. Name Of The Medicinal Product

Wasp-Eze Spray.

2. Qualitative And Quantitative Composition

Benzocaine 1.0% w/w

Mepyramine Maleate 0.5% w/w

For excipients, see 6.1.

3. Pharmaceutical Form

Aerosol spray.

4. Clinical Particulars 4.1 Therapeutic Indications

For the treatment of all insect bites and stings, nettle stings and jellyfish stings.

4.2 Posology And Method Of Administration

Route of administration

Topical.

Adults, the elderly and children:

Hold nozzle approximately five inches from the skin and spray once for 2-3 seconds. Stop spraying immediately if a white deposit or “frost” appears. Repeat once after 15 minutes if necessary. If pain persists, seek medical advice.

4.3 Contraindications

Do not apply to broken skin.

Do not use near the eyes.

Do not use if you are sensitive to benzocaine.

4.4 Special Warnings And Precautions For Use

Patients with any known allergy should seek medical advice. If pain persists seek medical advice.

For external use only. Keep out of reach of children.

Flammable. Do not use near fire or flame. Pressurised container. Protect from sunlight and do not expose to temperatures exceeding 50oC. Do not pierce or burn, even after use. Do not spray on a naked flame or any incandescent material. Do not use near or place container on polished or painted surfaces.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

No known effects in pregnancy and lactation. However, as with all medicines, use with caution.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Skin rash. Methaemoglobinaemia, especially in infants and children.

4.9 Overdose

Overdose is unlikely with this dosage form. There are no known effects and no specific treatment.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antipruritics, incl. Antihistamines, Anesthetics, etc., ATC code: D04A.

The active ingredients, benzocaine and mepyramine maleate, reduce pain and histamine responses to stings. The physical effects of the cooling propellants help reduce pain.

5.2 Pharmacokinetic Properties

Not applicable.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Propylene glycol

Ethanol (denatured)

Iso-butane

N-Pentane

Dimethyl ether

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months unopened

6.4 Special Precautions For Storage

Do not store above 25oC.

6.5 Nature And Contents Of Container

Aluminium cans (30 and 60 ml) internally coated with epoxyphenolic lacquer fitted with valve assembly and actuator button, protected by a plastic cap.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Seton Products Ltd,

Tubiton House

Oldham

OL1 3HS

8. Marketing Authorisation Number(S)

PL 11314/0032.

9. Date Of First Authorisation/Renewal Of The Authorisation

15/12/94 / 13/03/00 / 13/03/05

10. Date Of Revision Of The Text

15/09/05


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Prestim Tablets


Prestim Tablets

10 mg timolol maleate

2.5 mg bendroflumethiazide

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 you experience any side effect and this becomes serious, tell your doctor or pharmacist. In this leaflet:

1. What Prestim is and what it is used for
2. Before you take Prestim Tablets
3. How to take Prestim Tablets
4. Possible side effects
5. How to store Prestim Tablets
6. Further information

What Prestim Is And What It Is Used For

Prestim Tablets are a combination of two medicines, one slows your heart rate and the other increases water removal from your body.

Prestim tablets are used to treat raised blood pressure.Your doctor has prescribed these tablets for you because your blood pressure is too high.

Before You Take Prestim Tablets

Do not take Prestim Tablets if you:

Are allergic (hypersensitive) to timolol maleate, bendroflumethiazide, any of the other ingredients of Prestim (these are listed in section 6, “Further Information”), or any medicine known as a thiazide diuretic. Have bronchial asthma or a chronic lung disease. Have a history of wheezing or asthma. Have serious kidney problems. Have difficulty urinating. Have uncontrolled heart failure, a very slow heart rate, other heart problems or a certain type of angina called Prinzmetal’s angina. Have low blood pressure or problems with your blood circulation. Have a condition affecting your adrenal glands called phaeochromocytoma. Have a condition that causes acidity of the blood called metabolic acidosis. Are taking medicines used for relieving depression such as lithium, monoamine oxidase inhibitors (e.g. selegiline, moclobedine) and tricyclic antidepressants (e.g. amitriptyline, lofepramine). Are pregnant, or think that you might be pregnant. Take special care with Prestim Tablets

Tell your doctor before you start treatment if you have or have had in the past one of the following problems or if you develop any of these during treatment:

Suffer from diabetes, low blood sugar levels (hypoglycaemia), heart, liver or kidney problems. Suffer from an overactive thyroid gland. Psoriasis (this is a skin disease with thickened patches of red skin, often with silvery scales). Taking other medicines

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

This is extremely important, as using more than one medicine at the same time can strengthen or weaken the effect of the medicines.

In particular, tell your doctor if you are taking any of the following:

Any other medicines for high blood pressure or heart problems such as: lignocaine, verapamil, disopyramide, tocainide, diltiazem, quinidine, amiodarone, clonidine, digitalis glycosides, reserpine, hydralazine, guanethidine, dihydropyridine derivatives (e.g. nifedipine) and any of the medicines known as class I antiarrhythmic agents. Medicines used for treating depression (e.g. lithium, tricyclic antidepressants and monoamine oxidase inhibitors) or other mental problems (e.g. phenothiazines). Medicines known as barbiturates, used to treat sleeping disorders. An anti-ulcer medicine called cimetidine. An antibiotic called rifampicin. Medicines known as prostaglandin synthetase inhibitors (e.g. ibuprofen, aspirin). Medicines known as sympathomimetic agents used for asthma (e.g. salbutamol), to stimulate your heart (e.g. isoprenaline) and in some cough and cold preparations. Medicines for treating diabetes (e.g. insulin or oral anti-diabetic medicines). Medicines that work by reducing the amount of important chemicals; adrenaline and catecholamines, that are involved in nerve function (e.g. reserpine). If you are going to have surgery

If you are going to have an operation in hospital or going to the dentist, tell the doctor at the hospital or the dentist that you are taking Prestim Tablets.

Certain anaesthetics should not be used with these tablets (e.g. ether, cyclopropane, trichloroethylene). You should not be given a local anaesthetic combined with adrenaline while you are taking Prestim Tablets.

Taking Prestim Tablets with food and drink

You should avoid excessive alcohol consumption while taking Prestim.

Pregnancy and breast-feeding

Tell your doctor before you take any tablets if you are pregnant or breast-feeding. Also, tell your doctor if you become pregnant during treatment.

Do not take Prestim tablets if you are pregnant.

Your doctor will decide if you should take Prestim while you are breast-feeding.

Driving and using machines

This medicine may cause tiredness or dizziness as a side effect.

Therefore you should be careful if you are going to drive or operate machinery.

How To Take Prestim Tablets

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

The usual dose can vary from 1 to 4 tablets.

You can take the tablets as a single dose in the morning or in two doses, one in the morning and the other in the evening.

Prestim Tablets should be swallowed whole with water.

If you take more Prestim Tablets than you should

If you or anyone else accidentally take more than the recommended dose of these tablets, call your doctor straight away or go to your nearest hospital casualty department.

If you forget to take Prestim

If you forget to take your tablet(s), take the next dose as normal.

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

If you stop taking Prestim

Keep taking the Prestim Tablets for as long as your doctor tells you to. Do not stop taking them without consulting your doctor first. If it is right for you to stop taking Prestim then your doctor will probably reduce the dose gradually since it is important not to stop suddenly.

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

Prestim Tablets Side Effects

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

Tell your doctor immediately if you experience severe abdominal pain and vomiting or you notice inflammation of your blood vessels (e.g. veins).

Tell your doctor if you notice a skin rash and/ or your eyes feel dry. Your doctor may decide to change your treatment. If you have a skin rash, this may be associated with an increased sensitivity to sunlight.

Tell your doctor if you have any of the side effects mentioned below and you are concerned:

Upset stomach, dizziness, tiredness, depression, weakness, sleeplessness, breathing difficulties, a slow heart beat or other heart problems. You may also experience tired or painful muscles, feel thirsty and pass less urine than normal. If you are short sighted this may get worse.

Some side effects will not normally be noticed. These include an increase in blood sugar and sugar in the urine (particularly in people who are diabetic), changes in levels of some substances in the blood, such as decrease in potassium or an increase in urea, and changed blood cells. Your doctor may therefore need to do some tests.

Tell your doctor or pharmacist if you notice any side effects not listed in this leaflet, or if any of these effects become serious.

How To Store Prestim Tablets

Keep out of the reach and sight of children.

Store Prestim Tablets below 25°C.

Do not use Prestim after the expiry date which is stated on the bottle label and outer carton after the text “EXP“. The expiry date refers to the last day of that month.

Medicines must 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 Prestim contains

Active substance: Timolol maleate and bendroflumethiazide. Each tablet contains 10 mg of timolol maleate and 2.5 mg of bendroflumethiazide.

Other ingredients: Microcrystalline cellulose, starch and magnesium stearate.

What Prestim looks like and contents of the pack

Prestim Tablets are white, flat and oval with “ ” imprinted on one side and a break-mark on the other.

Prestim comes in bottles of 30 tablets.

Marketing Authorisation Holder Meda Pharmaceuticals Ltd. Skyway House Parsonage Road Takeley Bishop’s Stortford CM22 6PU United Kingdom Manufacturer Labiana Pharmaceuticals S.L.U. Casanova 27-31 08757- Corbera de Llobregat (Barcelona) Spain

For any information about this medicine, please contact the Marketing Authorisation Holder.

This leaflet was last revised in July 2010.

34842E0EU-D00

562103V4130UK00


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Methylergonovine Maleate Tablets



Methylergonovine Maleate Tablets, USP

Rx Only

Methylergonovine Maleate Tablets Description

Methylergonovine Maleate is a semi-synthetic ergot alkaloid used for the prevention and control of postpartum hemorrhage.

Methylergonovine Maleate Tablets, USP is available in tablets for oral ingestion containing 0.2 mg methylergonovine maleate.

Tablets

Active ingredient: Methylergonovine maleate, USP, 0.2 mg.

Inactive ingredients: acacia, corn starch, gelatin, lactose monohydrate, methylparaben, microcrystalline cellulose, povidone, propylparaben, stearic acid, and tartaric acid.

Chemically, methylergonovine maleate is designated as ergoline-8-carboxamide, 9, 10-didehydro-N-[1-(hydroxymethyl) propyl]-6-methyl-, [8?(S)]-, (Z)-2-butenedioate (1:1) (salt). Its structural formula is:

C20H25N3O2•C4H4O4                  Mol Wt: 455.51

Methylergonovine Maleate Tablets - Clinical Pharmacology

Methylergonovine maleate acts directly on the smooth muscle of the uterus and increases the tone, rate and amplitude of rhythmic contractions. Thus, it induces a rapid and sustained tetanic uterotonic effect which shortens the third stage of labor and reduces blood loss. The onset of action after I.V. administration is immediate; after I.M. administration, 2-5 minutes, and after oral administration, 5-10 minutes.

Pharmacokinetic studies following an I.V. injection have shown that methylergonovine is rapidly distributed from plasma to peripheral tissues within 2-3 minutes or less. The bioavailability after oral administration was reported to be about 60% with no accumulation after repeated doses. During delivery, with intramuscular injection, bioavailability increased to 78%. Ergot alkaloids are mostly eliminated by hepatic metabolism and excretion, and the decrease in bioavailability following oral administration is probably a result of first-pass metabolism in the liver.

Bioavailability studies conducted in fasting healthy female volunteers have shown that oral absorption of a 0.2 mg methylergonovine tablet was fairly rapid with a mean peak plasma concentration of 3243 ± 1308 pg/mL observed at 1.12 ± 0.82 hours. For a 0.2 mg intramuscular injection, a mean peak plasma concentration of 5918 ± 1952 pg/mL was observed at 0.41 ± 0.21 hours. The extent of absorption of the tablet, based upon methylergonovine plasma concentrations, was found to be equivalent to that of the I.M. solution given orally, and the extent of oral absorption of the I.M. solution was proportional to the dose following administration of 0.1, 0.2, and 0.4 mg. When given intramuscularly, the extent of absorption of methylergonovine maleate solution was about 25% greater than the tablet. The volume of distribution (Vdss/F) of methylergonovine was calculated to be 56.1 ± 17.0 liters, and the plasma clearance (CLp/F) was calculated to be 14.4 ± 4.5 liters per hour. The plasma level decline was biphasic with a mean elimination half-life of 3.39 hours (range 1.5 to 12.7 hours). A delayed gastrointestinal absorption (Tmax about 3 hours) of methylergonovine maleate tablet might be observed in postpartum women during continuous treatment with this oxytocic agent.

Indications and Usage for Methylergonovine Maleate Tablets

For routine management after delivery of the placenta; postpartum atony and hemorrhage; subinvolution. Under full obstetric supervision, it may be given in the second stage of labor following delivery of the anterior shoulder.

Contraindications

Hypertension; toxemia; pregnancy; and hypersensitivity.

Warnings

This drug should not be administered I.V. routinely because of the possibility of inducing sudden hypertensive and cerebrovascular accidents. If I.V administration is considered essential as a lifesaving measure, methylergonovine maleate should be given slowly over a period of no less than 60 seconds with careful monitoring of blood pressure. Intra-arterial or periarterial injection should be strictly avoided.

Precautions GENERAL

Caution should be exercised in the presence of sepsis, obliterative vascular disease, hepatic or renal involvement. Also use with caution during the second stage of labor. The necessity for manual removal of a retained placenta should occur only rarely with proper technique and adequate allowance of time for its spontaneous separation.

Drug Interactions CYP 3A4 inhibitors (e.g., Macrolide Antibiotics and Protease Inhibitors)

There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g., dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with Methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine.

No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.

Caution should be exercised when Methylergonovine maleate is used concurrently with other vasoconstrictors or ergot alkaloids.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies have been performed in animals to evaluate carcinogenic potential. The effect of the drug on mutagenesis or fertility has not been determined.

Pregnancy Category C

Animal reproductive studies have not been conducted with methylergonovine maleate. It is also not known whether methylergonovine maleate can cause fetal harm or can affect reproductive capacity. Use of methylergonovine maleate is contraindicated during pregnancy because of its uterotonic effects. (See INDICATIONS AND USAGE).

Labor and Delivery

The uterotonic effect of methylergonovine maleate is utilized after delivery to assist involution and decrease hemorrhage, shortening the third stage of labor.

NURSING MOTHERS

Methylergonovine maleate may be administered orally for a maximum of 1 week postpartum to control uterine bleeding. Recommended dosage is 1 tablet (0.2 mg) 3 or 4 times daily. At this dosage level a small quantity of drug appears in mothers' milk. Caution should be exercised when methylergonovine maleate is administered to a nursing woman.

PEDIATRIC USE

Safety and effectiveness in pediatric patients have not been established.

GERIATRIC USE

Clinical studies of methylergonovine maleate did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Adverse Reactions

The most common adverse reaction is hypertension associated in several cases with seizure and/or headache. Hypotension has also been reported. Nausea and vomiting have occurred occasionally. Rarely observed reactions have included: acute myocardial infarction, transient chest pains, arterial spasm (coronary and peripheral), bradycardia, tachycardia, dyspnea, hematuria, thrombophlebitis, water intoxication, hallucinations, leg cramps, dizziness, tinnitus, nasal congestion, diarrhea, diaphoresis, palpitation, rash, and foul taste.1

There have been rare isolated reports of anaphylaxis, without a proven causal relationship to the drug product.

Drug Abuse and Dependence

Methylergonovine maleate has not been associated with drug abuse or dependence of either a physical or psychological nature.

Overdosage

Symptoms of acute overdose may include: nausea, vomiting, abdominal pain, numbness, tingling of the extremities, rise in blood pressure, in severe cases followed by hypotension, respiratory depression, hypothermia, convulsions, and coma. Because reports of overdosage with Methylergonovine maleate are infrequent, the lethal dose in humans has not been established. The oral LD50 (in mg/kg) for the mouse is 187, the rat is 93, and the rabbit 4.5.2 Several cases of accidental methylergonovine Maleate injection in newborn infants have been reported, and in such cases 0.2 mg represents an overdose of great magnitude. However, recovery occurred in all but in one case following a period of respiratory depression, hypothermia, hypertonicity with jerking movements, and, in one case, a single convulsion. Also, several children 1-3 years of age have accidentally ingested up to 10 tablets (2 mg) with no apparent ill effects. A postpartum patient took 4 tablets at one time in error and reported paresthesias and clamminess as her only symptoms. Treatment of acute overdosage is symptomatic and includes the usual procedures of:

removal of offending drug by inducing emesis, gastric lavage, catharsis, and supportive diuresis. maintenance of adequate pulmonary ventilation, especially if convulsions or coma develop. correction of hypotension with pressor drugs as needed. control of convulsions with standard anticonvulsant agents. control of peripheral vasospasm with warmth to the extremities if needed.3 Methylergonovine Maleate Tablets Dosage and Administration

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

Intramuscularly

1 mL, 0.2 mg, after delivery of the anterior shoulder, after delivery of the placenta, or during the puerperium. May be repeated as required, at intervals of 2-4 hours.

Intravenously

Dosage same as intramuscular. (See WARNINGS.)

Orally

One tablet, 0.2 mg, 3 to 4 times daily in the puerperium for a maximum of 1 week.

How is Methylergonovine Maleate Tablets Supplied

White, round, biconvex compressed tablets debossed with "N" on one side and "01" on the other side. Available in bottles of 28 and 100 tablets.

STORE AND DISPENSE

Tablets: Store below 25°C (77°F); in tight, light-resistant container.

REFERENCES Information on Adverse Reactions supplied by Medical Services Department, Novartis Pharmaceuticals, E. Hanover, N.J., based on computerized clinical reports. Berde, B. and Schild, H.O.: Ergot Alkaloids and Related Compounds, Springer-Verlag, New York, 1978, p. 810. Treatment of Acute Overdosage. Novartis Consumer Health, Inc. Rx Products. Novartis, Medical Services Department.

Manufactured by:
Novel Laboratories, Inc.
Somerset, NJ 08873

GIN-140-01
Rev. 04/2011

PRINCIPAL DISPLAY PANEL - 0.2 mg Bottle Label

NDC 63704-006-01

Methylergonovine
Maleate
Tablets, USP

0.2 mg

Rx Only

100 TABLETS

PHARMACIST
PHARMACEUTICAL


METHYLERGONOVINE MALEATE 
methylergonovine maleate  tablet Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 63704-006 Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength methylergonovine maleate (methylergonovine) methylergonovine maleate 0.2 mg Inactive Ingredients Ingredient Name Strength acacia   starch, corn   gelatin   lactose monohydrate   methylparaben   cellulose, microcrystalline   povidone   propylparaben   stearic acid   tartaric acid   Product Characteristics Color WHITE Score no score Shape ROUND Size 6mm Flavor Imprint Code N;01 Contains          Packaging # NDC Package Description Multilevel Packaging 1 63704-006-01 100 TABLET In 1 BOTTLE None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA091577 08/01/2011
Labeler - Pharmacist Pharmaceutical, LLC (830838251) Establishment Name Address ID/FEI Operations Novel Laboratories, Inc. 793518643 MANUFACTURE Revised: 05/2011Pharmacist Pharmaceutical, LLC More Methylergonovine Maleate Tablets resources Methylergonovine Maleate Tablets Side Effects (in more detail) Methylergonovine Maleate Tablets Dosage Methylergonovine Maleate Tablets Use in Pregnancy & Breastfeeding Methylergonovine Maleate Tablets Drug Interactions Methylergonovine Maleate Tablets Support Group 3 Reviews for Methylergonovine Maleates - Add your own review/rating Compare Methylergonovine Maleate Tablets with other medications Migraine Postpartum Bleeding
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Wasp-Eze Bites and Stings Spray


1. Name Of The Medicinal Product

Wasp-Eze Bites and Stings Spray

2. Qualitative And Quantitative Composition

Benzocaine 1.0% w/w

Mepyramine Maleate 0.5% w/w

For excipients, see 6.1.

3. Pharmaceutical Form

Cutaneous Spray.

A clear uniform spray.

4. Clinical Particulars 4.1 Therapeutic Indications

For the treatment of all insect bites and stings, nettle stings and jellyfish stings in adults and children aged 2 years and over.

4.2 Posology And Method Of Administration

For cutaneous application.

For adults and children aged 2 years and over:

Hold nozzle approximately five inches from the skin and spray once for 2-3 seconds. Stop spraying immediately if a white deposit or “frost” appears. Repeat once after 15 minutes if necessary. If pain persists, seek medical advice.

4.3 Contraindications

Do not use if you are sensitive to any of the ingredients

Do not apply to large areas of skin, eczematous, sunburnt or broken skin.

Do not use the spray on the face.

4.4 Special Warnings And Precautions For Use

Patients with any known allergy to insect bites or stings should seek medical advice. If pain persists, seek medical advice.

Not for repeated or prolonged use.

For external use only. Keep out of the reach and sight of children.

Flammable. Do not use near fire or flame. Pressurised container. Protect from sunlight and do not expose to temperatures exceeding 50oC. Do not pierce or burn, even after use. Do not spray on a naked flame or any incandescent material. Do not use near or place container on polished or painted surfaces.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Not for use in pregnancy or lactation unless on medical advice.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Skin rash.

Methaemoglobinaemia especially in infants and children.

