Consumer medicine information

Cosopt

Dorzolamide; Timolol

BRAND INFORMATION

Brand name

Cosopt

Active ingredient

Dorzolamide; Timolol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cosopt.

What is in this leaflet

This leaflet answers some common questions about COSOPT. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using COSOPT against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What COSOPT is used for

COSOPT is used to lower raised pressure in the eye and to treat glaucoma. Glaucoma is a condition in which the pressure of fluid in the eye may be high. However, some people with glaucoma may have normal eye pressure. Also, some people with raised eye pressure may not have glaucoma.

Glaucoma is usually caused by a build-up of the fluid which flows through the eye. This build up occurs because the fluid drains out of your eye more slowly than it is being pumped in. Since new fluid continues to enter the eye, joining the fluid already there, the pressure continues to rise. This raised pressure may damage the back of the eye resulting in gradual loss of sight. Damage can progress so slowly that the person is not aware of this gradual loss of sight. Sometimes even normal eye pressure is associated with damage to the back of the eye.

There are usually no symptoms of glaucoma. The only way of knowing that you have glaucoma is to have your eye pressure, optic nerve and visual field checked by an eye specialist or optometrist. If glaucoma is not treated it can lead to serious problems. You may have no symptoms but eventually glaucoma can lead to total blindness. In fact, untreated glaucoma is one of the most common causes of blindness.

Although COSOPT helps control your glaucoma it does not cure it.

For more information about glaucoma, contact Glaucoma Australia Inc., PO Box 420, Crows Nest 1585, telephone 1800 500 880.

COSOPT contains two active ingredients, dorzolamide hydrochloride and timolol maleate. Both of these active ingredients lower pressure in the eye by reducing the production of fluid, but they do this in different ways.

Dorzolamide hydrochloride belongs to a family of medicines called carbonic anhydrase inhibitors. Timolol maleate belongs to a family of medicines called beta-blockers.

COSOPT is not addictive.

Before you use COSOPT

When you must not use it

Do not use COSOPT if you have an allergy to COSOPT or any of the ingredients listed at the end of this leaflet.

Do not use COSOPT if:

  • you have now or have had in the past certain serious breathing problem such as asthma, chronic obstructive lung disease (emphysema), or other breathing problems
  • you have certain heart conditions, such as slow heart rate, an irregular heartbeat, or heart failure.

Do not use COSOPT if you are breast-feeding or intend to breast-feed. Your baby may absorb this medicine from breast milk and therefore there is a possibility of harm to the baby.

Do not put the eye drops into your eye(s) while you are wearing contact lenses. The preservative in COSOPT (benzalkonium chloride) may be deposited in soft contact lenses. You can put your contact lenses back into your eyes 15 minutes after you have used COSOPT.

Do not use COSOPT if:

  • the seal around the cap is broken
  • the bottle shows signs of tampering
  • the expiry date on the pack has passed.
    If you use this medicine after the expiry date has passed, it may not work.

If you are not sure whether you should start using COSOPT, talk to your doctor.

There is limited experience with COSOPT in children.

Before you start to use it

Tell your doctor if:

  1. you are pregnant or intend to become pregnant
Your doctor will discuss the possible risks and benefits of using COSOPT during pregnancy and a decision can be made if you should or should not use it.
  1. you have any medical conditions, especially the following:
  • heart problems (such as coronary heart disease, heart failure or low blood pressure)
  • heart rate disturbances (such as slow or irregular heartbeats)
  • poor blood circulation problems (such as Raynaud's syndrome)
  • lung or breathing problems (such as asthma or chronic obstructive lung disease)
  • diabetes or other blood sugar problems
  • thyroid disease
  • kidney disease
  • liver disease
  1. if you have an allergy to sulfonamide medicines
One of the active ingredients of COSOPT, dorzolamide hydrochloride, is a sulfonamide-related compound. Therefore, if you are allergic to sulfonamide medicines you may be allergic to COSOPT. Check with your doctor or pharmacist if you are not sure whether you are allergic to sulfonamides.
  1. you are already using another beta-blocker eye drop
It is not recommended to use two beta-blocker eye drops at the same time.
  1. you have a history of allergic problems, including eczema, hives or hay fever
  2. you have had an allergy to any other medicines or any other substances, such as foods, preservatives or dyes.

If you have not told your doctor about any of the above, tell them before you use COSOPT.

Tell your doctor before you have an operation that you are using COSOPT, as it may change the effects of some medicines during anaesthesia.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines and COSOPT may interfere with each other. These include:

  • medicines for high blood pressure or heart conditions, including a group of medicines called beta-blockers
  • quinidine, a medicine used to treat irregular heart beats
  • medicines to treat diabetes
  • tablets used to treat glaucoma
  • large amounts of aspirin or salicylates
  • medicines to treat depression

These medicines may be affected by COSOPT, or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while using COSOPT.