4.9 Overdose

Overdose is unlikely with this dosage form. There are no known effects and no specific treatment.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

The ingredients, benzocaine (D04 AB04) and mepyramine maleate (D04 AA02), reduce pain and histamine responses to stings. The physical effects of the cooling propellants help reduce pain.

5.2 Pharmacokinetic Properties

Not applicable.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Propylene glycol

Ethanol, denatured

Iso-butane

N-pentane

Dimethyl ether

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Do not store above 25oC.

6.5 Nature And Contents Of Container

30 ml Aluminium cans internally coated with epoxyphenolic lacquer fitted with valve assembly and actuator button, protected by a plastic cap.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Seton Products Limited

Tubiton House

Oldham

OL1 3HS

8. Marketing Authorisation Number(S)

PL 11314/0145

9. Date Of First Authorisation/Renewal Of The Authorisation

25th November 2004

10. Date Of Revision Of The Text

January 2005


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Timolol Eye Drops 0.25%, Timolol Eye Drops 0.5%


TIMOLOL Eye drops 0.25 %

TIMOLOL Eye drops 0.5 %

Timolol 2.5 mg/ml (as timolol maleate 3.4mg/ml)

Timolol 5.0 mg/ml (as timolol maleate 6.8mg/ml)

Please read this leaflet carefully before you start to take your 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 in this leaflet, please tell your doctor or pharmacist.

This medicine will be called Timolol in this leaflet.

In this leaflet:

1. What Timolol is and what is it used for
2. Before you use Timolol
3. How to use Timolol
4. Possible side effects
5. How to store Timolol
6. Further information

What Timolol Is And What Is It Used For

The active ingredient timolol belongs to a group of medicines called beta-blockers.

Timolol is used to treat raised pressure of eye (intraocular pressure) which occurs in various conditions including glaucoma and ocular hypertension.

Before You Use Timolol

Do not use if you:

are allergic (hypersensitive) to timolol maleate or beta-blockers or to any other ingredient of this medicine (see section 6. for more details) suffer from asthma or have history of asthma or any other breathing disorder suffer from a condition known as heart block, which causes your heart to beat at an abnormally slow rate suffer from cardiac failure, a condition where your heart cannot work normally. Take special care with Timolol

Before you use Timolol please tell your doctor if you:

are taking beta-blocking agents or calcium antagonists by mouth or as eye drops are suffering from muscle weakness, condition called myasthenia gravis Taking other medicines

Check with your doctor before using the eye drops if you are taking or using any other medicines, in particular:

a calcium antagonist (e.g. verapamil or diltiazem) often used to treat high blood pressure, angina, or an abnormal heartbeat digoxin, often used to treat heart failure or an abnormal heartbeat medicines known as a catecholamine-depleting agents (e.g. rauwolfia alkaloids/reserpine) used to treat high blood pressure a pressor amine (e.g. adrenaline) used to treat severe allergic reaction clonidine to treat high blood pressure quinidine, a medicine often used to treat abnormal heartbeat other beta-blockers (e.g. other preparations of timolol both oral and/or ocular), which belong to the same group of medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without any prescription.

Pregnancy and breast-feeding

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

Timolol should not be used during pregnancy and breast-feeding unless considered essential by your doctor.

Driving and using machines

No effects on ability to drive and use machines have been reported. However do not drive or operate machines if you experience any visual disturbance after using the product. Wait until this clears before driving or using machines.

Important information about some of the ingredients of Timolol Eye Drops:

The eye drops contain benzalkonium chloride as preservative which may cause eye irritation. Avoid contact with soft contact lenses. Remove contact lenses before using the eye drops and wait at least 15 minutes before reinserting. The preservative is known to discolour soft contact lenses.

How To Use Timolol

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

The usual starting dose is one drop of 0.25% eye drops into each affected eye(s) twice daily, approximately 12 hours apart. Your doctor will change your treatment as necessary. If you are using in combination with another eye drop medicine, wait 5-15 minutes before applying the second eye drop.

Use in children:

It is not recommended to use Timolol in children under 12 years of age.

Instructions for use:

(please also refer to pictograms at the end of the leaflet)

First wash your hands Avoid touching the eye (or any other surface) with the tip of the bottle If you wear soft contact lenses, they should be removed before using the eye drops and wait at least 15 minutes before reinserting These drops are supplied as a sealed bottle with a spiked cap. When using the bottle for the first time, screw the cap down tightly in order to pierce the tip of the bottle Tilt your head back and look at the ceiling Pull the lower eyelid gently downwards Hold the bottle upside down above the eye and gently squeeze the bottle to release a drop into your eye Keep the affected eye closed and press your fingertip against the inside corner of the closed eye, and hold for 1 minute Repeat for the other eye if necessary Replace and tighten the cap immediately after use.

Be careful not to touch the tip of the bottle on your eye or on any other surface.

Ocular solutions, if handled wrongly, can become contaminated by common bacteria and cause eye infections. If you do develop any other eye condition whilst using this product, see your doctor immediately.

Keep using your medicine until your doctor tells you to stop.

If you use more Timolol than you should

If you accidentally use too much, contact your doctor or go to the nearest hospital casualty department immediately.

Overdose

There is no experience of an overdosage with Timolol which is unlikely when given as eye drops.

The signs of overdosage include slow heart rate, drop of blood pressure, breathing difficulties, and heart attack.

If you forget to use Timolol

Apply the drops as soon as you remember. However, if it is almost time for your next dose, do not double your dose and carry on with the normal schedule dose.

Possible Side Effects

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

If you experience a rare (these may affect between 1 in 1,000 and 1 in 10,000 patients) but serious allergic reaction (difficulty breathing, closing of the throat, swelling of the lips, tongue, or face or hives) to timolol, stop using the medication and contact your doctor immediately.

Please tell your doctor if you notice any of the following side effects

irritation of the outer surface of the eye (conjunctivitis, keratitis and decreased corneal sensitivity) and of the eyelids (blepharitis) visual disturbance chest pain, high or low blood pressure, palpitations, irregular heart beat, heart failure, heart block, heart attack, stroke, swelling or coldness of your hands, feet and extremities, caused by constriction of the blood vessels in response to stimuli, including the cold dry mouth, nasal congestion pain or burning in the stomach, loss of appetite low blood pressure with faintness, dizziness depression, anxiety and other psychiatric disturbance increased signs of the condition myasthenia gravis (weakness, dropping eyelids, double vision) nausea headache weakness and somnolence hair loss

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 Timolol

Keep out of the reach and sight of children.

Do not store at a temperature above 25°C.

Protect from light.

Discard the bottle 28 days after opening, even if there is solution remaining.

Do not use Timolol after the expiry date which is stated on the bottle and on the carton the bottle is packed in.

Further Information What Timolol contains

The active ingredient is timolol maleate, where 5mg/ml timolol is equivalent to 6.8mg/ml of timolol maleate and 2.5mg/ml timolol is equivalent to 3.4mg/ml of timolol maleate.

This product also contains sodium dihydrogen phosphate dihydrate, disodium edetate, disodium phosphate dodecahydrate, benzalkonium chloride (as preservative) 0.01% w/v, sodium hydroxide, sodium chloride and water for injection.

What Timolol look like and contents of the pack

One bottle of Timolol contains 5 ml solution.

Your medicine is a clear colourless, sterile solution.

Marketing Authorisation Holder and Manufacturer FDC International Ltd At: Unit 6, Fulcrum 1 Solent Way Whiteley Fareham Hampshire PO15 7FE

PL numbers: 15872/0001 (0.25%) and 15872/0002 (0.5%)

Hard to see or read the leaflet? Call+ 44(0) 1489 565222 for help.

This leaflet was last approved in: 09/2009

MODE OF USE

Bottle as received

Tighten the cap on the nozzle till the cap touches the shoulder.

The spike in the cap will pierce the tip of the bottle.

Tilt head backwards. Dispense drops with gentle pressure. Do not touch dropper tip to the surface of the eye.

Replace cap after every use, and screw the cap down

W1IOLL02AESGB


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Spina bifida Medications


There are currently no drugs listed for "Spina bifida".

Definition of Spina bifida:

Spina bifida (SB) is a neural tube defect (a disorder involving incomplete development of the brain, spinal cord, and/or their protective coverings) caused by the failure of the fetus's spine to close properly during the first month of pregnancy.Learn more about Spina bifida

Harvard Health Guide:

Symptoms and treatment for Spina Bifida
Drug List:
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AlleRx Dose Pack PE


phenylephrine hydrochloride, chlorpheniramine maleate, and methscopolamine nitrate
Dosage Form: tablets

AlleRx® DOSE PACK PE

AM Dose - 40 mg phenylephrine HCI and 2.5 mg methscopolamine nitrate

PM Dose - 10 mg phenylephrine HCI, 8 mg chlorpheniramine maleate and 2.5 mg methscopolamine nitrate

AlleRx® DOSE PACK PE 30

AM Dose - 40 mg phenylephrine HCI and 2.5 mg methscopolamine nitrate

PM Dose - 10 mg phenylephrine HCI, 8 mg chlorpheniramine maleate and 2.5 mg methscopolamine nitrate

DESCRIPTION Each AM tablet contains: Each PM tablet contains: Phenylephrine HCl ................ 40 mg Phenylephrine HCl ....................10 mg Methscopolamine Nitrate ..... 2.5 mg Chlorpheniramine Maleate .......8 mg Methscopolamine Nitrate .........2.5 mg

Phenylephrine hydrochloride is a decongestant having the chemical name (-)-m-Hydroxy-?-[(methyl amino)methyl] benzyl alcohol hydrochloride.

Chlorpheniramine maleate is an antihistamine having the chemical name 2-pyridinepropanamine, gamma-(4 chlorophenyl)-N, N-dimethyl-, (Z)-2-butenedioate (1:1).

Methscopolamine nitrate is an anticholinergic having the chemical name 3-oxa-9-azoniatricyclo [3.3.1.0 2, 4] nonane, 7-(3-hydroxy-1-oxo-2-phenylpropoxy)-9, 9-dimethyl-, nitrate, [7(S)-(1?, 2?, 4?, 5?, 7?)]; C 17H21NO4•CH3NO3, MW = 80.4.

Inactive Ingredients:

AM tablets: Each orange AM tablet contains Hypromellose, Dicalcium Phosphate, Talc, Magnesium Stearate, Stearic Acid, D&C Red #30 and D&C Yellow #10.

PM tablets: Each blue PM tablet contains Hypromellose, Dicalcium Phosphate, Talc, FD&C Blue # 1, Stearic Acid and Magnesium Stearate.

CLINICAL PHARMACOLOGY

Phenylephrine HCl is a sympathomimetic amine which acts on the alpha adrenergic receptors. Clinically, phenylephrine shrinks swollen mucous membranes, reduces tissue hyperemia, edema, and nasal congestion, and increases nasal airway patency.

Chlorpheniramine maleate is an alkylamine-type antihistamine. This group of antihistamines is among the most active histamine antagonists and is generally effective in relatively low doses.

Methscopolamine nitrate is a quaternary ammonium derivative of the anticholinergic scopolamine which possesses the peripheral actions of the belladonna alkaloids, but does not exhibit the central actions because of its lack of ability to cross the blood-brain barrier. Its antimuscarinic effect causes inhibition of salivary secretions, reduction in volume and total acid content of gastric secretion, and inhibition of gastrointestinal motility. It is poorly and unreliably absorbed. Drug effects appear in about one hour and persist for about 4 to 6 hours. It is excreted primarily in the urine and bile, or as unabsorbed drug in feces.

INDICATIONS AND USAGE

For the temporary relief of symptoms associated with allergic rhinitis.

CONTRAINDICATIONS

This product is contraindicated in patients with hypersensitivity to phenylephrine HCl, methscopolamine nitrate, and chlorpheniramine maleate. AlleRx® PE is contraindicated in patients with severe hypertension, severe coronary artery disease, patients on monoamine oxidase inhibitor (MAOI) therapy or within 14 days of stopping monoamine oxidase inhibitor (MAOI) therapy, and in nursing mothers. AlleRx PE is also contraindicated in patients with narrow-angle glaucoma, urinary retention, peptic ulcer, and during an asthmatic attack.

WARNINGS

Sympathomimetic amines should be used cautiously in patients with hypertension, diabetes mellitus, ischemic heart disease, hyperthyroidism, increased intraocular pressure, and prostatic hypertrophy. Sympathomimetics may produce central nervous system stimulation with convulsions or cardiovascular collapse with accompanying hypotension. The elderly (60 years or older) are more likely to exhibit adverse reactions. Antihistamines may cause excitability, especially in children. At dosages higher than the recommended dose, nervousness, dizziness, or sleeplessness may occur. Do not exceed recommended dosage.

Methscopolamine nitrate may produce drowsiness or blurred vision. The patient should be cautioned regarding activities requiring mental alertness such as operating a motor vehicle or performing hazardous work while taking AlleRx PE.

Co-administration of sildenafil citrate and other organic nitrates has been shown to potentiate the hypotension effects of nitrates. Co-administration of AlleRx PE and sildenafil citrate has not been studied. Therefore, the use of sildenafil citrate and AlleRx PE together is not recommended.

PRECAUTIONS

General: AlleRx PE should be used with caution in patients with diabetes mellitus, cardiovascular disease, and hyperactivity to sympathomimetic amines. Hypertensive patients should only use with medical advice, as they may experience a change in blood pressure due to added vasoconstriction. Antihistamines may cause drowsiness, and ambulatory patients who operate machinery or motor vehicles should be cautioned accordingly. Methscopolamine nitrate should be used with caution in the elderly and all patients with autonomic neuropathy, hepatic or renal disease, or ulcerative colitis.

Drug Interactions: Monoamine oxidase (MAO) inhibitors and beta-adrenergic blockers increase the effects of sympathomimetic amines. Sympathomimetic amines may reduce the antihypertensive effects of methyldopa, guanethidine, mecamylamine, reserpine and veratrum alkaloids. Additive anticholinergic effects may result from concomitant use with antipsychotics, tricyclic antidepressants, and other drugs with anticholinergic effects. Concomitant administration with antacids may interfere with the absorption of methscopolamine nitrate.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Animal studies to assess the long-term carcinogenic and mutagenic potential or the effect on fertility in animals or humans have not been performed.

Pregnancy Category C: It is not known whether AlleRx can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. AlleRx should be given to a pregnant woman only if clearly needed.

Nursing Mothers: It is not known whether this combination drug is excreted in human milk. However, phenylephrine HCl administered alone distributes into the breast milk of lactating human females; therefore, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness in children under 12 years of age have not been established.

Geriatric Use: The elderly (60 years and older) are more likely to experience adverse reactions to sympathomimetics. Overdosage of sympathomimetics in this age group may cause hallucinations, convulsions, CNS depression, and/or death. Demonstrate safe use of a short-acting sympathomimetic amine before use of an extended-action formulation.

Adverse Reactions

Adverse reactions include drowsiness, lassitude, nausea, giddiness, dryness of mouth, blurred vision, cardiac palpitations, flushing, and increased irritability or excitement (especially in children). Some individuals may display sympathomimetic amine effects such as tachycardia, palpitations, headache, dizziness, or nausea. Sympathomimetics have been associated with certain untoward reactions including fear, anxiety, nervousness, restlessness, tremor, weakness, pallor, respiratory difficulty, dysuria, insomnia, hallucinations, convulsions, CNS depression, arrhythmias, and cardiovascular collapse with hypotension. Urinary retention may occur in patients with prostatic hypertrophy. Antihistamines and anticholinergics may cause drowsiness, dizziness, blurred vision, and excessive dryness of the nose, throat, and mouth.

DRUG ABUSE AND DEPENDENCE:

Central nervous system stimulants such as phenylephrine have been abused. At high doses, subjects commonly experience an elevation of mood, sense of increased energy and alertness, and decreased appetite. With continued use, tolerance develops, the user increases the dose, and toxic signs and symptoms appear. Depression may follow rapid withdraw.

OVERDOSAGE AND TREATMENT OF OVERDOSAGE

The treatment of overdosage should provide symptomatic and supportive care. Induction of emesis and gastric lavage may be performed if the patient is alert and seen within early hours after ingestion. Drug remaining in the stomach may be absorbed by the administration of activated charcoal. Stimulants should not be used because they may precipitate convulsions. If convulsions or marked CNS excitement occurs, treatment with appropriate measures is indicated. Since the effects of AlleRx last up to 12 hours, the patient should be monitored for at least that length of time and treated as necessary.

DOSAGE AND ADMINISTRATION

Adults and adolescents 12 years of age and over: One orange AM tablet in the morning and one blue PM tablet in the evening. AlleRx is not recommended for children under 12 years of age.

HOW SUPPLIED

(NDC 10122-705-20) AlleRx PE Tablets 10 Day Treatment Regimen, containing 20 tablets as follows:
10 orange, elongated and scored AM tablets debossed with “CBP” on one side and “04” to the right of the score on the other side, each containing 40 mg phenylephrine HCl and 2.5 mg of methscopolamine nitrate. 10 blue, elongated and scored PM tablets debossed with “CBP” on one side and “05” to the right of the score on the other side, each containing 10 mg phenylephrine HCl, 8 mg of chlorpheniramine maleate and 2.5 mg of methscopolamine nitrate.

(NDC 10122-705-60) AlleRx PE Tablets 30 Day Treatment Regimen, containing 60 tablets as follows:
30 orange, elongated and scored AM tablets debossed with “CBP” on one side and “04” to the right of the score on the other side, each containing 40 mg phenylephrine HCl and 2.5 mg of methscopolamine nitrate. 30 blue, elongated and scored PM tablets debossed with “CBP” on one side and “05” to the right of the score on the other side, each containing 10 mg phenylephrine HCl, 8 mg of chlorpheniramine maleate and 2.5 mg of methscopolamine nitrate.

(NDC 10122-705-02) AlleRx PE Tablets 2-pack sample containing 1 orange AM tablet and 1 blue PM tablet per sample.

Keep out of reach of pediatric population.

Store at 20° - 25°C (68° - 77°F); excursions permitted to 15° – 30° C (59° – 86° F). See USP Controlled Room Temperature.

Distributed by Cornerstone Therapeutics Inc., Cary, NC 27518.

This product is licensed and protected under U.S. Patent No. 6,843,372 issued 01/18/2005.

Rx Only

CORNERSTONE THERAPEUTICS INC.™

© 2009 Cornerstone Therapeutics Inc., Cary, NC 27518
CTA726F0109


ALLERX  DOSE PACK PE
phenylephrine hydrochloride, chlorpheniramine maleate, and methscopolamine nitrate  kit Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 10122-705 Packaging # NDC Package Description Multilevel Packaging 1 10122-705-20 1 BLISTER PACK In 1 DOSE PACK contains a BLISTER PACK 1 1 KIT In 1 BLISTER PACK This package is contained within the DOSE PACK (10122-705-20) 2 10122-705-60 3 BLISTER PACK In 1 DOSE PACK contains a BLISTER PACK 2 1 KIT In 1 BLISTER PACK This package is contained within the DOSE PACK (10122-705-60) QUANTITY OF PARTS Part # Package Quantity Total Product Quantity Part 1   10  Part 2   10  Part 1 of 2 AM DOSE 
phenylephrine hydrochloride and methscopolamine nitrate  tablet Product Information       Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength phenylephrine hydrochloride (phenylephrine) phenylephrine hydrochloride 40 mg methscopolamine nitrate (methscopolamine) methscopolamine nitrate 2.5 mg Inactive Ingredients Ingredient Name Strength Hypromelloses   Anhydrous Dibasic Calcium Phosphate   Talc   Magnesium Stearate   Stearic Acid   D&C RED NO. 30   D&C YELLOW NO. 10   Product Characteristics Color orange (orange) Score 2 pieces Shape OVAL (OVAL) Size 7mm Flavor Imprint Code CBP;04 Contains          Packaging # NDC Package Description Multilevel Packaging Package Information Not Applicable Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 09/01/2006
Part 2 of 2 PM DOSE 
phenylephrine hydrochloride, chlorpheniramine maleate, and methscopolamine nitrate  tablet Product Information       Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength phenylephrine hydrochloride (phenylephrine) phenylephrine hydrochloride 10 mg chlorpheniramine maleate (chlorpheniramine) chlorpheniramine maleate 8 mg methscopolamine nitrate (methscopolamine) methscopolamine nitrate 2.5 mg Inactive Ingredients Ingredient Name Strength Hypromelloses   Anhydrous Dibasic Calcium Phosphate   Talc   FD&C Blue No. 1   Stearic Acid   Magnesium Stearate   Product Characteristics Color blue (blue) Score 2 pieces Shape OVAL (OVAL) Size 7mm Flavor Imprint Code CBP;05 Contains          Packaging # NDC Package Description Multilevel Packaging Package Information Not Applicable Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 09/01/2006
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 09/01/2006
Labeler - Cornerstone Therapeutics Inc. (153886994) Establishment Name Address ID/FEI Operations Sovereign Pharmaceuticals, Ltd. 623168267 MANUFACTURE Revised: 04/2011Cornerstone Therapeutics Inc. More AlleRx Dose Pack PE resources AlleRx Dose Pack PE Side Effects (in more detail) AlleRx Dose Pack PE Use in Pregnancy & Breastfeeding AlleRx Dose Pack PE Drug Interactions AlleRx Dose Pack PE Support Group 0 Reviews for AlleRx Dose Pack PE - Add your own review/rating Compare AlleRx Dose Pack PE with other medications Nasal Congestion Rhinitis
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Cosopt Ophthalmic Solution


1. Name Of The Medicinal Product

COSOPT® 20 mg/ml + 5 mg/ml, eye drops, solution

2. Qualitative And Quantitative Composition

Each ml contains 22.26 mg of dorzolamide hydrochloride corresponding to 20 mg dorzolamide and 6.83 mg of timolol maleate corresponding to 5 mg timolol.

Excipients: Benzalkonium chloride 0.075 mg/ml

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Eye drops, solution.

Clear, colourless to nearly colourless, slightly viscous solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Indicated in the treatment of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or pseudoexfoliative glaucoma when topical beta-blocker monotherapy is not sufficient.

4.2 Posology And Method Of Administration

The dose is one drop of COSOPT in the (conjunctival sac of the) affected eye(s) two times daily.

If another topical ophthalmic agent is being used, COSOPT and the other agent should be administered at least ten minutes apart.

Patients should be instructed to wash their hands before use and avoid allowing the tip of the container to come into contact with the eye or surrounding structures.

Patients should also be instructed that ocular solutions, if handled improperly, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

Patients should be informed of the correct handling of the OCUMETER PLUS bottles.

Usage Instructions

1 Before using the medication for the first time, be sure the Safety Strip on the front of the bottle is unbroken. A gap between the bottle and the cap is normal for an unopened bottle.

2 Tear off the Safety Strip to break the seal.

3 To open the bottle, unscrew the cap by turning as indicated by the arrows on the top of the cap. Do not pull the cap directly up and away from the bottle. Pulling the cap directly up will prevent your dispenser from operating properly.

4 Tilt your head back and pull your lower eyelid down slightly to form a pocket between your eyelid and eye.

5. Invert the bottle, and press lightly with the thumb or index finger over the “Finger Push Area” until a single drop is dispensed into the eye as directed by your doctor. DO NOT TOUCH YOUR EYE OR EYELID WITH THE DROPPER TIP.

6. If drop dispensing is difficult after opening for the first time, replace the cap on the bottle and tighten (do not overtighten) and then remove by turning the cap in the opposite directions as indicated by the arrows on the top of the cap.

7. Repeat steps 4 & 5 with the other eye if instructed to do so by your doctor.

8. Replace the cap by turning until it is firmly touching the bottle. The arrow on the left side of the cap must be aligned with the arrow on the left side of the bottle label for proper closure. Do not overtighten or you may damage the bottle and cap.

9. The dispenser tip is designed to provide a single drop; therefore, do NOT enlarge the hole of the dispenser tip.

10. After you have used all doses, there will be some COSOPT left in the bottle. You should not be concerned since an extra amount of COSOPT has been added and you will get the full amount of COSOPT that your doctor prescribed. Do not attempt to remove the excess medicine from the bottle.

Paediatric Use

Efficacy in paediatric patients has not been established.

Safety in paediatric patients below the age of two years has not been established. (For information regarding safety in paediatric patients

4.3 Contraindications

COSOPT is contraindicated in patients with:

• reactive airway disease, including bronchial asthma or a history of bronchial asthma, or severe chronic obstructive pulmonary disease

• sinus bradycardia, second- or third-degree atrioventricular block, overt cardiac failure, cardiogenic shock

• severe renal impairment (CrCl < 30 ml/min) or hyperchloraemic acidosis

• hypersensitivity to one or both active substances or to any of the excipients.

The above are based on the components and are not unique to the combination.

4.4 Special Warnings And Precautions For Use

Cardiovascular/Respiratory Reactions

As with other topically-applied ophthalmic agents, this medicinal product may be absorbed systemically. The timolol component is a beta-blocker. Therefore, the same types of adverse reactions found with systemic administration of beta-blockers may occur with topical administration, including worsening of Prinzmetal's angina, worsening of severe peripheral and central circulatory disorders, and hypotension.

Because of the timolol maleate component, cardiac failure should be adequately controlled before beginning therapy with COSOPT. In patients with a history of severe cardiac disease, signs of cardiac failure should be watched for and pulse rates should be checked.

Respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma and rarely death in association with cardiac failure, have been reported following administration of timolol maleate.

Hepatic Impairment

COSOPT has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients.

Immunology and Hypersensitivity

As with other topically-applied ophthalmic agents, this medicinal product may be absorbed systemically. Dorzolamide contains a sulfonamido group, which also occurs in sulphonamides. Therefore, the same types of adverse reactions found with systemic administration of sulphonamides may occur with topical administration, including severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. If signs of serious reactions or hypersensitivity occur, discontinue use of this preparation.

Local ocular adverse effects, similar to those observed with dorzolamide hydrochloride eye drops, have been seen with COSOPT. If such reactions occur, discontinuation of COSOPT should be considered.

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to accidental, diagnostic, or therapeutic repeated challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

Concomitant Therapy

The following concomitant medication is not recommended:

? dorzolamide and oral carbonic anhydrase inhibitors

? topical beta-adrenergic blocking agents.

Withdrawal of Therapy

As with systemic beta-blockers, if discontinuation of ophthalmic timolol is needed in patients with coronary heart disease, therapy should be withdrawn gradually.

Additional Effects of Beta-Blockade

Therapy with beta-blockers may mask certain symptoms of hypoglycaemia in patients with diabetes mellitus or hypoglycaemia.

Therapy with beta-blockers may mask certain symptoms of hyperthyroidism. Abrupt withdrawal of beta-blocker therapy may precipitate a worsening of symptoms.

Therapy with beta-blockers may aggravate symptoms of myasthenia gravis.

Additional Effects of Carbonic Anhydrase Inhibition

Therapy with oral carbonic anhydrase inhibitors has been associated with urolithiasis as a result of acid-base disturbances, especially in patients with a prior history of renal calculi. Although no acid-base disturbances have been observed with COSOPT, urolithiasis has been reported infrequently. Because COSOPT contains a topical carbonic anhydrase inhibitor that is absorbed systemically, patients with a prior history of renal calculi may be at increased risk of urolithiasis while using COSOPT.

Other

The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. COSOPT has not been studied in patients with acute angle-closure glaucoma.

Corneal oedema and irreversible corneal decompensation have been reported in patients with pre-existing chronic corneal defects and/or a history of intraocular surgery while using dorzolamide. Topical dorzolamide should be used with caution in such patients.

Choroidal detachment concomitant with ocular hypotony have been reported after filtration procedures with administration of aqueous suppressant therapies.

As with the use of other antiglaucoma drugs, diminished responsiveness to ophthalmic timolol maleate after prolonged therapy has been reported in some patients. However, in clinical studies in which 164 patients have been followed for at least three years, no significant difference in mean intraocular pressure has been observed after initial stabilisation.

Contact Lens Use

COSOPT contains the preservative benzalkonium chloride, which may cause eye irritation. Remove contact lenses prior to application and wait at least 15 minutes before reinsertion. Benzalkonium chloride is known to discolour soft contact lenses.

Paediatric use

See section 5.1.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Specific drug interaction studies have not been performed with COSOPT.

In clinical studies, COSOPT was used concomitantly with the following systemic medications without evidence of adverse interactions: ACE-inhibitors, calcium channel blockers, diuretics, non-steroidal anti-inflammatory drugs including aspirin, and hormones (e.g. oestrogen, insulin, thyroxine).

However, the potential exists for additive effects and production of hypotension and/or marked bradycardia when timolol maleate ophthalmic solution is administered together with oral calcium channel blockers, catecholamine-depleting drugs or beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, narcotics, and monoamine oxidase (MAO) inhibitors.

Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, SSRIs) and timolol.

Although COSOPT alone has little or no effect on pupil size, mydriasis resulting from concomitant use of ophthalmic timolol maleate and epinephrine (adrenaline) has been reported occasionally.

Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents.

Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine.

4.6 Pregnancy And Lactation

Use During Pregnancy

COSOPT should not be used during pregnancy.

Dorzolamide

No adequate clinical data in exposed pregnancies are available. In rabbits, dorzolamide produced teratogenic effect at maternotoxic doses (see Section 5.3).

Timolol

Well controlled epidemiological studies with systemic beta-blockers showed no evidence of teratogenic effects, but some pharmacological effects such as bradycardia were observed in foetuses or neonates. If COSOPT is administered until delivery, the neonate should be carefully monitored during the first days of life.

Use During Lactation

It is not known whether dorzolamide is excreted in human milk. In lactating rats receiving dorzolamide, decreases in the body weight gain of offspring were observed. Timolol does appear in human milk. If treatment with COSOPT is required, then lactation is not recommended.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Possible side effects such as blurred vision may affect some patients' ability to drive and/or operate machinery.

4.8 Undesirable Effects

In clinical studies no adverse experiences specific to COSOPT have been observed; adverse reactions have been limited to those that were reported previously with dorzolamide hydrochloride and/or timolol maleate.

During clinical studies, 1035 patients were treated with COSOPT. Approximately 2.4% of all patients discontinued therapy with COSOPT because of local ocular adverse reactions, approximately 1.2% of all patients discontinued because of local adverse reactions suggestive of allergy or hypersensitivity (such as lid inflammation and conjunctivitis).

The following adverse reactions have been reported with COSOPT or one of its components either during clinical trials or during post-marketing experience:

[Very Common: (

Musculoskeletal and connective tissue disorders:

Timolol maleate eye drops, solution:

Rare: systemic lupus erythematosus

Nervous system disorders:

Dorzolamide hydrochloride eye drops, solution:

Common: headache*

Rare: dizziness*, paraesthesia*

Timolol maleate eye drops, solution:

Common: headache*

Uncommon: dizziness*, depression*

Rare: insomnia*, nightmares*, memory loss, paraesthesia*, increase in signs and symptoms of myasthenia gravis, decreased libido*, cerebrovascular accident*

Eye disorders:

COSOPT:

Very Common: burning and stinging

Common: conjunctival injection, blurred vision, corneal erosion, ocular itching, tearing

Dorzolamide hydrochloride eye drops, solution:

Common: eyelid inflammation*, eyelid irritation*

Uncommon: iridocyclitis*

Rare: irritation including redness*, pain*, eyelid crusting*, transient myopia (which resolved upon discontinuation of therapy), corneal oedema*, ocular hypotony*, choroidal detachment (following filtration surgery)*

Timolol maleate eye drops, solution:

Common: signs and symptoms of ocular irritation including blepharitis*, keratitis*, decreased corneal sensitivity, and dry eyes*

Uncommon: visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases)*

Rare: ptosis, diplopia, choroidal detachment (following filtration surgery)*

Ear and labyrinth disorders:

Timolol maleate eye drops, solution:

Rare: tinnitus*

Cardiac and vascular disorders:

Timolol maleate eye drops, solution:

Uncommon: bradycardia*, syncope*

Rare: hypotension*, chest pain*, palpitation*, oedema*, arrhythmia*, congestive heart failure*, heart block*, cardiac arrest*, cerebral ischaemia, claudication, Raynaud's phenomenon*, cold hands and feet*

Respiratory, thoracic, and mediastinal disorders:

COSOPT:

Common: sinusitis

Rare: shortness of breath, respiratory failure, rhinitis

Dorzolamide hydrochloride eye drops, solution:

Rare: epistaxis*

Timolol maleate eye drops, solution:

Uncommon: dyspnoea*

Rare: bronchospasm (predominantly in patients with pre-existing bronchospastic disease)*, cough*

Gastro-intestinal disorders:

COSOPT:

Very Common: taste perversion

Dorzolamide hydrochloride eye drops, solution:

Common: nausea*

Rare: throat irritation, dry mouth*

Timolol maleate eye drops, solution:

Uncommon: nausea*, dyspepsia*

Rare: diarrhoea, dry mouth*

Skin and subcutaneous tissue disorders:

COSOPT:

Rare: contact dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis

Dorzolamide hydrochloride eye drops, solution:

Rare: rash*

Timolol maleate eye drops, solution:

Rare: alopecia*, psoriasiform rash or exacerbation of psoriasis*

Renal and urinary disorders:

COSOPT:

Uncommon: urolithiasis

Reproductive system and breast disorders:

Timolol maleate eye drops, solution:

Rare: Peyronie's disease*

General disorders and administration site conditions:

COSOPT:

Rare: signs and symptoms of systemic allergic reactions, including angioedema, urticaria, pruritus, rash, anaphylaxis, rarely bronchospasm

Dorzolamide hydrochloride eye drops, solution:

Common: asthenia/fatigue*

Timolol maleate eye drops, solution:

Uncommon: asthenia/fatigue*

*These adverse reactions were also observed with COSOPT during post-marketing experience.

Laboratory findings

COSOPT was not associated with clinically meaningful electrolyte disturbances in clinical studies.

4.9 Overdose

No data are available in humans in regard to overdose by accidental or deliberate ingestion of COSOPT.

Symptoms

There have been reports of inadvertent overdoses with timolol maleate ophthalmic solution resulting in systemic effects similar to those seen with systemic beta

Only limited information is available with regard to human overdose by accidental or deliberate ingestion of dorzolamide hydrochloride. With oral ingestion, somnolence has been reported. With topical application the following have been reported: nausea, dizziness, headache, fatigue, abnormal dreams, and dysphagia.

Treatment

Treatment should be symptomatic and supportive. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. Studies have shown that timolol does not dialyse readily.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiglaucoma preparations and miotics, Beta blocking agents, Timolol, combinations, ATC code: S01ED51

Mechanism of Action

COSOPT is comprised of two components: dorzolamide hydrochloride and timolol maleate. Each of these two components decreases elevated intraocular pressure by reducing aqueous humor secretion, but does so by a different mechanism of action.

Dorzolamide hydrochloride is a potent inhibitor of human carbonic anhydrase II. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. Timolol maleate is a non-selective beta-adrenergic receptor blocking agent. The precise mechanism of action of timolol maleate in lowering intraocular pressure is not clearly established at this time, although a fluorescein study and tonography studies indicate that the predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed. The combined effect of these two agents results in additional intraocular pressure (IOP) reduction compared to either component administered alone.

Following topical administration, COSOPT reduces elevated intraocular pressure, whether or not associated with glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. COSOPT reduces intra-ocular pressure without the common side effects of miotics such as night blindness, accommodative spasm and pupillary constriction.

Pharmacodynamic effects

Clinical effects:

Clinical studies of up to 15 months duration were conducted to compare the IOP-lowering effect of COSOPT b.i.d. (dosed morning and bedtime) to individually- and concomitantly-administered 0.5% timolol and 2.0% dorzolamide in patients with glaucoma or ocular hypertension for whom concomitant therapy was considered appropriate in the trials. This included both untreated patients and patients inadequately controlled with timolol monotherapy. The majority of patients were treated with topical beta-blocker monotherapy prior to study enrollment. In an analysis of the combined studies, the IOP-lowering effect of COSOPT b.i.d. was greater than that of monotherapy with either 2% dorzolamide t.i.d. or 0.5% timolol b.i.d. The IOP-lowering effect of COSOPT b.i.d. was equivalent to that of concomitant therapy with dorzolamide b.i.d. and timolol b.i.d. The IOP-lowering effect of COSOPT b.i.d. was demonstrated when measured at various time points throughout the day and this effect was maintained during long-term administration.

Paediatric use

A 3 month controlled study, with the primary objective of documenting the safety of 2% dorzolamide hydrochloride ophthalmic solution in children under the age of 6 years has been conducted. In this study, 30 patients under 6 and greater than or equal to 2 years of age whose IOP was not adequately controlled with monotherapy by dorzolamide or timolol received COSOPT in an open label phase. Efficacy in those patients has not been established. In this small group of patients, twice daily administration of COSOPT was generally well tolerated with 19 patients completing the treatment period and 11 patients discontinuing for surgery, a change in medication, or other reasons.

5.2 Pharmacokinetic Properties

Dorzolamide hydrochloride:

Unlike oral carbonic anhydrase inhibitors, topical administration of dorzolamide hydrochloride allows for the active substance to exert its effects directly in the eye at substantially lower doses and therefore with less systemic exposure. In clinical trials, this resulted in a reduction in IOP without the acid-base disturbances or alterations in electrolytes characteristic of oral carbonic anhydrase inhibitors.

When topically applied, dorzolamide reaches the systemic circulation. To assess the potential for systemic carbonic anhydrase inhibition following topical administration, active substance and metabolite concentrations in red blood cells (RBCs) and plasma and carbonic anhydrase inhibition in RBCs were measured. Dorzolamide accumulates in RBCs during chronic dosing as a result of selective binding to CA-II while extremely low concentrations of free active substance in plasma are maintained. The parent active substance forms a single N-desethyl metabolite that inhibits CA-II less potently than the parent active substance but also inhibits a less active isoenzyme (CA-I). The metabolite also accumulates in RBCs where it binds primarily to CA-I. Dorzolamide binds moderately to plasma proteins (approximately 33%). Dorzolamide is primarily excreted unchanged in the urine; the metabolite is also excreted in urine. After dosing ends, dorzolamide washes out of RBCs non-linearly, resulting in a rapid decline of active substance concentration initially, followed by a slower elimination phase with a half-life of about four months.

When dorzolamide was given orally to simulate the maximum systemic exposure after long term topical ocular administration, steady state was reached within 13 weeks. At steady state, there was virtually no free active substance or metabolite in plasma; CA inhibition in RBCs was less than that anticipated to be necessary for a pharmacological effect on renal function or respiration. Similar pharmacokinetic results were observed after chronic, topical administration of dorzolamide hydrochloride. However, some elderly patients with renal impairment (estimated CrCl 30-60 ml/min) had higher metabolite concentrations in RBCs, but no meaningful differences in carbonic anhydrase inhibition and no clinically significant systemic side effects were directly attributable to this finding.

Timolol maleate:

In a study of plasma active substance concentration in six subjects, the systemic exposure to timolol was determined following twice daily topical administration of timolol maleate ophthalmic solution 0.5%. The mean peak plasma concentration following morning dosing was 0.46 ng/ml and following afternoon dosing was 0.35 ng/ml.

5.3 Preclinical Safety Data

The ocular and systemic safety profile of the individual components is well established.

Dorzolamide

In rabbits given maternotoxic doses of dorzolamide associated with metabolic acidosis, malformations of the vertebral bodies were observed

Timolol

Animal studies have not shown teratogenic effect.

Furthermore, no adverse ocular effects were seen in animals treated topically with dorzolamide hydrochloride and timolol maleate ophthalmic solution or with concomitantly-administered dorzolamide hydrochloride and timolol maleate. In vitro and in vivo studies with each of the components did not reveal a mutagenic potential. Therefore, no significant risk for human safety is expected with therapeutic doses of COSOPT.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Benzalkonium chloride

Hydroxyethyl cellulose

Mannitol (E421)

Sodium citrate (E331)

Sodium hydroxide (E524) for pH adjustment

Water for injections

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

COSOPT should be used no longer than 28 days after first opening the container.

6.4 Special Precautions For Storage

This medicinal product does not require any special temperature storage conditions.

Keep the bottle in the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

The OCUMETER Plus Ophthalmic Dispenser consists of a translucent, high-density polyethylene container with a sealed dropper tip, a flexible fluted side area which is depressed to dispense the drops, and a 2-piece cap assembly. The 2-piece cap mechanism punctures the sealed dropper tip upon initial use, then locks together to provide a single cap during the usage period. Tamper evidence is provided by a safety strip on the container label. The OCUMETER Plus ophthalmic dispenser contains 5 ml of solution.

COSOPT is available in the following packaging configurations:

1 x 5 ml (single 5-ml container)

3 x 5 ml (three 5-ml containers)

6 x 5 ml (six 5-ml containers)

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK.

8. Marketing Authorisation Number(S)

PL 0025/0373

9. Date Of First Authorisation/Renewal Of The Authorisation

04 August 1998 / 10 December 2008.

10. Date Of Revision Of The Text

June 2010

LEGAL CATEGORY

POM

® denotes registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA.

© Merck Sharp & Dohme Limited 2010. All rights reserved.

MSD (logo)

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK

SPC.CST.10.UK.3211 (II-043)


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Allergy DN II


chlorpheniramine maleate and methscopolamine nitrate
Dosage Form: tablets
AllergyDN II™

Day Dose - 4 mg chlorpheniramine maleate and 2.5 mg methscopolamine nitrate
Night Dose - 8 mg chlorpheniramine maleate and 2.5 mg methscopolamine nitrate

Allergy DN II Description Each Day tablet contains: Each Night tablet contains: Chlorpheniramine Maleate    4 mg Chlorpheniramine Maleate  8 mg Methscopolamine Nitrate 2.5 mg Methscopolamine Nitrate 2.5 mg

Chlorpheniramine maleate is an antihistamine having the chemical name 2-Pyridinepropanamine, ?-(4-chlorophenyl)-N, N-dimethyl-, (Z)-2-butenedioate (1:1); C16H19CIN2•C4H4O4, MW = 390.86.

Methscopolamine nitrate is an anticholinergic having the chemical name 3-Oxa-9-azoniatricyclo [3.3.1.02,4] nonane, 7-(3-hydroxy-1-oxo-2-phenylpropoxy)-9, 9-dimethyl-, nitrate, [7(S)-(1?, 2?, 4?, 5?, 7?)]; C18H24NO4•NO3 MW = 380.40.

Inactive Ingredients:

Day tablets: Each beige Day tablet contains: Dicalcium Phosphate Dihydrate, Microcrystalline Cellulose, 1FD&C Yellow No. 6, FD&C Blue No. 2, Hypromellose, Silicon Dioxide, Croscarmellose Sodium, Magnesium Stearate.

Night tablets: Each green Night tablet contains: Dicalcium Phosphate Dihydrate, Microcrystalline Cellulose, 2FD&C Yellow No. 5 (tartrazine - see PRECAUTIONS), FD&C Blue No. 1, Hypromellose, Silicon Dioxide, Croscarmellose Sodium, Magnesium Stearate.

1 Contains FD&C Yellow No. 6 as a color additive. 2 This product contains FD&C Yellow No. 5 (tartrazine) as a color additive. Allergy DN II - Clinical Pharmacology

Chlorpheniramine Maleate is an alkylamine-type antihistamine, which possesses anticholinergic and sedative effects. Antihistamines competitively antagonize histamine at the H1 receptor site. Thus, activation of H1 receptors by released histamine is prevented, resulting in increased vascular permeability and increased mucus production. Pruritus and sneezing are reduced.

Methscopolamine Nitrate is a quaternary ammonium derivative of the anticholinergic scopolamine which possesses the peripheral actions of the belladonna alkaloids, but does not exhibit the central actions because if its lack of ability to cross the blood-brain barrier. It competitively inhibits the action of acetylcholine at muscarinic receptors.

Indications and Usage for Allergy DN II

For the temporary relief of symptoms associated with allergic rhinitis.

Contraindications

This product is contraindicated in patients with a hypersensitivity or idiosyncratic reaction to chlorpheniramine maleate or methscopolamine nitrate. This product is also contraindicated in nursing mothers, and in patients with the following conditions: severe coronary artery disease; narrow-angle glaucoma; urinary retention; hyperthyroidism; peptic ulcer; asthma attack; MAOI therapy (or for 2 weeks after stopping MAOI therapy).

Warnings

Do not exceed recommended dosage. If nervousness, dizziness, or sleeplessness occurs, discontinue use and consult a doctor. If symptoms do not improve within 7 days or are accompanied by a fever, consult a doctor. Methscopolamine nitrate may produce dizziness or blurred vision. Patients taking this product should be warned not to engage in activities requiring mental alertness such as operating a motor vehicle or other machinery or to perform hazardous tasks while taking this drug. Alkylamine-type antihistamines should be used with extreme caution in patients with narrow-angle glaucoma; stenosing peptic ulcer; pyloroduodenal obstruction; symptomatic prostatic hypertrophy, or bladder neck obstruction. Due to its mild atropine-like action, chlorpheniramine should be used cautiously in patients with bronchial asthma, emphysema, or chronic pulmonary disease. May cause excitability, especially in children.

Heat prostration can occur with methscopolamine used where the environmental temperature is high. Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy; in this instance, use of methscopolamine would be inappropriate and possibly harmful.

Co-administration of sildenafil citrate and other organic nitrates has been shown to potentiate the hypotension effects of nitrates. Co-administration of Allergy DN II™ and sildenafil citrate has not been studied. Therefore, the use of sildenafil citrate and Allergy DN II™ together is not recommended.

Precautions

This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

General

Antihistamines have an atropine-like action and should be used with caution in patients with a history of bronchial asthma, emphysema, increased intraocular pressure, hyperthyroidism, cardiovascular disease and hypertension.

Use methscopolamine with caution in patients with hiatal hernia associated with reflux esophagitis. Use extreme caution and only when needed in patients with autonomic neuropathy, hyperthyroidism, coronary heart disease, congestive heart failure, and cardiac arrhythmia. Investigate any tachycardia before giving any anticholinergic drugs since they may increase the heart rate. Prolonged use of anticholinergics may decrease or inhibit salivary flow, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort.

Drug Interactions

Concomitant use of antihistamines with alcohol, tricyclic antidepressants, barbiturates, and other CNS depressants may have an additive effect. MAO inhibitors (or for 14 days after stopping MAOI therapy) and tricyclic antidepressants may prolong and intensify the anticholinergic (drying) effects of antihistamines. Concomitant administration with antacids may interfere with the absorption of methscopolamine nitrate.

Information for Patients

Patient consultation should include the following information regarding proper use of this medication:

Do not take more medication than the amount recommended. This medication should be used with caution during exercise or hot weather; overheating may result in heat stroke. Do not drive or operate machinery if drowsiness or dizziness occurs. Do not ingest alcoholic beverages, monoamine oxidase inhibitors (MAOI)s, or CNS depression producing medications (hypnotics, sedatives, tranquilizers) while taking this medication. Methscopolamine nitrate may cause blurred vision. Patients should observe caution before driving, using machinery or performing other tasks requiring visual alertness. If a dose is missed, the medication should be taken as soon as possible unless it is almost time for the next dose: do not double doses. Keep all medications out of the reach of children. In case of accidental overdose, seek professional assistance or contact a poison control center immediately.

Caution patients about the signs of potential side effects, especially:

Anticholinergic effects - clumsiness or unsteadiness; severe drowsiness; severe dryness of mouth, nose, or throat; flushing or redness of face; shortness of breath or troubled breathing Blood dyscrasias - sore throat and fever; unusual bleeding or bruising; unusual tiredness or weakness Fast or irregular heartbeat Psychotic episodes Tightness in chest

Note: When anticholinergics are given to patients especially children, where the environmental temperature is high there is risk of a rapid increase in body temperature because of suppression of sweat gland activity. Infants, patients with Down's syndrome, and children with spastic paralysis or brain damage may show an increased response to anticholinergics, thus increasing the potential for side effects. Geriatric or debilitated patients may respond to usual doses of anticholinergics with excitement, agitation, drowsiness, or confusion.

Laboratory Tests

The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on conditions):

Blood pressure determination - recommended at frequent intervals during therapy Electrocardiogram (ECG) - monitoring may be required Intraocular pressure determination - recommended at periodic intervals, as these medications may increase the intraocular pressure Laboratory Test Interactions

Antihistamines may interfere with diagnostic test results for skin tests using allergen extracts. Anticholinergics may interfere with diagnostic test results for gastric acid secretion by antagonizing the effect of pentagastrin and histamine, and for radionucleotide gastric emptying studies by delaying gastric emptying.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies to assess the long-term carcinogenic and mutagenic potential or the effect on fertility in animals or humans have not been performed.

Pregnancy: Category C

Animal reproduction studies have not been conducted with this product. It is also not known whether is product can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.

This product should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether this combination product is excreted in human milk, and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the product, taking into account the importance of the product to the mother.

Pediatric Use

The safety and effectiveness in children under 12 years of age have not been established.

Geriatric Use

The elderly (60 years and older) are more likely to experience adverse reactions to methscopolamine.

Adverse Reactions

Antihistamines and anticholinergics may cause drowsiness, dizziness, lassitude, blurred vision and excessive drying of the nose, throat and mouth, nausea, giddiness, increased irritability or excitement (especially in children).

OVERDOSAGE AND TREATMENT OF OVERDOSAGE

The treatment of overdosage should provide symptomatic and supportive care. Induction of emesis and gastric lavage may be performed if the patient is alert and seen within early hours after ingestion. Drug remaining in the stomach may be absorbed by the administration of activated charcoal. Since the effects of Allergy DN II™ last up to 12 hours, the patient should be monitored for at least that length of time and treated as necessary.

Allergy DN II Dosage and Administration

Adults and adolescents 12 years of age and over: One beige Day tablet in the morning and one green Night tablet in the evening. Allergy DN II™ is not recommended for children under 12 years of age.

How is Allergy DN II Supplied

Allergy DN II™ is supplied in boxes of 20 tablets NDC #51991-534-20 One blister card of 10 Day Tablets NDC # 51991-533-17, and one blister card of 10 Night tablets NDC #51991-489-17.

Day tablets are beige, oval-shaped and scored, debossed with B 533.

Night tablets are green, oval-shaped and scored, debossed with B 489.

WARNING: Keep this and all medications out of the reach of children. In case of accidental overdose, seek professional assistance or contact a poison control center immediately.

PHARMACIST: Dispense in original container.

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) . See USP Controlled Room Temperature.

All prescription substitutions using this product shall be pursuant to state statutes as applicable. This is not an Orange Book product.

Manufactured by: Provident Pharmaceuticals, Colorado Springs, CO 80919
Distributed by: Breckenridge Pharmaceutical, Inc. Boca Raton, FL 33487

Rx Only

360672501 ISS. 4/08

PRINCIPAL DISPLAY PANEL - 20 Tablet Carton

Breckenridge
Pharmaceutical, Inc.

NDC 51991-534-20

Allergy DN II™

Day Dose - 4 mg chlorpheniramine maleate and 2.5 mg methscopolamine nitrate
Night Dose - 8 mg chlorpheniramine maleate and 2.5 mg methscopolamine nitrate

20 Tablets containing the Following:

10 Beige Day Tablets each contain:    10 Green Night Tablets each contain:
Chlorpheniramine Maleate......4 mg    Chlorpheniramine Maleate......8 mg
Methscopolamine Nitrate......2.5 mg   Methscopolamine Nitrate......2.5 mg

20 Tablets (2 blister cards of 10 tablets)

Rx Only


Allergy DN II 
chlorpheniramine maleate and methscopolamine nitrate  kit Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 51991-534 Packaging # NDC Package Description Multilevel Packaging 1 51991-534-20 1 KIT In 1 CARTON None QUANTITY OF PARTS Part # Package Quantity Total Product Quantity Part 1 1 BLISTER PACK   10  Part 2 1 BLISTER PACK   10  Part 1 of 2 DAY DOSE 
chlorpheniramine maleate and methscopolamine nitrate  tablet Product Information NDC Product Code (Source) 51991-533     Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Chlorpheniramine Maleate (Chlorpheniramine) Chlorpheniramine Maleate 4 mg Methscopolamine Nitrate (Methscopolamine) Methscopolamine Nitrate 2.5 mg Inactive Ingredients Ingredient Name Strength Dibasic Calcium Phosphate Dihydrate   Cellulose, Microcrystalline   FD&C Yellow no. 6   FD&C Blue no. 2   Hypromellose   Silicon Dioxide   Croscarmellose Sodium   Magnesium Stearate   Product Characteristics Color BROWN (beige) Score 2 pieces Shape OVAL Size 13mm Flavor Imprint Code B;533 Contains          Packaging # NDC Package Description Multilevel Packaging 1 51991-533-17 10 TABLET In 1 BLISTER PACK None Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date Unapproved drug other 11/01/2008
Part 2 of 2 NIGHT DOSE 
chlorpheniramine maleate and methscopolamine nitrate  tablet Product Information NDC Product Code (Source) 51991-489     Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Chlorpheniramine Maleate (Chlorpheniramine) Chlorpheniramine Maleate 8 mg Methscopolamine Nitrate (Methscopolamine) Methscopolamine Nitrate 2.5 mg Inactive Ingredients Ingredient Name Strength Dibasic Calcium Phosphate Dihydrate   Cellulose, Microcrystalline   FD&C Yellow no. 5   FD&C Blue no. 1   Hypromellose   Silicon Dioxide   Croscarmellose Sodium   Magnesium Stearate   Product Characteristics Color GREEN Score 2 pieces Shape OVAL Size 13mm Flavor Imprint Code B;489 Contains          Packaging # NDC Package Description Multilevel Packaging 1 51991-489-17 10 TABLET In 1 BLISTER PACK None Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date Unapproved drug other 11/01/2008
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date Unapproved drug other 11/01/2008
Labeler - Breckenridge Pharmaceutical, Inc. (150554335) Establishment Name Address ID/FEI Operations Provident Pharmaceuticals, LLC 171901445 MANUFACTURE Revised: 10/2009Breckenridge Pharmaceutical, Inc. More Allergy DN II resources Allergy DN II Side Effects (in more detail) Allergy DN II Use in Pregnancy & Breastfeeding Allergy DN II Drug Interactions 0 Reviews for Allergy DN II - Add your own review/rating Dexodryl Chewable Tablet MedFacts Consumer Leaflet (Wolters Kluwer) Ryneze 12-Hour Tablets MedFacts Consumer Leaflet (Wolters Kluwer) aeroHist Concise Consumer Information (Cerner Multum) Compare Allergy DN II with other medications Rhinitis
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Timoptol-LA 0.25 and 0.5% w / v Gel-Forming Eye Drops Solution


Timoptol-LA 0.25% w/v Gel-Forming Eye Drops Solution

Timoptol-LA 0.5% w/v Gel-Forming Eye Drops Solution

timolol (as maleate)

Read all of this leaflet carefully before you start using this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or pharmacist. This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects 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 Timoptol-LA is and what it is used for 2. Before you use Timoptol-LA 3. How to use Timoptol-LA 4. Possible side effects 5. How to store Timoptol-LA 6. Further information What Timoptol-La Is And What It Is Used For

Timoptol-LA contains a substance called timolol which belongs to a group of medicines called beta-blockers. Timolol lowers the pressure in your eye(s). It is used to treat glaucoma, when the pressure in the eye is raised.

Before You Use Timoptol-La Do not use Timoptol-LA if: you are allergic (hypersensitive) to timolol maleate or any of the other ingredients of Timoptol-LA (see section 6 for Further Information) you have respiratory disease, such as asthma, a history of asthma or chronic obstructive lung disease you have heart problems slow or irregular heartbeat heart failure "cardiogenic shock" – a serious heart condition caused by very low blood pressure, which may result in the following symptoms: dizziness and lightheadedness, fast pulse rate, white skin, sweating, restlessness, loss of consciousness you wear contact lenses.

If you are not sure whether you should use Timoptol-LA talk to your doctor or pharmacist.

Take special care with Timoptol-LA

Tell your doctor about any medical problems you have now or have had in the past. In particular tell them about any of the following, before you use Timoptol-LA.

asthma and other lung problems heart or circulation problems low blood pressure allergies to any medicines.

If your eye becomes irritated or any new eye problems come on, talk to your doctor straight away. Eye problems could include redness of the eye or swelling of the eyelids (see Section 4: Possible Side Effects).

If you suspect that Timoptol-LA is causing an allergic reaction or hypersensitivity (for example, skin rash, or redness and itching of the eye), stop using Timoptol-LA and contact your doctor immediately.

Tell you doctor if:

you get an eye infection you injure your eye or have an operation on it your eye problems get worse or you get any new symptoms. Use in children

Timoptol-LA is not recommended for use in children and adolescents

Using other medicines

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including other eye drops or medicines obtained without a prescription. It is important to tell your doctor before using Timoptol-LA if you are taking one or more of the following medicines:

a calcium antagonist, such as nifedipine, verapamil or diltiazem, often used to treat high blood pressure, angina, an abnormal heartbeat or Raynaud’s syndrome digoxin, a medicine used for heart failure or abnormal heartbeat medicines known as catecholamine-depleting agents, such as, rauwolfia alkaloids and reserpine used for high blood pressure medicines called pressor amines, such as adrenaline used to treat severe allergic reaction quinidine, a medicine often used for abnormal heartbeat clonidine, a medicine used for high blood pressure other beta-blockers taken by mouth or used as eye drops, because they belong to the same group of medicines as Timoptol-LA and could have an additive effect. Pregnancy and breast-feeding

Ask your doctor for advice before taking any medicine.

Use in pregnancy

You should not use Timopol-LA during pregnancy. Tell your doctor if you are pregnant or intend to become pregnant.

Use in breast-feeding

You should not use Timoptol-LA if you are breast-feeding. Tell your doctor if you are breast-feeding or intend to breast-feed.

Driving and using machines

After putting your eye drops in your eye, your vision may be blurred for 30 seconds up to 5 minutes. In some patients this may last up to 30 minutes or longer. You may also feel dizzy which may affect your ability to drive or operate machinery. Do not drive and/or operate machinery until you feel well and your vision is clear.

How To Use Timoptol-La

Always use Timoptol-LA exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. The doctor will decide how many drops you should take each day and how long you should use them.

The usual dose is one drop in the affected eye(s) once each day.

If your doctor recommends that you use Timoptol-LA with another eye drop, the other medicine should be administered at least 10 minutes before Timoptol-LA.

Do not change your usual dose without talking to your doctor.

Do not allow the tip of the container to touch the eye or areas around the eye. It may become contaminated with bacteria that can cause eye infection leading to serious damage of the eye, even loss of vision. To avoid possible contamination of the container, keep the tip of the container away from contact with any surface.

Instructions for use.

It is recommended that you wash your hands before putting in your eye drops.

1. Before using the medication for the first time, be sure the Safety Strip on the front of the bottle is unbroken. A gap between the bottle and the cap is normal for an unopened bottle. 2. Tear off the safety strip to break the seal. 3. Invert the closed bottle and shake ONCE before each use. (it is not necessary to shake the bottle more than once). To open the bottle, unscrew the cap by turning as indicated by the arrows on top of the cap. Do not pull the cap directly up and away from the bottle.

Pulling the cap directly up will prevent your dispenser from operating properly.

4. Tilt your head back and pull your lower eyelid down slightly to form a pocket between your eyelid and your eye. 5. Invert the bottle, and press lightly with your thumb or first finger over the ‘Finger Push Area’ as shown, until a single drop is dispensed into your eye, as directed by your doctor.

DO NOT TOUCH YOUR EYE OR EYELID WITH THE DROPPER TIP.

Ophthalmic medications, if handled improperly, can become contaminated by common bacteria known to cause infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic medications. If you think your medication may be contaminated, or if you develop an eye infection, contact your doctor immediately concerning continued use of this bottle.

6. If drop dispensing is difficult after opening for the first time, replace the cap on the bottle and tighten (do not overtighten) and then remove by turning the cap in the opposite direction as indicated by the arrows on top of the cap.
7. Repeat steps 4 & 5 with the other eye if instructed to do so by your doctor.
8. Replace the cap by turning until it is firmly touching the bottle. The arrow on the left side of the cap must be aligned with the arrow on the left side of the bottle label for proper closure. Do not overtighten or you may damage the bottle and cap.
9. The dispenser tip is designed to provide a single drop; therefore do NOT enlarge the hole of the dispenser tip.
10. After you have used all doses there will be some Timoptol-LA left in the bottle. You should not be concerned since an extra amount of Timoptol-LA has been added and you will get the full amount of Timoptol-LA that your doctor has prescribed. Do not attempt to remove the excess medicine from the bottle. If you use more Timoptol-LA than you should

If you put too many drops in your eye or swallow any of the drops, you may:

have a headache feel dizzy or light-headed have difficulty breathing feel that your heart rate has slowed down.

If this happens, contact your doctor immediately.

If you forget to use Timoptol-LA

It is important to take Timoptol-LA as prescribed by your doctor.

If you miss a dose, use the drops as soon as possible. If it is almost time for the next dose, skip the missed dose and take the next dose at the usual time. Do not take a double dose to make up for the forgotten dose. If you stop using Timoptol-LA

If you want to stop using this medicine talk to your doctor first. If you have any further questions on the use of this product, ask your doctor or pharmacist.

Possible Side Effects

Like all medicines Timoptol-LA may cause side effects, although not everybody gets them. If they do occur, you may need medical attention. In some patients these may include:

Allergic reactions allergic skin rash and hives severe allergic reaction which causes difficulty in breathing or dizziness. Eyes and ears burning and stinging dry eyes irritation and redness of eye or eyelid sensitivity to light discharge from your eye visual changes such as double vision decreased sensation of your eye surface pain in your eye drooping eyelid ringing in your ears. Heart and circulation chest pain heart attack fainting palpitations an irregular heartbeat a slowing of your heart rate low blood pressure interference with your blood supply to the brain which may lead to a stroke too much fluid, mainly water, accumulating in your body limping because there is a reduced blood supply to your legs swelling or coldness of your hands, feet and extremities, caused by constriction of your blood vessels. Chest wheezing shortness of breath difficulty breathing cough. Stomach and gut nausea diarrhoea indigestion dry mouth. Sexual decreased sex drive in men a condition which effects your penis called Peyronie’s disease. The signs may be abnormal curve, pain or hardening of the tissue of your penis. Skin and hair hair loss a skin disease called psoriasis, where areas of skin such as knees and elbows are covered in scales worsening of psoriasis. Nervous system dizziness depression unable to sleep nightmares memory loss increase in signs and symptoms of myasthenia gravis tingling sensation General headache tiredness weakness a condition called lupus (systemic lupus erythematosus)

Ask your doctor or pharmacist for more information about the side effects. Both have a more complete list of side effects.

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 Timoptol-La

Keep your eye drops out of the reach and sight of children.

Do not store your eye drops above 25°C. Do not freeze. Store the bottle in the outer carton. You can use Timoptol-LA for 28 days after first opening the bottle.

Do not use Timoptol-LA after the expiry date which is stated on the carton 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 Timoptol-LA contains

The active substance is timolol maleate.

Timoptol-LA is available in two strengths:

0.25% w/v solution of timolol maleate 0.5% w/v solution of timolol maleate.

The other ingredients are:

benzododecinium bromide as preservative gellan gum mannitol E421 trometamol water for injections. What Timoptol-LA looks like and contents of the pack

Timoptol-LA is a sterile gel-forming eye drops solution and is available in bottles containing 2.5 ml of sterile eye drops solution.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder UK and Malta

Merck Sharp & Dohme Ltd Hertford Road Hoddesdon Hertfordshire EN11 9BU United Kingdom

Marketing Authorisation Holder Ireland

Merck Sharp & Dohme Ireland (Human Health) Ltd Pelham House South County Business Park Leopardstown Dublin 18 Ireland

Manufacturer

Laboratories Merck Sharp & Dohme – Chibret (Mirabel) Route de Marsat RIOM 63963Clermont –Ferrand Cedex 9 France

This leaflet was last approved in June 2008.

This leaflet gives the most important patient information about Timoptol-LA. If you have any questions after you have read it, ask your doctor or pharmacist who will give you further information.

Further information about glaucoma is available from:

International Glaucoma Association (IGA) 15A Highpoint Business Village Henwood Ashford Kent TN24 8DH Tel:01233 648170 E-mail: info@iga.org.uk

Registered Charity number 274681.

(The IGA is an independent charity organisation which helps glaucoma patients and their relatives, and is not associated with Merck Sharp & Dohme Limited.)

Alternatively, if you or someone you know has problems with their vision, and you require further advice or information, please phone the Royal National Institute for the Blind (RNIB) Helpline on 0845 776 9999, Monday to Friday 9am to 5 pm, calls charged at local rates.

(The RNIB is an independent UK charity and is not associated with Merck Sharp & Dohme Limited).

denotes registered trademark of

Merck & Co., Inc. Whitehouse Station NJ USA

© Merck Sharp & Dohme Limited 2008. All rights reserved.

PIL.TOTX.09.UK.2765 230209


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Timolol 0.5% w / v Eye Drops, Solution


1. Name Of The Medicinal Product

Timolol Eye Drops, 0.5%

2. Qualitative And Quantitative Composition

Timolol 0.50% w/v (as timolol maleate).

For excipients, see 6.1.

3. Pharmaceutical Form

Eye Drops, Solution

A clear, colourless sterile, multi-dose drops, solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Timolol Eye Drops 0.5% are indicated for the treatment of open-angle glaucoma, aphakic glaucoma, some patients with secondary glaucoma, and other patients with elevated intraocular pressure who are at sufficient risk to require lowering of their ocular pressure.

Timolol Eye Drops 0.50% may be used alone or in combination with other glaucoma medications

4.2 Posology And Method Of Administration

Apply one drop in the eye(s) twice a day.

Since the intraocular pressure lowering response to timolol may require several weeks to stabilise, intraocular pressure should be re-assessed approximately one month after starting treatment with timolol.

Transfer from Other Agents:

When a patient is transferred from a single anti-glaucoma agent other than a topical beta-blocking agent, continue the agent already used and add one drop of timolol in the affected eye(s) twice a day. On the following day, discontinue the previous anti-glaucoma agent completely and continue with timolol.

When a patient is transferred from a single topical beta-blocking agent, discontinue its use after a full day of therapy and start treatment with timolol on the next day.

When a patient is transferred from several concomitantly administered anti-glaucoma agents, individualisation is required. Adjustment should involve one agent at a time made at intervals of not less that one week. A recommended approach is to continue the agents being used and add one drop of timolol in the affected eye(s) twice a day. On the following day, discontinue one of the other anti-glaucoma agents. The remaining anti-glaucoma agents may be decreased or discontinued according to the patient's response to treatment. The physician may be able to discontinue some or all of the other anti-glaucoma agents.

Elderly and Paediatric Use:

There are currently no clinical data indicating that dosage modifications are required for use in the elderly.

Safety and effectiveness in children have not been established by adequate and well-controlled studies.

Patients should be instructed to remove soft contact lenses before using timolol.

4.3 Contraindications

Timolol Eye Drops 0.50% are contraindicated in patients with bronchial asthma or with a history of bronchial asthma, or severe chronic obstructive pulmonary disease; sinus bradycardia; second and third degree atrioventricular block; overt cardiac failure; and cardiogenic shock.

This product is contraindicated in patients who are hypersensitive to any of its components.

4.4 Special Warnings And Precautions For Use

As with other topically applied ophthalmic drugs, this drug may be absorbed systemically. The same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely death in association with cardiac failure, have been reported following administration of Timolol Eye Drops 0.50%.

Patients who are receiving a beta-adrenergic blocking agent orally and Timolol Eye Drops 0.50% should be observed for a potential additive effect either on the intraocular pressure or on the known systemic effects of beta blockade.

Patients should not receive two topical ophthalmic beta-adrenergic blocking agents concurrently.

Because of potential effects of beta-adrenergic blockade agents relative to blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with Timolol Eye Drops 0.50%, alternative therapy should be considered.

Muscle Weakness: Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g. diplopia, ptosis, and generalized weakness). Timolol Eye Drops have been reported rarely to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.

In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil with a miotic. Timolol Eye Drops 0.50% have little or no effect on the pupil. When Timolol Eye Drops 0.50% are used to reduce elevated intraocular pressure in angle-closure glaucoma, it should be used with a miotic and not alone.

As with the use of other antiglaucoma drugs, diminished responsiveness to Timolol Eye Drops 0.50% after prolonged therapy has been reported in some patients. However, in one long-term study in which 96 patients have been followed for at least 3 years, no significant difference in mean intraocular pressure has been observed after initial stabilisation.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Although Timolol Eye Drops 0.50% used alone have little or no effect on pupil size, mydriasis resulting from concomitant therapy with Timolol Eye Drops and epinephrine has been reported occasionally.

Close observation of the patients is recommended when a beta blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

Caution should be used in the co-administration of beta-adrenergic agents, such as Timolol Eye Drops 0.50%, with oral or intravenous calcium antagonists, because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, co-administration should be avoided.

The concomitant use of beta-adrenergic blocking agents with digitalis may have additive effects in prolonging atrioventricular conduction time.

4.6 Pregnancy And Lactation

Teratogenicity studies with timolol in mice and rabbits at doses up to 50 mg/kg/day (40 times the maximum recommended human oral dose*) showed no evidence of foetal malformations. Although delayed foetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1000 mg/kg/day (approx. 830 time the maximum recommended human oral dose) were maternotoxic in mice and resulted in an increased number of foetal resorptions. Increased foetal resorptions were also seen in rabbits at doses of 40 times the maximum recommended human oral dose, in this case without apparent maternotoxicity. There are no adequate and well- controlled studies in pregnant women. Timolol Eye Drops 0.50% should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Nursing Mothers: Timolol maleate has been detected in human milk following oral and ophthalmic drug administration. Because of the potential for serious adverse reactions from timolol in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

*The maximum recommended daily oral dose is 60 mg of timolol. One drop of Timolol Eye Drops 0.50% contains about 1/300 of this dose which is about 0.2 mg.

4.7 Effects On Ability To Drive And Use Machines

There are currently no data available on the effects of this product with regard to the ability to drive. It has to be taken into account that during driving and using machines the possibility of transient ocular irritation, blurred vision and lacrimation may occur occasionally.

4.8 Undesirable Effects

Timolol Eye Drops 0.50% are usually well tolerated. The following adverse reactions have been reported either in clinical trials of up to 3 years duration prior to release in 1978 or since the drug has been marketed:

Body as a whole: headache, asthenia, chest pain

Cardiovascular: bradycardia, arrhythmia, hypotension, syncope, heart block, cerebral vascular accident, cerebral ischemia, cardiac failure, palpitation, cardiac arrest

Digestive: nausea, diarrhoea

Nervous System/Psychiatric: dizziness, depression, increase in signs and symptoms of myasthenia gravis, parasthesia

Skin: hypersensitivity, including localised and generalized rash; urticaria, alopecia

Respiratory: bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnoea, nasal congestion, cough

Endocrine: masked symptoms of hypoglycaemia in insulin-dependant diabetics

Special Senses: Signs and symptoms of ocular irritation, including conjunctivitis, blepharitis, keratitis, blepharoptosis, decreased corneal sensitivity, visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, ptosis.

Causal Relationship Unknown: The following adverse effects have been reported, and a causal relationship to therapy with Timolol Eye Drops has not been established: Body as a whole: Fatigue; Cardiovascular: Hypertension, pulmonary oedema, worsening of angina pectoris; Digestive: Dyspepsia, anorexia, dry mouth; Nervous System/Psychiatric: Behavioural changes including confusion, hallucinations, anxiety, disorientation, nervousness, somnolence, and other psychic disturbances; Special Senses: Aphakic systoid macular oedema; Urogenital: Retroperitoneal fibrosis, impotence.

The following additional adverse effects have been reported in clinical experience with oral timolol maleate, and may be considered potential effects of ophthalmic timolol maleate: Body as a Whole: Extremity pain, decreased exercise tolerance, weight loss; Cardiovascular: Oedema, worsening of arterial insufficiency, Raynaud's phenomenon, vasodilatation; Digestive: Gastrointestinal pain, hepatomegaly, vomiting; Haematologic: Nonthrombocytopenic purpura; Endocrine: Hyper-glycaemia, hypoglycaemia; Skin: Pruritus, skin irritation, increased pigmentation, sweating, cold hands and feet; Musculoskeletal: Arthralgia, claudication; Nervous System/Psychiatric: Vertigo, local weakness, decreased libido, nightmares, insomnia, diminished concentration; Respiratory: Rales, bronchial obstruction; Special Senses: Tinnitus, dry eyes; Urogenital: Urination difficulties.

Potential Adverse Effects: In addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and may be considered potential effects of ophthalmic timolol maleate: Digestive: Mesenteric arterial thrombosis, ischemic colitis; Haematologic: Agranulocytosis, thrombocytopenic purpura; Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics; Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress; Urogenital: Peyronie's disease.

There have been reports of a syndrome comprising psoriasiform skin rash, conjunctivitis sicca, otitis and sclerosing serositis attributed to the beta-adrenergic receptor blocking agent, practolol. This syndrome has not been reported with timolol maleate.

4.9 Overdose

No data are available in regard to overdosage in humans. The oral LD50 of the drug is 1190 and 900 mg/kg in female mice and female rats, respectively.

A. Signs and Overdosage Overdosage may lead to hypotension, cardiac failure, cardiogenic shock, bradycardia to the extreme of cardiac arrest. In addition respiratory distress, bronchospasms, vomiting, disturbed consciousness and generalized seizures may occur.

B. Treatment of Overdosage Apart from general measures, monitoring and if necessary, correction of vital signs under intensive care conditions are imperative. Antidotes include:

atropine:

0.5 to 2 mg IV bolus injection

glucagon:

Initial treatment with 1-10 mg IV, to be followed by 2-2.5 mg/h as continuous drip infusion.

?-sympathomimetic agents according to body weight and (desired) effect: dobutamine, isoprenaline, orciprenaline or adrenaline

Pacemaker control should be considered in refractory bradycardia.

?2-sympathomimetics (as aerosol or, intravenously, if the aerosol effect proves inadequate) or intravenous aminophylline can be used in bronchospasms.

Slow intravenous injection of diazepam is recommended to control seizures.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Therapeutic Group: Ophthalmologicals: Antiglaucoma Preparations & Miotics. ATC Code: S01E D01

Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic (membrane-stabilising) activity.

Beta-adrenergic receptor blockade reduces cardiac output in both healthy subjects and patients with heart disease. In patients with severe impairment of myocardial function, betaadrenergic receptor blockade may inhibit the stimulatory effect of the sympathetic nervous system necessary to maintain adequate cardiac function.

Beta-adrenergic receptor blockade in the bronchi and bronchioles results in increased airway resistance from unopposed para-sympathetic activity. Such an effect in patients with asthma or other bronchospastic conditions is potentially dangerous.

Timolol Eye Drops 0.50%, when applied topically in the eye, has the action of reducing elevated as well as normal intraocular pressure, whether or not accompanied by glaucoma.

Elevated intraocular pressure is major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous visual field loss and optic nerve damage.

The precise mechanism of the ocular hypotensive action of Timolol Eye Drops is not clearly established at this time. Tonography and fluoro-photometry studies in man suggest that this predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed. Unlike miotics, Timolol Eye Drops 0.50% reduces intraocular pressure with little or no effect on accommodation or pupil size. Thus, changes in visual acuity due to increased accommodation are uncommon, and dim or blurred vision and night blindness produced by miotics are not evident. In addition, in patients with cataracts the inability to see around lenticular opacities when the pupil is constricted is avoided.

5.2 Pharmacokinetic Properties

The onset of reduction in intraocular pressure following administration of Timolol can usually be detected within one-half hour after a single dose. The maximum effect usually occurs in one to two hours and significant lowering of intraocular pressure can be maintained for periods as long as 24 hours with a single dose. Repeated observations over a period of one year indicate that the intraocular pressure-lowering effect of Timolol Eye Drops 0.50% is well maintained.

5.3 Preclinical Safety Data

Carcinogenicity/Tumorigenicity - In a two-year study of timolol maleate in rats, there was a statistically significant increase in the incidence of adrenal phaeochromocytomas in male rats administered 300 mg/kg/day (250 time the maximum recommended human oral dose). The maximum recommended single oral dose is 60 mg of timolol. One drop of Timolol Eye Drops 0.50%, contains about 1/300 of this dose which is about 0.2 mg. Similar differences were not observed in rats administered oral doses equivalent to 20 or 80 times the maximum recommended human oral dose. In a life-time oral study in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumours and benign uterine polyps in female mice at 500 mg/kg/day (approximately 400 times the recommended daily human oral dose), but not at 5 or 50 mg/kg/day. In a subsequent study in female mice, in which post-mortem examinations were limited to uterus and lungs, a statistically significant increase in the incidence of pulmonary tumours was again observed at 500 mg/kg/day. The increased occurrence of mammary adenocarcinoma was associated with elevations in serum prolactin which occurred in female mice administered timolol at 500 mg/kg, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents which elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumours has been established in man. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate, the maximum recommended human oral dosage, there were no clinically meaningful changes in serum prolactin.

Mutagenicity - Timolol maleate was devoid of mutagenic potential when evaluated in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 µg/mL). In Ames tests the highest concentrations of timolol employed, 5000 or 10,000 µg/plate, were associated with statistically significant elevation of revertants observed with tester strain TA100 (in seven replicate assays), but not in the remaining three strains. In the assays with tester strain TA100, no consistent dose response relationship was observed, nor did the ratio of test to control revertants reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test.

Reproduction - Reproduction and fertility studies in rats showed no adverse effect on male or female fertility at doses up to 125 times the maximum recommended human oral dose.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium dihydrogen phosphate dihydrate

Disodium phosphate dodecahydrate

Benzalkonium chloride

Sodium hydroxide and/or hydrochloric acid (to adjust pH)

Purified water

6.2 Incompatibilities

Not known

6.3 Shelf Life

36 months for the 5 ml and 10 ml bottles (unopened), one month after the bottle is opened.

6.4 Special Precautions For Storage

Do not store above 25°C

6.5 Nature And Contents Of Container

Multi-dose opaque or natural low density polyethylene DROP-TAINER® bottles containing 5 ml or 10 ml of the ophthalmic solution.

6.6 Special Precautions For Disposal And Other Handling

Do not touch dropper tip to any surface as this may contaminate the contents. If the drop of medication is not retained in the eye upon dosing for any reason, instil another drop.

ADMINISTRATIVE DATA 7. Marketing Authorisation Holder

Cusi (UK) Ltd

Pentagon Park

Boundary Way

Hemel Hempstead

Herts., HP2 7UD

U.K.

8. Marketing Authorisation Number(S)

PL 16020/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

9th June 1998

10. Date Of Revision Of The Text

May 2003


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Timolol GFS


Generic Name: timolol maleate
Dosage Form: ophthlamic gel forming solution, extended release
FULL PRESCRIBING INFORMATION Indications and Usage for Timolol GFS

Timolol GFS 0.25% and 0.5% are indicated for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

Timolol GFS Dosage and Administration

Instill one drop of Timolol GFS (either 0.25% or 0.5%) in the affected eye(s) once daily. It may be used alone or in combination with other intraocular pressure lowering medications.

Dosage Forms and Strengths

5 mL size bottle filled with 2.5 mL or 5 mL of 0.25% or 0.5% sterile ophthalmic gel forming solution

Contraindications

Timolol GFS is contraindicated in patients with:

• bronchial asthma

• history of bronchial asthma

• severe chronic obstructive pulmonary disease

• sinus bradycardia

• second or third degree atrioventricular block

• overt cardiac failure

• cardiogenic shock

• hypersensitivity to any component of this product.

Warnings and Precautions General

As with many topically applied ophthalmic drugs, this drug is absorbed systemically.

The same adverse reactions found with systemic administration of beta-adrenergic receptor inhibitors may occur with topical ophthalmic administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and death due to cardiac failure, have been reported following systemic or ophthalmic administration of timolol maleate [see Contraindications (4)].

Cardiac Failure

Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure.

In patients without a history of cardiac failure, continued depression of the myocardium with beta-adrenergic receptor inhibitors over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac failure, Timolol GFS should be discontinued.

Bronchospasm and Obstructive Pulmonary Disease

Bronchospasm may occur. Patients with chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) of mild or moderate severity, bronchospastic disease, or a history of bronchospastic disease (other than bronchial asthma or a history of bronchial asthma, in which Timolol GFS is contraindicated [see Contraindications (4)]) should, in general, not receive beta-adrenergic receptor inhibitors, including Timolol GFS.

Surgical Anesthesia

The necessity or desirability of withdrawal of beta-adrenergic receptor inhibitors prior to major surgery is controversial. Beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli. This may augment the risk of general anesthesia in surgical procedures. Some patients receiving beta-adrenergic receptor inhibitors have experienced protracted, severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported. In patients undergoing elective surgery, consider gradual withdrawal of beta-adrenergic receptor inhibitors. If necessary during surgery, the effects of beta-adrenergic receptor inhibitors may be reversed by sufficient doses of adrenergic agonists.

Diabetes Mellitus

Beta-adrenergic receptor inhibitors should be administered with caution in diabetic patients subject to hypoglycemia who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic receptor inhibitors may mask the signs and symptoms of acute hypoglycemia.

Thyrotoxicosis

Beta-adrenergic receptor inhibitors may mask certain clinical signs (e.g. tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic receptor inhibitors that might precipitate a thyroid storm.

Cerebrovascular Insufficiency

Because of potential effects of beta-adrenergic receptor inhibitors on blood pressure and pulse, these agents should be used with caution in patients with cerebrovascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of therapy with Timolol GFS, alternative therapy should be considered.

Bacterial Keratitis

Bacterial keratitis may occur with use of multiple dose containers of topical ophthalmic products when these containers are inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. Instruct patients on appropriate instillation techniques [see Patient Counseling Information (17)].

Choroidal Detachment

Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant (e.g., timolol) therapy.

Angle-Closure Glaucoma

In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This may require constricting the pupil. Timolol GFS has little or no effect on the pupil and should not be used alone in the treatment of angle-closure glaucoma.

Atopy/Anaphylaxis

While taking beta receptor inhibitors, patients with a history of atopy or a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

Muscle Weakness

Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness). Timolol has been reported to increase muscle weakness in some patients with myasthenia gravis or myasthenic symptoms.

Adverse Reactions Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials with Timolol GFS, transient blurred vision upon instillation of the drop was reported in approximately one in three patients. The frequency of patients reporting burning and stinging upon instillation was approximately one in eight patients which was comparable to that observed for TIMOPTIC*.

Adverse reactions reported in 1-5% of patients were:

Ocular: Blepharitis, conjunctivitis, crusting, discomfort, foreign body sensation, hyperemia, pruritus and tearing;

Systemic: Headache, hypertension, and upper respiratory infections.

In a 3-month, double-masked, active-controlled, multicenter study in pediatric patients, the adverse reactions profile of Timolol GFS 0.25% and 0.5% was comparable to that seen in adult patients.

Additional Potential Adverse Reactions Associated with Timolol Maleate

The following additional adverse experiences have been reported with the ocular administration of this or other timolol maleate formulations:

BODY AS A WHOLE

Asthenia/fatigue and chest pain.

CARDIOVASCULAR

Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart block, cerebral vascular accident, cerebral ischemia, cardiac failure, worsening of angina pectoris, palpitation, cardiac arrest, pulmonary edema, dizziness, edema, claudication, Raynaud's phenomenon, and cold hands and feet.

DIGESTIVE

Nausea, diarrhea, dyspepsia, anorexia, and dry mouth.

IMMUNOLOGIC

Systemic lupus erythematosus.

NERVOUS SYSTEM/PSYCHIATRIC

Increase in signs and symptoms of myasthenia gravis, paresthesia, somnolence, insomnia, nightmares, behavioral changes and psychic disturbances including confusion, hallucinations, anxiety, depression, disorientation, nervousness, and memory loss.

SKIN

Alopecia and psoriasiform rash or exacerbation of psoriasis.

HYPERSENSITIVITY

Signs and symptoms of systemic allergic reactions, including anaphylaxis, angioedema, urticaria and localized and generalized rash.

RESPIRATORY

Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnea, nasal congestion, and cough.

ENDOCRINE

Masked symptoms of hypoglycemia in diabetic patients [see Warnings and Precautions (5.5)].

SPECIAL SENSES

Signs and symptoms of ocular irritation including blepharitis, keratitis, and dry eyes; ptosis; decreased corneal sensitivity; cystoid macular edema; visual disturbances including refractive changes and diplopia; pseudopemphigoid; choroidal detachment following filtration surgery [see Warnings and Precautions (5.9)]; and tinnitus.

UROGENITAL

Retroperitoneal fibrosis, decreased libido, impotence and Peyronie's disease.

Drug Interactions Oral Beta-Adrenergic Receptor Inhibitors

Patients who are receiving a beta-adrenergic receptor inhibiting agent orally and Timolol GFS should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure. Patients should not usually receive two topical ophthalmic beta-adrenergic receptor inhibiting agents concurrently.

Digitalis and Calcium Antagonists

The concomitant use of beta-adrenergic receptor inhibiting agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time.

Caution should be used in the co-administration of beta-adrenergic receptor inhibitors, such as Timolol GFS, and oral or intravenous calcium antagonists because of possible atrioventricular conduction disturbances, left ventricular failure, or hypotension. In patients with impaired cardiac function, co-administration should be avoided.

Catecholamine-Depleting Drugs

Close observation of the patient is recommended when a beta receptor inhibitor is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo, syncope, or postural hypotension.

Quinidine

Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol, possibly because quinidine inhibits the metabolism of timolol via the P-450 enzyme, CYP2D6.

Clonidine

Oral beta-adrenergic receptor inhibiting agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. There have been no reports of exacerbation of rebound hypertension with ophthalmic timolol maleate.

Injectable Epinephrine

[See Warnings and Precautions (5.11)]

USE IN SPECIFIC POPULATIONS Pregnancy

Teratogenic effects

Pregnancy Category C: Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose) demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1,000 mg/kg/day (142,000 times the systemic exposure following the maximum recommended human ophthalmic dose) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses of 14,000 times the systemic exposure following the maximum recommended human ophthalmic dose, in this case without apparent maternotoxicity.

There are no adequate and well-controlled studies in pregnant women. Timolol GFS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Timolol maleate has been detected in human milk following oral and ophthalmic drug administration. Because of the potential for serious adverse reactions in nursing infants from Timolol GFS, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and IOP-lowering effect of Timolol GFS 0.25% and 0.5% has been demonstrated in pediatric patients in a 3-month, multicenter, double-masked, active-controlled trial.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Overdosage

No data are available with regard to human overdose with, or accidental oral ingestion of Timolol GFS. There have been reports of inadvertent overdose with Timolol maleate ophthalmic solution resulting in systemic effects similar to those seen with systemic beta-adrenergic receptor inhibitors such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest [see also Adverse Reactions (6)].

Overdosage has been reported with timolol maleate tablets. A 30-year old female ingested 650 mg of timolol maleate tablets (maximum recommended oral daily dose is 60 mg) and experienced second and third degree heart block. She recovered without treatment but approximately two months later developed irregular heartbeat, hypertension, dizziness, tinnitus, faintness, increased pulse rate, and borderline first degree heart block.

An in vitro hemodialysis study, using 14C timolol added to human plasma or whole blood, showed that timolol was readily dialyzed from these fluids; however, a study of patients with renal failure showed that timolol did not dialyze readily.

Timolol GFS Description

Timolol GFS (timolol maleate ophthalmic gel forming solution) is a non-selective beta-adrenergic receptor inhibitor. Its chemical name is (-)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thia diazol-3-yl)oxy]-2-propanol maleate (1:1) (salt).

Timolol maleate possesses an asymmetric carbon atom in its structure and is provided at the levo-isomer. The nominal optical rotation of timolol maleate is:

[?] 25° in 0.1N HCl (C=5%) = -12.2°

     405 nm

Its molecular formula is C13H24N4O3S·C4H4O4 and its structural formula is:

Timolol maleate has a molecular weight of 432.50. It is a white, odorless, crystalline powder which is soluble in water, methanol, and alcohol. Timolol GFS is a colorless to nearly colorless, slightly opalescent, and slightly viscous, is supplied as a sterile, isotonic, buffered, aqueous topical ophthalmic solution of timolol maleate in two dosage strengths. Timolol GFS has a pH of approximately 6.9 and an osmolality of approximately 290 mOsmol/kg. Each mL of Timolol GFS 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate). Each mL of Timolol GFS 0.5% contains 5.0 mg of timolol (6.8 mg of timolol maleate). Inactive ingredients: xanthan gum, tromethamine, boric acid, mannitol, polysorbate-80, and purified water. Preservative: benzododecinium bromide 0.012%.

Xanthan gum is a purified high molecular weight polysaccharide gum produced from the fermentation by bacterium Xanthomonas campestris. An aqueous solution of xanthan gum, in the presence of tear protein (lysozyme), forms a gel. Upon contact with the precorneal tear film, Timolol GFS forms a gel that is subsequently removed by the flow of tears.

Timolol GFS - Clinical Pharmacology Mechanism of Action

Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor inhibitor that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity. Timolol GFS, when applied topically to the eye, has the action of reducing elevated, as well as normal, intraocular pressure, whether or not accompanied by glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss and optic nerve damage. The precise mechanism of the ocular hypotensive action of Timolol GFS is not clearly established at this time. Tonography and fluorophotometry studies of Timolol GFS in man suggest that its predominant action may be related to reduced aqueous formation. However, in some studies, a slight increase in outflow facility was also observed. Beta-adrenergic receptor blockade reduces cardiac output in both healthy subjects and patients with heart disease. In patients with severe impairment of myocardial function beta-adrenergic receptor inhibitors may inhibit the stimulatory effect of the sympathetic nervous system necessary to maintain adequate cardiac function. Beta-adrenergic receptor blockade in the bronchi and bronchioles results in increased airway resistance from unopposed parasympathetic activities. Such an effect in patients with asthma or other bronchospastic conditions is potentially dangerous.

Pharmacodynamics

Because in some patients the intraocular pressure-lowering response to Timolol GFS may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with Timolol GFS. If the patient's intraocular pressure is still not at a satisfactory level on this regimen, concomitant therapy can be considered.

Pharmacokinetics

Following topical ocular administration of timolol to humans, low concentrations of drug are found in plasma. After bilateral administration of a 0.5% timolol maleate solution to healthy volunteers, maximum plasma concentrations were generally below 5 ng/mL. Dosages higher than one drop of 0.5% Timolol GFS once daily have not been studied.

Pharmacokinetic studies in humans using this gel forming solution formulation were not performed. However, systemic uptake from a gel matrix is expected to be slower than from a non-gel forming solution based on studies using other gel forming solutions. The maximum plasma timolol concentration from the gel forming drop is not expected to exceed those of the 0.5% timolol maleate solution.

Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year study of timolol maleate administered orally to rats, there was a statistically significant increase in the incidence of adrenal pheochromocytomas in male rats administered 300 mg/kg/day (approximately 42,000 times the systemic exposure following the maximum recommended human ophthalmic dose). Similar differences were not observed in rats administered oral doses equivalent to approximately 14,000 times the maximum recommended human ophthalmic dose. In a lifetime oral study in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumors, benign uterine polyps, and mammary adenocarcinomas in female mice at 500 mg/kg/day (approximately 71,000 times the systemic exposure following the maximum recommended human ophthalmic dose), but not at 5 or 50 mg/kg/day (approximately 700 or 7,000, respectively, times the systemic exposure following the maximum recommended human ophthalmic dose). In a subsequent study in female mice, in which postmortem examinations were limited to the uterus and the lungs, a statistically significant increase in the incidence of pulmonary tumors was again observed at 500 mg/kg/day. The increased occurrence of mammary adenocarcinomas was associated with elevations in serum prolactin, which occurred in female mice administered oral timolol at 500 mg/kg/day, but not at oral doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents that elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumors has been established in humans. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate (the maximum recommended human oral dosage), there were no clinically meaningful changes in serum prolactin.

Timolol maleate was devoid of mutagenic potential when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg) and in vitro in a neoplastic cell transformation assay (up to 100 mcg/mL). In Ames tests, the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with statistically significant elevations of revertants observed with tester strain TA 100 (in seven replicate assays), but not in the remaining three strains. In the assays with tester strain TA 100, no consistent dose-response relationship was observed, and the ratio of test to control revertants did not reach 2. A ratio of 2 is usually considered the criterion for a positive Ames test.

Reproduction and fertility studies in rats demonstrated no adverse effect on male or female fertility at doses up to 21,000 times the systemic exposure following the maximum recommended human ophthalmic dose.

Clinical Studies

In controlled, double-masked, multicenter clinical studies, Timolol GFS administered once daily was compared to equivalent concentrations of TIMOPTIC* (timolol maleate ophthalmic solution) [Merck and Co., Inc.] administered twice daily. Timolol GFS once daily was shown to be equally effective in lowering intraocular pressure as the equivalent concentration of TIMOPTIC administered twice daily.

The effect of timolol in lowering intraocular pressure was evident for 24 hours with a single dose of Timolol GFS. Repeated observations over a three-month study period indicate that the intraocular pressure-lowering effect of Timolol GFS was consistent. The results from the clinical trials are shown in the following figures.

Timolol GFS administered once daily had a safety profile similar to that of an equivalent concentration of TIMOPTIC administered twice daily. Due to the physical characteristics of the formulation, transient blurred vision was reported more frequently in patients administered Timolol GFS [see Adverse Reactions (6)]. Timolol GFS has not been studied in patients wearing contact lenses.

How Supplied/Storage and Handling

Timolol GFS, 0.25% timolol equivalent and 0.5% timolol equivalent, are both supplied as either a 2.5 mL or 5 mL solution in a 5 mL white polyethylene bottle with a natural polyethylene dropper tip and a yellow polypropylene overcap. Tamper evidence is provided with a shrink band around the closure and neck area of the DROP-TAINER®** package.

• 0.25% 2.5 mL fill NDC 61314-224-25

              5 mL fill NDC 61314-224-05

• 0.5%   2.5 mL fill NDC 61314-225-25

              5 mL fill NDC 61314-225-05

Storage and Handling

Store at 2° to 25°C (36° to 77°F).

Protect from light.

Patient Counseling Information

How to Use the DROP-TAINER® Bottle

The DROP-TAINER® bottle is designed to assure the delivery of a precise dose of medication. Before using your DROP-TAINER® bottle, read the complete instructions carefully.

1. If you use other topically applied ophthalmic medications, they should be administered at least 10 minutes before Timolol GFS.

2. Wash hands before each use.

3. Before using the medication for the first time, be sure the Safety Seal on the bottle is unbroken.

4. Tear off the Safety Seal to break the seal.

5. Before each use, shake once and remove the screw cap.

6. Invert the bottle and hold the bottle between your thumb and middle finger, with the tips of the fingers pointing towards you.

7. Tilt your head back and position the bottle above the affected eye. DO NOT TOUCH THE EYE WITH THE TIP OF THE DROPPER.

8. With the opposite hand, place a finger under the eye. Gently pull down until a "V" pocket is made between your eye and lower lid.

9. With the hand holding the bottle, place your index finger on the bottom of the bottle. Push the bottom of the bottle to dispense one drop of medication. DO NOT SQUEEZE THE SIDES OF THE BOTTLE.

10. Repeat 6, 7, 8, and 9 with other eye if instructed to do so.

11. Replace screw cap by turning until firmly touching the bottle.

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye(s) or surrounding structures. Patients should also be instructed that ocular solutions, if handled improperly, could become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye(s) and subsequent loss of vision may result from using contaminated solutions. [see Warnings and Precautions (5.8)]

Patients should be advised that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container.

Patients should be instructed to invert the closed container and shake once before each use. It is not necessary to shake the container more than once.

Patients requiring concomitant topical ophthalmic medications should be instructed to administer these at least 10 minutes before instilling Timolol GFS.

Patients with bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second or third degree atrioventricular block, or cardiac failure should be advised not to take this product [see Contraindications (4)].

Patients should be advised that transient blurred vision or visual disturbance, generally lasting from 30 seconds to 5 minutes, following instillation may impair the ability to perform hazardous tasks such as operating machinery or driving a motor vehicle.

*TIMOPTIC is a Registered trademark of Merck & Co., Inc.

**DROP-TAINER® is a registered trademark of Alcon Manufacturing, Ltd.

Distributed by:

FALCON Pharmaceuticals, Ltd.

Fort Worth, Texas 76134

Manufactured by:

ALCON LABORATORIES, INC.

Fort Worth, Texas 76134

9002739-0807

PRINCIPAL DISPLAY PANEL

NDC 61314-224-05

Rx Only

FALCON® PHARMACEUTICALS

Timolol GFS

Timolol maleate ophthalmic gel forming solution

0.25%

5 mL STERILE

AFFILIATE OF ALCON LABORATORIES, INC.

QUALITY RX

    

    


Timolol GFS 
timolol maleate  solution, gel forming, extended release Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 61314-225 Route of Administration OPHTHALMIC DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength TIMOLOL MALEATE (TIMOLOL) TIMOLOL MALEATE 5 mg  in 1 mL Inactive Ingredients Ingredient Name Strength BENZODODECINIUM BROMIDE   XANTHAN GUM   TROMETHAMINE   BORIC ACID   MANNITOL   POLYSORBATE 80   WATER   Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 61314-225-25 2.5 mL In 1 BOTTLE None 2 61314-225-05 5 mL In 1 BOTTLE None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA020963 12/24/1998
Timolol GFS 
timolol maleate  solution, gel forming, extended release Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 61314-224 Route of Administration OPHTHALMIC DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength TIMOLOL MALEATE (TIMOLOL) TIMOLOL MALEATE 2.5 mg  in 1 mL Inactive Ingredients Ingredient Name Strength BENZODODECINIUM BROMIDE   XANTHAN GUM   TROMETHAMINE   BORIC ACID   MANNITOL   POLYSORBATE 80   WATER   Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 61314-224-25 2.5 mL In 1 BOTTLE None 2 61314-224-05 5 mL In 1 BOTTLE None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA020963 12/24/1998
Labeler - FALCON Pharmaceuticals, Ltd. (874345820) Registrant - ALCON LABORATORIES, INC. (008018525) Establishment Name Address ID/FEI Operations ALCON LABORATORIES, INC. 008018525 MANUFACTURE Revised: 07/2011FALCON Pharmaceuticals, Ltd. More Timolol GFS resources Timolol GFS Use in Pregnancy & Breastfeeding Timolol GFS Drug Interactions Timolol GFS Support Group 1 Review for Timolol GFS - Add your own review/rating Compare Timolol GFS with other medications Glaucoma, Open Angle Intraocular Hypertension
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Dorzolamide / Timolol eye drops


1. Name Of The Medicinal Product

Dorzolamide/Timolol 20mg/ml + 5mg/ml eye drops, solution

2. Qualitative And Quantitative Composition

Each ml contains 20mg dorzolamide (as Dorzolamide hydrochloride) and 5mg timolol (as timolol maleate).

Excipients: each ml of eye drops solution contains 0.075mg benzalkonium chloride.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Eye drops, solution.

Clear, slightly viscous, colourless aqueous solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Dorzolamide/Timolol is indicated in the treatment of elevated intra-ocular pressure (IOP) in patients with open-angle glaucoma or pseudo-exfoliative glaucoma when topical beta-blocker monotherapy is not sufficient.

4.2 Posology And Method Of Administration

The dose is one drop of Dorzolamide/Timolol in the (conjunctival sac of the) affected eye(s) two times daily.

If another topical ophthalmic medicinal product is being used, the other agent should be administered at least ten minutes apart.

Paediatric population:

Efficacy in paediatric patients has not been established.

Safety in paediatric patients below the age of two years has not been established. (For information regarding safety in paediatric patients

Patients should be instructed to wash their hands before use and avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.

In order to secure correct dosage – the dropper tip should not be enlarged.

Patients should also be instructed that ocular solutions, if handled improperly, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

Patients should be informed of the correct handling of the ophthalmic Dorzolamide/Timolol.

Usage instructions:

1. The tamper-proof seal on the bottle neck must be unbroken before the product is being used for the first time. A gap between the bottle and the cap is normal for an unopened bottle.

2. The cap of the bottle should be taken off.

3. The patient's head must be tilted back and the lower eyelid must be pulled gently down to form a small pocket between the eyelid and the eye.

4. The bottle should be inverted and squeezed until a single drop is dispensed into the eye. THE EYE OR EYELID MUST NOT BE TOUCHED WITH THE DROPPER TIP.

5. Steps 3 & 4 should be repeated with the other eye if it is necessary.

6. The cap must be put back on and the bottle must be closed straight after it has been used.

4.3 Contraindications

Dorzolamide/Timolol is contra-indicated in patients with:

• reactive airway disease, including bronchial asthma or a history of bronchial asthma, or severe chronic obstructive pulmonary disease

• sinus bradycardia, second- or third-degree atrioventricular block, overt cardiac failure, cardiogenic shock

• severe renal impairment (creatinine clearance < 30ml/min) or hyperchloraemic acidosis

• hypersensitivity to one or both active substances or to any of the excipients.

The above are based on the components and are not unique to the combination.

4.4 Special Warnings And Precautions For Use

Cardiovascular/respiratory reactions

As with other topically-applied ophthalmic agents, this drug may be absorbed systemically. The timolol component is a beta-blocker. Therefore, the same types of adverse reactions found with systemic administration of beta-blockers may occur with topical administration, including worsening of Prinzmetal's angina, worsening of severe peripheral and central circulatory disorders, and hypotension.

Because of the timolol maleate component, cardiac failure should be adequately controlled before beginning therapy with Dorzolamide/Timolol. In patients with a history of severe cardiac disease, signs of cardiac failure should be watched for and pulse rates should be checked.

Respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma and rarely death in association with cardiac failure, have been reported following administration of timolol maleate.

Hepatic impairment

Dorzolamide/Timolol eye drops solution has not been studied in patients with hepatic impairment and therefore should be used with caution in such patients.

Immunology and hypersensitivity

As with other topically-applied ophthalmic agents, this drug may be absorbed systemically. The dorzolamide component is a sulphonamide. Therefore the same types of adverse reactions found with systemic administration of sulphonamides may occur with topical administration. If signs of serious reactions or hypersensitivity occur, discontinue use of this preparation.

Local ocular adverse effects, similar to those observed with dorzolamide hydrochloride eye drops, have been seen with Dorzolamide/Timolol eye drops solution. If such reactions occur, discontinuation of Dorzolamide/Timolol should be considered.

While taking ?-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to accidental, diagnostic, or therapeutic repeated challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

Concomitant therapy

The following concomitant medication is not recommended:

? dorzolamide and oral carbonic anhydrase inhibitors

? topical beta-adrenergic blocking agents.

Withdrawal of therapy

As with systemic beta-blockers, if discontinuation of ophthalmic timolol is needed in patients with coronary heart disease, therapy should be withdrawn gradually.

Additional effects of beta-blockade

Therapy with beta-blockers may mask certain symptoms of hypoglycaemia in patients with diabetes mellitus or hypoglycaemia.

Therapy with beta-blockers may mask certain symptoms of hyperthyroidism. Abrupt withdrawal of beta-blocker therapy may precipitate a worsening of symptoms.

Therapy with beta-blockers may aggravate symptoms of myasthenia gravis.

Additional effects of carbonic anhydrase inhibition

Therapy with oral carbonic anhydrase inhibitors has been associated with urolithiasis as a result of acid-base disturbances, especially in patients with a prior history of renal calculi. Although no acid-base disturbances have been observed with Dorzolamide/Timolol eye drops solution, urolithiasis has been reported infrequently. Because Dorzolamide/Timolol contains a topical carbonic anhydrase inhibitor that is absorbed systemically, patients with a prior history of renal calculi may be at increased risk of urolithiasis while using Dorzolamide/Timolol.

Other

The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. Dorzolamide/Timolol eye drops solution has not been studied in patients with acute angle-closure glaucoma.

Corneal oedema and irreversible corneal decompensation have been reported in patients with pre-existing chronic corneal defects and/or a history of intra-ocular surgery while using dorzolamide. Topical dorzolamide should be used with caution in such patients.

Choroidal detachment concomitant with ocular hypotony have been reported after filtration procedures with administration of aqueous suppressant therapies.

As with the use of other antiglaucoma drugs, diminished responsiveness to ophthalmic timolol maleate after prolonged therapy has been reported in some patients. However, in clinical studies in which 164 patients have been followed for at least three years, no significant difference in mean intra-ocular pressure has been observed after initial stabilisation.

Contact lens use

Dorzolamide/Timolol contains the preservative benzalkonium chloride, which may cause eye irritation. Benzalkonium chloride is known to discolour soft contact lenses. Remove contact lenses prior to application and wait at least 15 minutes before reinsertion.

Paediatric use

See section 5.1.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Specific drug interaction studies have not been performed with Dorzolamide/Timolol eye drops solution.

In clinical studies, Dorzolamide/Timolol eye drops solution was used concomitantly with the following systemic medications without evidence of adverse interactions: ACE-inhibitors, calcium channel blockers, diuretics, non-steroidal anti-inflammatory drugs including aspirin, and hormones (e.g. oestrogen, insulin, thyroxine).

However, the potential exists for additive effects and production of hypotension and/or marked bradycardia when timolol maleate ophthalmic solution is administered together with oral calcium channel blockers, catecholamine-depleting drugs or beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, narcotics, and monoamine oxidase (MAO) inhibitors.

Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, SSRIs) and timolol.

The dorzolamide component of Dorzolamide/Timolol is a carbonic anhydrase inhibitor and although administered topically, is absorbed systemically. In clinical studies, dorzolamide hydrochloride ophthalmic solution was not associated with acid-base disturbances. However, these disturbances have been reported with oral carbonic anhydrase inhibitors and have in some instances, resulted in drug interactions (e.g., toxicity associated with high-dose salicylate therapy). Therefore, the potential for such drug interactions should be considered in patients receiving Dorzolamide/Timolol.

Although Dorzolamide/Timolol alone has little or no effect on pupil size, mydriasis resulting from concomitant use of ophthalmic timolol maleate and epinephrine has been reported occasionally.

Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents.

Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine.

4.6 Pregnancy And Lactation

Pregnancy

Dorzolamide/Timolol should not be used during pregnancy.

Dorzolamide

No adequate clinical data in exposed pregnancies are available. In rabbits, dorzolamide produced teratogenic effects at maternotoxic doses (see Section 5.3).

Timolol

Well controlled epidemiological studies with systemic beta blockers showed no evidence of teratogenic effects, but some pharmacological effects such as bradycardia were observed in fetuses or neonates. If Dorzolamide/Timolol is administered until delivery, the neonate should be carefully monitored during the first days of life.

Lactation

It is not known whether dorzolamide is excreted in human milk. In lactating rats receiving dorzolamide, decreases in the body weight gain of offspring were observed. Timolol does appear in human milk. Dorzolamide/Timolol should not be used during lactation.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Possible side effects such as blurred vision may affect some patients' ability to drive and/or operate machinery.

4.8 Undesirable Effects

In clinical studies no adverse experiences specific to Dorzolamide/Timolol have been observed; adverse experiences have been limited to those that were reported previously with dorzolamide hydrochloride and/or timolol maleate. In general, common adverse experiences were mild and did not cause discontinuation.

During clinical studies, 1,035 patients were treated with Dorzolamide/Timolol eye drops solution. Approximately 2.4% of all patients discontinued therapy with Dorzolamide/Timolol eye drops solution because of local ocular adverse reactions, approximately 1.2% of all patients discontinued because of local adverse reactions suggestive of allergy or hypersensitivity (such as lid inflammation and conjunctivitis).

The following adverse reactions have been reported with Dorzolamide/Timolol eye drops solution or one of its components either during clinical trials or during post-marketing experience:

[Very Common: (

Nervous system and Psychiatric disorders:

Dorzolamide hydrochloride ophthalmic solution:

Common: headache*

Rare: dizziness*, paresthesia*

Timolol maleate ophthalmic solution:

Common: headache*

Uncommon: dizziness*, depression*

Rare: insomnia*, nightmares*, memory loss, paraesthesia*, increase in signs and symptoms of myasthenia gravis, decreased libido*, cerebrovascular accident*

Eye disorders:

Dorzolamide/Timolol ophthalmic solution:

Very Common: burning and stinging

Common: conjunctival injection, blurred vision, corneal erosion, ocular itching, tearing

Dorzolamide hydrochloride ophthalmic solution:

Common: eyelid inflammation*, eyelid irritation*

Uncommon: iridocyclitis*

Rare: irritation including redness*, pain*, eyelid crusting*, transient myopia (which resolved upon discontinuation of therapy), corneal oedema*, ocular hypotony*, choroidal detachment (following filtration surgery)*

Timolol maleate ophthalmic solution:

Common: signs and symptoms of ocular irritation including blepharitis*, keratitis*, decreased corneal sensitivity, and dry eyes*

Uncommon: visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases)*

Rare: ptosis, diplopia, choroidal detachment (following filtration surgery)*

Ear and labyrinth disorders:

Timolol maleate ophthalmic solution:

Rare: tinnitus*

Cardiac and Vascular disorders:

Timolol maleate ophthalmic solution:

Uncommon: bradycardia*, syncope*

Rare: hypotension*, chest pain*, palpitation*, oedema*, arrhythmia*, congestive heart failure*, heart block*, cardiac arrest*, cerebral ischaemia, claudication, Raynaud's phenomenon*, cold hands and feet*

Respiratory, thoracic, and mediastinal disorders:

Dorzolamide/Timolol ophthalmic solution:

Common: sinusitis

Rare: shortness of breath, respiratory failure, rhinitis

Dorzolamide hydrochloride ophthalmic solution:

Rare: epistaxis*

Timolol maleate ophthalmic solution:

Uncommon: dyspnoea*

Rare: bronchospasm (predominantly in patients with pre-existing bronchospastic disease)*, cough*

Gastro-intestinal disorders:

Dorzolamide/Timolol ophthalmic solution:

Very Common: taste perversion

Dorzolamide hydrochloride ophthalmic solution:

Common: nausea*

Rare: throat irritation, dry mouth*

Timolol maleate ophthalmic solution:

Uncommon: nausea*, dyspepsia*

Rare: diarrhoea, dry mouth*

Skin and subcutaneous tissue disorders:

Dorzolamide/Timolol ophthalmic solution:

Rare: contact dermatitis

Dorzolamide hydrochloride ophthalmic solution:

Rare: rash*

Timolol maleate ophthalmic solution:

Rare: alopecia*, psoriasiform rash or exacerbation of psoriasis*

Musculoskeletal and connective tissue disorders:

Timolol maleate ophthalmic solution:

Rare: systemic lupus erythematosus

Renal and Urinary disorders:

Dorzolamide/Timolol ophthalmic solution:

Uncommon: urolithiasis

Reproductive system and breast disorders:

Timolol maleate ophthalmic solution:

Rare: Peyronie's disease*

General disorders and administration site disorders:

Dorzolamide/Timolol ophthalmic solution:

Rare: signs and symptoms of systemic allergic reactions, including angioedema, urticaria, pruritus, rash, anaphylaxis, rarely bronchospasm

Dorzolamide hydrochloride ophthalmic solution:

Common: asthenia/fatigue*

Timolol maleate ophthalmic solution:

Uncommon: asthenia/fatigue*

*These adverse reactions were also observed with Dorzolamide/Timolol ophthalmic solution during post-marketing experience.

Laboratory findings

Dorzolamide/Timolol eye drops solution was not associated with clinically meaningful electrolyte disturbances in clinical studies.

4.9 Overdose

No data are available in humans in regard to overdosage by accidental or deliberate ingestion of Dorzolamide/Timolol eye drops solution.

There have been reports of inadvertent overdosage with timolol maleate ophthalmic solution resulting in systemic effects similar to those seen with systemic beta

Only limited information is available with regard to human overdosage by accidental or deliberate ingestion of dorzolamide hydrochloride. With oral ingestion, somnolence has been reported. With topical application the following have been reported: nausea, dizziness, headache, fatigue, abnormal dreams, and dysphagia.

Treatment should be symptomatic and supportive. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. Studies have shown that timolol does not dialyse readily.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiglaucoma preparations and miotics, Beta-Blocking Agents, Timolol, Combinations.

ATC code: S01E D51

Mechanism of action

Dorzolamide/Timolol eye drops solution is comprised of two components: dorzolamide hydrochloride and timolol maleate. Each of these two components decreases elevated intra-ocular pressure by reducing aqueous humor secretion, but does so by a different mechanism of action.

Dorzolamide hydrochloride is a potent inhibitor of human carbonic anhydrase II.

Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. Timolol maleate is a non-selective beta-adrenergic receptor blocking agent. The precise mechanism of action of timolol maleate in lowering intra-ocular pressure is not clearly established at this time, although a fluorescein study and tonography studies indicate that the predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed. The combined effect of these two agents results in additional intra-ocular pressure reduction compared to either component administered alone.

Following topical administration, Dorzolamide/Timolol eye drops solution reduces elevated intra-ocular pressure, whether or not associated with glaucoma. Elevated intra-ocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss.

Dorzolamide/Timolol eye drops solution reduces intra-ocular pressure without the common side effects of miotics such as night blindness, accommodative spasm and pupillary constriction.

Pharmacodynamic effects

Clinical effects:

Adult Patients

Clinical studies of up to 15 months duration were conducted to compare the IOP-lowering effect of Dorzolamide/Timolol eye drops solution b.i.d. (dosed morning and bedtime) to individually- and concomitantly-administered 0.5% timolol and 2.0% dorzolamide in patients with glaucoma or ocular hypertension for whom concomitant therapy was considered appropriate in the trials. This included both untreated patients and patients inadequately controlled with timolol monotherapy. The majority of patients were treated with topical beta-blocker monotherapy prior to study enrollment. In an analysis of the combined studies, the IOP-lowering effect of Dorzolamide/Timolol eye drops solution b.i.d. was greater than that of monotherapy with either 2% dorzolamide t.i.d. or 0.5% timolol b.i.d. The IOP-lowering effect of Dorzolamide/Timolol eye drops solution b.i.d. was equivalent to that of concomitant therapy with dorzolamide b.i.d. and timolol b.i.d. The IOP-lowering effect of Dorzolamide/Timolol eye drops solution b.i.d. was demonstrated when measured at various time points throughout the day and this effect was maintained during long-term administration.

Paediatric Population

A three month controlled study, with the primary objective of documenting the safety of 2% dorzolamide hydrochloride ophthalmic solution in children under the age of 6 years has been conducted. In this study, 30 patients under six and greater than or equal to two years of age whose IOP was not adequately controlled with monotherapy by dorzolamide or timolol received Dorzolamide/Timolol eye drops solution in an open label phase. Efficacy in those patients has not been established. In this small group of patients, twice daily administration of Dorzolamide/Timolol eye drops solution was generally well tolerated with 19 patients completing the treatment period and 11 patients discontinuing for surgery, a change in medication, or other reasons.

5.2 Pharmacokinetic Properties

Dorzolamide hydrochloride:

Unlike oral carbonic anhydrase inhibitors, topical administration of dorzolamide hydrochloride allows for the drug to exert its effects directly in the eye at substantially lower doses and therefore with less systemic exposure. In clinical trials, this resulted in a reduction in IOP without the acid-base disturbances or alterations in electrolytes characteristic of oral carbonic anhydrase inhibitors.

When topically applied, dorzolamide reaches the systemic circulation. To assess the potential for systemic carbonic anhydrase inhibition following topical administration, drug and metabolite concentrations in red blood cells (RBCs) and plasma and carbonic anhydrase inhibition in RBCs were measured. Dorzolamide accumulates in RBCs during chronic dosing as a result of selective binding to CA-II while extremely low concentrations of free drug in plasma are maintained. The parent drug forms a single N-desethyl metabolite that inhibits CA-II less potently than the parent drug but also inhibits a less active isoenzyme (CA-I). The metabolite also accumulates in RBCs where it binds primarily to CA-I. Dorzolamide binds moderately to plasma proteins (approximately 33%). Dorzolamide is primarily excreted unchanged in the urine; the metabolite is also excreted in urine. After dosing ends, dorzolamide washes out of RBCs non-linearly, resulting in a rapid decline of drug concentration initially, followed by a slower elimination phase with a half-life of about four months.

When dorzolamide was given orally to simulate the maximum systemic exposure after long term topical ocular administration, steady state was reached within 13 weeks. At steady state, there was virtually no free drug or metabolite in plasma; CA inhibition in RBCs was less than that anticipated to be necessary for a pharmacological effect on renal function or respiration. Similar pharmacokinetic results were observed after chronic, topical administration of dorzolamide hydrochloride. However, some elderly patients with renal impairment (estimated creatinine clearance 30-60 millilitre/min) had higher metabolite concentrations in RBCs, but no meaningful differences in carbonic anhydrase inhibition and no clinically significant systemic side effects were directly attributable to this finding.

Timolol maleate:

In a study of plasma drug concentration in six subjects, the systemic exposure to timolol was determined following twice daily topical administration of timolol maleate ophthalmic solution 0.5%. The mean peak plasma concentration following morning dosing was 0.46ng/millilitre and following afternoon dosing was 0.35ng/millilitre.

5.3 Preclinical Safety Data

The ocular and systemic safety profile of the individual components is well established.

Dorzolamide

In rabbits given maternotoxic doses of dorzolamide associated with metabolic acidosis, malformations of the vertebral bodies were observed.

Timolol

Animal studies have not shown a teratogenic effect.

Furthermore, no adverse ocular effects were seen in animals treated topically with dorzolamide hydrochloride and timolol maleate ophthalmic solution or with concomitantly-administered dorzolamide hydrochloride and timolol maleate. In vitro and in vivo studies with each of the components did not reveal a mutagenic potential. Therefore, no significant risk for human safety is expected with therapeutic doses of Dorzolamide/Timolol eye drops solution.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Mannitol (E421)

Hydroxyethyl Cellulose

Sodium Citrate (E331)

Sodium Hydroxide (E524)(for pH adjustment)

Benzalkonium chloride

Water for injections

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years

After first opening: 28 days

6.4 Special Precautions For Storage

This medicinal product does not require any special temperature storage conditions

6.5 Nature And Contents Of Container

White opaque medium density polyethylene bottle ophthalmic dispenser with a sealed LDPE dropper tip and a HDPE screw cap with tamper proof seal in a cardboard box.

Pack size: 1 bottle of 5ml each

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Pharmathen S.A.

6 Dervenakion str.,

15351 Pallini, Attiki

Greece

8. Marketing Authorisation Number(S)

PL 17277/0243

9. Date Of First Authorisation/Renewal Of The Authorisation

11/03/2011

10. Date Of Revision Of The Text

11/03/2011

LEGAL CATEGORY

POM


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Tidomat 20mg / ml + 5mg / ml eye drops, solution


1. Name Of The Medicinal Product

Tidomat 20 mg/ml + 5 mg/ml eye drops, solution

2. Qualitative And Quantitative Composition

Each ml contains 20 mg dorzolamide (as Dorzolamide hydrochloride) and 5 mg timolol (as timolol maleate).

Excipients: each ml of eye drops solution contains 0.075 mg benzalkonium chloride.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Eye drops, solution.

Clear, slightly viscous, colourless aqueous solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Tidomat is indicated in the treatment of elevated intra-ocular pressure (IOP) in patients with open-angle glaucoma or pseudo-exfoliative glaucoma when topical beta-blocker monotherapy is not sufficient.

4.2 Posology And Method Of Administration

The dose is one drop of Tidomat in the (conjunctival sac of the) affected eye(s) two times daily.

If another topical ophthalmic medicinal product is being used, the other agent should be administered at least ten minutes apart.

Paediatric population:

Efficacy in paediatric patients has not been established.

Safety in paediatric patients below the age of two years has not been established. (For information regarding safety in paediatric patients

Patients should be instructed to wash their hands before use and avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.

In order to secure correct dosage - the dropper tip should not be enlarged.

Patients should also be instructed that ocular solutions, if handled improperly, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

Patients should be informed of the correct handling of the ophthalmic Tidomat.

Usage instructions:

1. The tamper-proof seal on the bottle neck must be unbroken before the product is being used for the first time. A gap between the bottle and the cap is normal for an unopened bottle.

2. The cap of the bottle should be taken off.

3. The patient's head must be tilted back and the lower eyelid must be pulled gently down to form a small pocket between the eyelid and the eye.

4. The bottle should be inverted and squeezed until a single drop is dispensed into the eye. THE EYE OR EYELID MUST NOT BE TOUCHED WITH THE DROPPER TIP.

5. Steps 3 & 4 should be repeated with the other eye if it is necessary.

6. The cap must be put back on and the bottle must be closed straight after it has been used.

4.3 Contraindications

Tidomat is contra-indicated in patients with:

• reactive airway disease, including bronchial asthma or a history of bronchial asthma, or severe chronic obstructive pulmonary disease

• sinus bradycardia, second- or third-degree atrioventricular block, overt cardiac failure, cardiogenic shock

• severe renal impairment (creatinine clearance < 30 ml/min) or hyperchloraemic acidosis

• hypersensitivity to one or both active substances or to any of the excipients.

The above are based on the components and are not unique to the combination.

4.4 Special Warnings And Precautions For Use

Cardiovascular/respiratory reactions

As with other topically-applied ophthalmic agents, this drug may be absorbed systemically. The timolol component is a beta-blocker. Therefore, the same types of adverse reactions found with systemic administration of beta-blockers may occur with topical administration, including worsening of Prinzmetal's angina, worsening of severe peripheral and central circulatory disorders, and hypotension.

Because of the timolol maleate component, cardiac failure should be adequately controlled before beginning therapy with Tidomat. In patients with a history of severe cardiac disease, signs of cardiac failure should be watched for and pulse rates should be checked.

Respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma and rarely death in association with cardiac failure, have been reported following administration of timolol maleate.

Hepatic impairment

Dorzolamide/Timolol eye drops solution has not been studied in patients with hepatic impairment and therefore should be used with caution in such patients.

Immunology and hypersensitivity

As with other topically-applied ophthalmic agents, this drug may be absorbed systemically. The dorzolamide component is a sulphonamide. Therefore the same types of adverse reactions found with systemic administration of sulphonamides may occur with topical administration. If signs of serious reactions or hypersensitivity occur, discontinue use of this preparation.

Local ocular adverse effects, similar to those observed with dorzolamide hydrochloride eye drops, have been seen with Dorzolamide/Timolol eye drops solution. If such reactions occur, discontinuation of Tidomat should be considered.

While taking ?-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to accidental, diagnostic, or therapeutic repeated challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

Concomitant therapy

The following concomitant medication is not recommended:

? dorzolamide and oral carbonic anhydrase inhibitors

? topical betaadrenergic blocking agents.

Withdrawal of therapy

As with systemic beta-blockers, if discontinuation of ophthalmic timolol is needed in patients with coronary heart disease, therapy should be withdrawn gradually.

Additional effects of beta-blockade

Therapy with beta-blockers may mask certain symptoms of hypoglycaemia in patients with diabetes mellitus or hypoglycaemia.

Therapy with beta-blockers may mask certain symptoms of hyperthyroidism. Abrupt withdrawal of beta-blocker therapy may precipitate a worsening of symptoms.

Therapy with beta-blockers may aggravate symptoms of myasthenia gravis.

Additional effects of carbonic anhydrase inhibition

Therapy with oral carbonic anhydrase inhibitors has been associated with urolithiasis as a result of acid-base disturbances, especially in patients with a prior history of renal calculi. Although no acid-base disturbances have been observed with Dorzolamide/Timolol eye drops solution, urolithiasis has been reported infrequently. Because Tidomat contains a topical carbonic anhydrase inhibitor that is absorbed systemically, patients with a prior history of renal calculi may be at increased risk of urolithiasis while using Tidomat.

Other

The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. Dorzolamide/Timolol eye drops solution has not been studied in patients with acute angle-closure glaucoma.

Corneal oedema and irreversible corneal decompensation have been reported in patients with pre-existing chronic corneal defects and/or a history of intra-ocular surgery while using dorzolamide. Topical dorzolamide should be used with caution in such patients.

Choroidal detachment concomitant with ocular hypotony have been reported after filtration procedures with administration of aqueous suppressant therapies.

As with the use of other antiglaucoma drugs, diminished responsiveness to ophthalmic timolol maleate after prolonged therapy has been reported in some patients. However, in clinical studies in which 164 patients have been followed for at least three years, no significant difference in mean intra-ocular pressure has been observed after initial stabilisation.

Contact lens use

Tidomat contains the preservative benzalkonium chloride, which may cause eye irritation. Benzalkonium chloride is known to discolour soft contact lenses. Remove contact lenses prior to application and wait at least 15 minutes before reinsertion.

Paediatric use

See section 5.1.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Specific drug interaction studies have not been performed with Dorzolamide/Timolol eye drops solution.

In clinical studies, Dorzolamide/Timolol eye drops solution was used concomitantly with the following systemic medications without evidence of adverse interactions: ACE-inhibitors, calcium channel blockers, diuretics, non-steroidal anti-inflammatory drugs including aspirin, and hormones (e.g. oestrogen, insulin, thyroxine).

However, the potential exists for additive effects and production of hypotension and/or marked bradycardia when timolol maleate ophthalmic solution is administered together with oral calcium channel blockers, catecholamine-depleting drugs or beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, narcotics, and monoamine oxidase (MAO) inhibitors.

Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, SSRIs) and timolol.

The dorzolamide component of Tidomat is a carbonic anhydrase inhibitor and although administered topically, is absorbed systemically. In clinical studies, dorzolamide hydrochloride ophthalmic solution was not associated with acid-base disturbances. However, these disturbances have been reported with oral carbonic anhydrase inhibitors and have in some instances, resulted in drug interactions (e.g., toxicity associated with high-dose salicylate therapy). Therefore, the potential for such drug interactions should be considered in patients receiving Tidomat.

Although Tidomat alone has little or no effect on pupil size, mydriasis resulting from concomitant use of ophthalmic timolol maleate and epinephrine has been reported occasionally.

Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents.

Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine.

4.6 Pregnancy And Lactation

Pregnancy

Tidomat should not be used during pregnancy.

Dorzolamide

No adequate clinical data in exposed pregnancies are available. In rabbits, dorzolamide produced teratogenic effects at maternotoxic doses (see Section 5.3).

Timolol

Well controlled epidemiological studies with systemic beta blockers showed no evidence of teratogenic effects, but some pharmacological effects such as bradycardia were observed in fetuses or neonates. If Tidomat is administered until delivery, the neonate should be carefully monitored during the first days of life.

Lactation

It is not known whether dorzolamide is excreted in human milk. In lactating rats receiving dorzolamide, decreases in the body weight gain of offspring were observed. Timolol does appear in human milk. Tidomat should not be used during lactation.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Possible side effects such as blurred vision may affect some patients' ability to drive and/or operate machinery.

4.8 Undesirable Effects

In clinical studies no adverse experiences specific to Dorzolamide/Timolol have been observed; adverse experiences have been limited to those that were reported previously with dorzolamide hydrochloride and/or timolol maleate. In general, common adverse experiences were mild and did not cause discontinuation.

During clinical studies, 1,035 patients were treated with Dorzolamide/Timolol eye drops solution. Approximately 2.4% of all patients discontinued therapy with Dorzolamide/Timolol eye drops solution because of local ocular adverse reactions, approximately 1.2% of all patients discontinued because of local adverse reactions suggestive of allergy or hypersensitivity (such as lid inflammation and conjunctivitis).

The following adverse reactions have been reported with Dorzolamide/Timolol eye drops solution or one of its components either during clinical trials or during post-marketing experience:

[Very Common: (

Nervous system and Psychiatric disorders:

Dorzolamide hydrochloride ophthalmic solution:

Common: headache*

Rare: dizziness*, paresthesia*

Timolol maleate ophthalmic solution:

Common: headache*

Uncommon: dizziness*, depression*

Rare: insomnia*, nightmares*, memory loss, paraesthesia*, increase in signs and symptoms of myasthenia gravis, decreased libido*, cerebrovascular accident*

Eye disorders:

Dorzolamide/Timolol ophthalmic solution:

Very Common: burning and stinging

Common: conjunctival injection, blurred vision, corneal erosion, ocular itching, tearing

Dorzolamide hydrochloride ophthalmic solution:

Common: eyelid inflammation*, eyelid irritation*

Uncommon: iridocyclitis*

Rare: irritation including redness*, pain*, eyelid crusting*, transient myopia (which resolved upon discontinuation of therapy), corneal oedema*, ocular hypotony*, choroidal detachment (following filtration surgery)*

Timolol maleate ophthalmic solution:

Common: signs and symptoms of ocular irritation including blepharitis*, keratitis*, decreased corneal sensitivity, and dry eyes*

Uncommon: visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases)*

Rare: ptosis, diplopia, choroidal detachment (following filtration surgery)*

Ear and labyrinth disorders:

Timolol maleate ophthalmic solution:

Rare: tinnitus*

Cardiac and Vascular disorders:

Timolol maleate ophthalmic solution:

Uncommon: bradycardia*, syncope*

Rare: hypotension*, chest pain*, palpitation*, oedema*, arrhythmia*, congestive heart failure*, heart block*, cardiac arrest*, cerebral ischaemia, claudication, Raynaud's phenomenon*, cold hands and feet*

Respiratory, thoracic, and mediastinal disorders:

Dorzolamide/Timolol ophthalmic solution:

Common: sinusitis

Rare: shortness of breath, respiratory failure, rhinitis

Dorzolamide hydrochloride ophthalmic solution:

Rare: epistaxis*

Timolol maleate ophthalmic solution:

Uncommon: dyspnoea*

Rare: bronchospasm (predominantly in patients with pre-existing bronchospastic disease)*, cough*

Gastro-intestinal disorders:

Dorzolamide/Timolol ophthalmic solution:

Very Common: taste perversion

Dorzolamide hydrochloride ophthalmic solution:

Common: nausea*

Rare: throat irritation, dry mouth*

Timolol maleate ophthalmic solution:

Uncommon: nausea*, dyspepsia*

Rare: diarrhoea, dry mouth*

Skin and subcutaneous tissue disorders:

Dorzolamide/Timolol ophthalmic solution:

Rare: contact dermatitis

Dorzolamide hydrochloride ophthalmic solution:

Rare: rash*

Timolol maleate ophthalmic solution:

Rare: alopecia*, psoriasiform rash or exacerbation of psoriasis*

Musculoskeletal and connective tissue disorders:

Timolol maleate ophthalmic solution:

Rare: systemic lupus erythematosus

Renal and Urinary disorders:

Dorzolamide/Timolol ophthalmic solution:

Uncommon: urolithiasis

Reproductive system and breast disorders:

Timolol maleate ophthalmic solution:

Rare: Peyronie's disease*

General disorders and administration site disorders:

Dorzolamide/Timolol ophthalmic solution:

Rare: signs and symptoms of systemic allergic reactions, including angioedema, urticaria, pruritus, rash, anaphylaxis, rarely bronchospasm

Dorzolamide hydrochloride ophthalmic solution:

Common: asthenia/fatigue*

Timolol maleate ophthalmic solution:

Uncommon: asthenia/fatigue*

*These adverse reactions were also observed with Dorzolamide/Timolol ophthalmic solution during post-marketing experience.

Laboratory findings

Dorzolamide/Timolol eye drops solution was not associated with clinically meaningful electrolyte disturbances in clinical studies.

4.9 Overdose

No data are available in humans in regard to overdosage by accidental or deliberate ingestion of Dorzolamide/Timolol eye drops solution.

There have been reports of inadvertent overdosage with timolol maleate ophthalmic solution resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest. The most common signs and symptoms to be expected with overdosage of dorzolamide are electrolyte imbalance, development of an acidotic state, and possibly central nervous system effects.

Only limited information is available with regard to human overdosage by accidental or deliberate ingestion of dorzolamide hydrochloride. With oral ingestion, somnolence has been reported. With topical application the following have been reported: nausea, dizziness, headache, fatigue, abnormal dreams, and dysphagia.

Treatment should be symptomatic and supportive. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. Studies have shown that timolol does not dialyse readily.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiglaucoma preparations and miotics, Beta-Blocking Agents, Timolol, Combinations.

ATC code: S01E D51

Mechanism of action

Dorzolamide/Timolol eye drops solution is comprised of two components: dorzolamide hydrochloride and timolol maleate. Each of these two components decreases elevated intra-ocular pressure by reducing aqueous humor secretion, but does so by a different mechanism of action.

Dorzolamide hydrochloride is a potent inhibitor of human carbonic anhydrase II. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. Timolol maleate is a non-selective beta-adrenergic receptor blocking agent. The precise mechanism of action of timolol maleate in lowering intra-ocular pressure is not clearly established at this time, although a fluorescein study and tonography studies indicate that the predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed. The combined effect of these two agents results in additional intra-ocular pressure reduction compared to either component administered alone.

Following topical administration, Dorzolamide/Timolol eye drops solution reduces elevated intra-ocular pressure, whether or not associated with glaucoma. Elevated intra-ocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss.

Dorzolamide/Timolol eye drops solution reduces intra-ocular pressure without the common side effects of miotics such as night blindness, accommodative spasm and pupillary constriction.

Pharmacodynamic effects

Clinical effects:

Adult Patients

Clinical studies of up to 15 months duration were conducted to compare the IOP-lowering effect of Dorzolamide/Timolol eye drops solution b.i.d. (dosed morning and bedtime) to individually- and concomitantly-administered 0.5% timolol and 2.0% dorzolamide in patients with glaucoma or ocular hypertension for whom concomitant therapy was considered appropriate in the trials. This included both untreated patients and patients inadequately controlled with timolol monotherapy. The majority of patients were treated with topical beta-blocker monotherapy prior to study enrollment. In an analysis of the combined studies, the IOP-lowering effect of Dorzolamide/Timolol eye drops solution b.i.d. was greater than that of monotherapy with either 2% dorzolamide t.i.d. or 0.5% timolol b.i.d. The IOP-lowering effect of Dorzolamide/Timolol eye drops solution b.i.d. was equivalent to that of concomitant therapy with dorzolamide b.i.d. and timolol b.i.d. The IOP-lowering effect of Dorzolamide/Timolol eye drops solution b.i.d. was demonstrated when measured at various time points throughout the day and this effect was maintained during long-term administration.

Paediatric Population

A three month controlled study, with the primary objective of documenting the safety of 2% dorzolamide hydrochloride ophthalmic solution in children under the age of 6 years has been conducted. In this study, 30 patients under six and greater than or equal to two years of age whose IOP was not adequately controlled with monotherapy by dorzolamide or timolol received Dorzolamide/Timolol eye drops solution in an open label phase. Efficacy in those patients has not been established. In this small group of patients, twice daily administration of Dorzolamide/Timolol eye drops solution was generally well tolerated with 19 patients completing the treatment period and 11 patients discontinuing for surgery, a change in medication, or other reasons.

5.2 Pharmacokinetic Properties

Dorzolamide hydrochloride:

Unlike oral carbonic anhydrase inhibitors, topical administration of dorzolamide hydrochloride allows for the drug to exert its effects directly in the eye at substantially lower doses and therefore with less systemic exposure. In clinical trials, this resulted in a reduction in IOP without the acid-base disturbances or alterations in electrolytes characteristic of oral carbonic anhydrase inhibitors.

When topically applied, dorzolamide reaches the systemic circulation. To assess the potential for systemic carbonic anhydrase inhibition following topical administration, drug and metabolite concentrations in red blood cells (RBCs) and plasma and carbonic anhydrase inhibition in RBCs were measured. Dorzolamide accumulates in RBCs during chronic dosing as a result of selective binding to CA-II while extremely low concentrations of free drug in plasma are maintained. The parent drug forms a single N-desethyl metabolite that inhibits CA-II less potently than the parent drug but also inhibits a less active isoenzyme (CA-I). The metabolite also accumulates in RBCs where it binds primarily to CA-I. Dorzolamide binds moderately to plasma proteins (approximately 33%). Dorzolamide is primarily excreted unchanged in the urine; the metabolite is also excreted in urine. After dosing ends, dorzolamide washes out of RBCs non-linearly, resulting in a rapid decline of drug concentration initially, followed by a slower elimination phase with a half-life of about four months.

When dorzolamide was given orally to simulate the maximum systemic exposure after long term topical ocular administration, steady state was reached within 13 weeks. At steady state, there was virtually no free drug or metabolite in plasma; CA inhibition in RBCs was less than that anticipated to be necessary for a pharmacological effect on renal function or respiration. Similar pharmacokinetic results were observed after chronic, topical administration of dorzolamide hydrochloride. However, some elderly patients with renal impairment (estimated creatinine clearance 30-60 millilitre/min) had higher metabolite concentrations in RBCs, but no meaningful differences in carbonic anhydrase inhibition and no clinically significant systemic side effects were directly attributable to this finding.

Timolol maleate:

In a study of plasma drug concentration in six subjects, the systemic exposure to timolol was determined following twice daily topical administration of timolol maleate ophthalmic solution 0.5%. The mean peak plasma concentration following morning dosing was 0.46 ng/millilitre and following afternoon dosing was 0.35 ng/millilitre.

5.3 Preclinical Safety Data

The ocular and systemic safety profile of the individual components is well established.

Dorzolamide

In rabbits given maternotoxic doses of dorzolamide associated with metabolic acidosis, malformations of the vertebral bodies were observed.

Timolol

Animal studies have not shown a teratogenic effect.

Furthermore, no adverse ocular effects were seen in animals treated topically with dorzolamide hydrochloride and timolol maleate ophthalmic solution or with concomitantly-administered dorzolamide hydrochloride and timolol maleate. In vitro and in vivo studies with each of the components did not reveal a mutagenic potential. Therefore, no significant risk for human safety is expected with therapeutic doses of Dorzolamide/Timolol eye drops solution.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Mannitol (E421)

Hydroxyethyl Cellulose

Sodium Citrate (E331)

Sodium Hydroxide (E524)(for pH adjustment)

Benzalkonium chloride

Water for injections

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years

After first opening: 28 days

6.4 Special Precautions For Storage

This medicinal product does not require any special temperature storage conditions.

6.5 Nature And Contents Of Container

White opaque medium density polyethylene bottle ophthalmic dispenser with a sealed LDPE dropper tip and a HDPE screw cap with tamper proof seal in a cardboard box.

Pack size: 1, 3 or 6 bottles of 5 ml each

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Pharmathen S.A.

6 Dervenakion str.,

15351 Pallini, Attiki

Greece

8. Marketing Authorisation Number(S)

PL 17277/0156

9. Date Of First Authorisation/Renewal Of The Authorisation

18/3/2011

10. Date Of Revision Of The Text

18/3/2011


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Deseril Tablets 1mg


1. Name Of The Medicinal Product

Deseril® tablets 1mg

2. Qualitative And Quantitative Composition

Methysergide maleate BP 1.33 mg.

3. Pharmaceutical Form

White, biconvex, sugar-coated tablet, branded DSL on one side.

4. Clinical Particulars 4.1 Therapeutic Indications

Prophylactic treatment of migraine with or without aura, and cluster headache and other vascular headaches in patients who, despite attempts at control, experience headaches of such severity or regularity that social or economic life is seriously disrupted. (Note: Deseril is not recommended for treatment of the acute attack).

Diarrhoea caused by carcinoid disease.

4.2 Posology And Method Of Administration

Prophylactic treatment of headache: 1 or 2 tablets three times a day with meals. Treatment should start with one tablet at bedtime and dosage should then be increased gradually over about two weeks until effective levels are reached. The minimum effective dose should be used, often that which will prevent 75% of attacks rather than all headaches.

From the outset, patients should understand that regular clinical supervision and periodic withdrawal of treatment are essential so that adverse effects can be recognised and minimised (see Section 4.4 Special warnings and precautions for use).

Carcinoid Syndrome: High doses are usually necessary. In most reported cases, dosage ranged between 12 and 20 tablets daily.

Children: Not recommended.

Elderly: No evidence exists that elderly patients require different dosage from younger patients.

4.3 Contraindications

Hypersensitivity to methysergide or any of the excipients of Deseril, pregnancy, lactation, peripheral vascular disorders, progressive arteriosclerosis, inadequately controlled hypertension, coronary heart disease, valvular heart disease, phlebitis or cellulitis of the lower extremities, impaired kidney or liver function, temporal arteritis, hemiplegic or basilar migraine, history of drug – induced fibrotic disorders (e.g. retroperitoneal fibrosis), pulmonary fibrosis, collagen diseases, obstructive diseases of the urinary tract, cachectic or septic conditions.

Concomitant treatment with macrolide antibiotics, HIV-protease or reverse-transcriptase inhibitors, azole antifungals (see section 4.5 Interaction with other medicinal products and other forms of interaction).

Concomitant treatment with vasoconstrictive agents (including ergot alkaloids), sumatriptan and other 5HT1-receptor agonists (see section 4.5 Interaction with other medicinal products and other forms of interaction).

4.4 Special Warnings And Precautions For Use

Continuous Deseril administration should not exceed six months without a drug-free interval of at least one month for re-assessment; dosage should be reduced gradually over two to three weeks to avoid rebound headaches. In patients undergoing treatment with Deseril the dose of ergotamine required to control acute attacks may have to be reduced.

Regular clinical supervision of patients treated with Deseril is essential. Particular attention should be paid to complaints of urinary dysfunction, pain in the loin, flank or chest, and pain, coldness or numbness in the limbs. Patients should be regularly examined for the presence of cardiac murmurs, vascular bruits, pleural or pericardial friction rubs and abdominal or flank masses or tenderness. Caution is also advised during drug administration to patients with a past history of peptic ulceration.

At the first signs of impaired peripheral circulation, prompt withdrawal of the drug is recommended.

In carcinoid syndrome the risk of adverse reactions due to the higher dosage must be weighed against the therapeutic benefit.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of Deseril and vasoconstrictors or vasopressors, including ergot alkaloids, sumatriptan and other 5-HT1-receptor agonists, and nicotine (e.g. heavy smoking) must be avoided since this may result in enhanced vasoconstriction (see section 4.3 Contra-indications). Methysergide should not be administered within six hours of therapy with 5-HT1 receptor agonists. In addition, use of 5-HT1 receptor agonists should be avoided for at least 24 hours after the last methysergide dose.

The concomitant use of cytochrome P450 3A (CYP3A) inhibitors such as macrolide antibiotics (e.g. troleandomycin, erythromycin, clarithromycin), HIV protease or reverse transcriptase inhibitors (e.g. ritonavir, indinavir, nelfinavir, delavirdine), azole antifungals (e.g. ketoconazole, itraconazole, voriconazole) or cimetidine and Deseril must be avoided (see 4.3 Contra-indications), since this can result in an elevated exposure to methysergide and ergot toxicity (vasospasm and ischemia of the extremities and other tissues). Ergot alkaloids have also been shown to be inhibitors of CYP3A. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known.

4.6 Pregnancy And Lactation

Deseril is contra-indicated during pregnancy. It is likely that methysergide is excreted in breast milk. Deseril is therefore contra-indicated for nursing mothers.

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, drowsiness or disturbances in vision.

4.8 Undesirable Effects

General: The most commonly reported side-effects are nausea, heartburn, abdominal discomfort, vomiting, dizziness, lassitude and drowsiness. These side-effects can often be minimised by taking Deseril with food. Tissue oedema, insomnia, vertigo, leg cramps and weight gain have occurred, and skin eruptions or loss of scalp hair have occasionally been reported. Mental and behavioural disturbances have occurred in isolated instances.

Fibrosis: Continuous long-term Deseril administration has been associated with the development of fibrosis particularly of the pleura and retroperitoneum but, in rare cases also of the pericardium and the cardiac valves.

Retroperitoneal fibrosis: May present with symptoms of urinary tract obstruction such as general malaise, backache, persistent loin or flank pain, oliguria, dysuria, increased blood nitrogen and vascular insufficiency of the lower limbs. Deseril must be withdrawn if retroperitoneal fibrosis develops; drug withdrawal is often associated with clinical improvement over a few days to several weeks.

Fibrosis in other areas: Fibrotic processes involving lungs, pleura, heart valves and major vessels have been reported. Fibrosis of the pericardium and cardiac valves is very rare when the drug was given for less than 6 months. Pleuro-pulmonary fibrosis may present with chest pain, dyspnoea or pleural friction rub and pleural effusion. Cardiac valve fibrosis may be noticed by cardiac murmurs, which may lead to impaired cardiac function. Appearance of these symptoms demands immediate withdrawal of Deseril. These fibrotic manifestations are often reversible although less readily so than retroperitoneal fibrosis.

Vascular: Vascular reactions, (affecting both large and small arteries) including arterial spasm, have been seen in some patients. The following have all been described; arterial spasm in a limb causing coldness, numbness, pain or intermittent claudication with or without paraesthesia and diminished or absent pulse; renal artery spasm giving rise to transitory hypertension; mesenteric artery spasm causing abdominal pain; retinal artery spasm causing reversible loss of vision; coronary artery spasm causing angina. Arterial spasm is rapidly reversible following drug withdrawal. There have been isolated reports of myocardial infarction particularly in patients not adhering to the contraindications of coronary heart disease or the use of other vasoconstrictive drugs.

4.9 Overdose

Experience with cases of overdoses with Deseril is limited. Symptoms: headache, agitation, hyperactivity, nausea, vomiting, abdominal pain, mydriasis, tachycardia, cyanosis, peripheral vasospasm with diminished pulses and coldness of extremities.

Treatment: Treatment is essentially symptomatic and supportive. Administration of activated charcoal is recommended; in case of very recent intake, gastric lavage may be considered. For controlling hyperactivity, conventional sedative measures may be used. In the event of severe vasospastic reactions, i.v. administration of a peripheral vasodilator such as nitroprusside, phentolamine, local administration of warmth to the affected area and nursing care to prevent tissue damage are recommended. In the case of coronary constriction, appropriate treatment should be initiated.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Deseril is effective in the prevention of migraine chiefly on account of its marked 5–HT receptor antagonism, probably by inhibition of 5-HT2B receptors (inhibition of pain-facilitating and permeability-increasing actions of 5-HT).

5.2 Pharmacokinetic Properties

Methysergide is rapidly and well absorbed. The parent drug is metabolised in the liver mainly to methylergometrine. Unchanged parent drug and metabolites are excreted predominantly via the kidney; the elimination is biphasic, with a half-life of 2.7 hours for the ?-phase and 10 hours for the ?-phase. Protein binding is moderate (66%).

5.3 Preclinical Safety Data

There are no findings of relevance to the prescriber which are additional to those already included in other sections of the SmPC.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Maleic acid, gelatin, stearic acid, talc, maize starch, lactose. The coating constituents are gum acacia, sugar, talc, titanium dioxide, silica, carnauba wax and printing ink (consisting of Shellac, black iron oxide, ethanol and isopropanol).

6.2 Incompatibilities

None.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

Aluminium/PVdC blister strips of 60 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

Administrative Data 7. Marketing Authorisation Holder

Alliance Pharmaceuticals Ltd

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

8. Marketing Authorisation Number(S)

PL16853/0006

9. Date Of First Authorisation/Renewal Of The Authorisation

25 June 1998

10. Date Of Revision Of The Text

December 2006

11. Legal status

POM

Alliance, Alliance Pharmaceuticals and associated devices are registered Trademarks of Alliance Pharmaceuticals Ltd.


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