How to use COSOPT

How much to use

Your doctor will tell you how many drops you need to use each day.

Use COSOPT only when prescribed by your doctor.

The usual dose for adults is one drop of COSOPT twice a day, in either one or both eyes.

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

Use COSOPT every day, at about the same time each day, unless your doctor tells you otherwise. Using your eye drops at the same time each day will have the best effect on your eye pressure. It will also help you remember when to use the eye drops.

After using COSOPT, wait at least 10 minutes before putting any other eye drops in your eye(s).

How to use it

You may find it easier to put drops in your eye while you are sitting or lying down.

Before opening the bottle for the first time, make sure the Safety Strip on the front of the bottle is not broken. If it is, do not use the bottle and return it to your pharmacist.

You will notice a small space between the cap and the bottle- this is normal.

If you are wearing soft contact lenses, remove them before putting the drops in your eye.

  1. Wash your hands well with soap and water.
  2. To open the bottle for the first time, tear off the Safety Strip to break the seal. Then hold the bottle upright, and turn the cap in the direction of the arrows until you can lift it off.
  3. Place the cap upside down (arrows face down) on a flat surface. Do not touch the inside of the cap. This will help keep the inside of the cap clean and keep germs out of the eye drops.
  4. Hold the bottle upside down in one hand, with your thumb or index finger over the "finger push" area.
  5. Using your other hand, gently pull down your lower eyelid to form a pouch.
  6. Tilt your head back and look up.
  7. Put the tip of the bottle close to your lower eyelid. Do not let it touch your eye.
  8. Release one drop into the pouch formed between your eye and eyelid by gently squeezing the bottle.
  9. Close your eye and keep it closed. Do not blink or rub your eye.
  10. While your eye is still closed, place your index finger against the inside corner of your eye and press against your nose for about two minutes. This will help to stop the medicine from draining through the tear duct to the nose and throat, from where it can be absorbed into other parts of your body. Ask your doctor for more specific instructions on this technique.
  11. Replace the cap, sealing it tightly. Do not overtighten the cap.
  12. Wash your hands again with soap and water to remove any residue.

Wait at least 15 minutes before replacing your contact lenses.

Be careful not to touch the dropper tip against your eye, eyelid or anything else to avoid contaminating the eye drops. Contaminated eye drops may give you an eye infection.

You may feel a slight burning sensation in the eye after using the eye drops.

If this persists, or is very uncomfortable, contact your doctor or pharmacist.

How long to use it

COSOPT helps control your condition but does not cure it. Therefore COSOPT must be used every day. Continue using COSOPT for as long as your doctor prescribes.

If you forget to use it

If it is almost time for your next dose, skip the dose you missed and have your next dose when you are meant to. Otherwise, use the drops as soon as you remember, and then go back to using them as you would normally.

If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

Do not use double the amount to make up for the dose that you missed.

If you have trouble remembering to use your eye drops, ask your pharmacist for some hints.

If you use too much (overdose)

If you think that you or anyone else may have swallowed any or all of the contents of a bottle of COSOPT, or used too many drops, immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, or go to accident or emergency at your nearest hospital. Do this even if there are no signs of discomfort or poisoning.

If COSOPT is accidentally swallowed, or if you use too many drops, you may feel light-headed or dizzy, you may faint, have a very slow pulse rate, or have wheezing or difficulty breathing.

While you are using COSOPT

Things you must do

Have your eye pressure checked when your eye specialist says, to make sure COSOPT is working.

If you develop an eye infection, receive an eye injury, or have eye surgery tell your doctor.

Your doctor may tell you to use a new bottle of COSOPT because of possible contamination of the old one, or may advise you to stop your treatment with COSOPT.

If you become pregnant while using COSOPT, tell your doctor.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are using COSOPT.

Things you must not do

Do not give COSOPT to anyone else, even if they have the same condition as you.

Do not stop using COSOPT without first talking to your doctor. If you stop using your eye drops, your eye pressure may rise again and damage to your eye may occur.

Things to be careful of

Be careful driving or operating machinery until you know how COSOPT affects you. COSOPT generally does not cause any problems with your ability to drive a car or operate machinery. However, COSOPT may cause blurred vision or dizziness in some people. Make sure you know how you react to COSOPT or that your vision is clear before driving a car or operating machinery.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using COSOPT.

COSOPT helps most people with high eye pressure and glaucoma, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • problems with your eye/s such as:
    - blurred vision, double vision or other visual problems
    - allergic reactions including redness, swelling and/or itching of the eye
    - burning and stinging of the eyes, eye pain
    - watering of the eyes or discharge
    - conjunctivitis
    - irritation or feeling of having something in the eye, dry eyes
    - swelling of the eyelids, drooping of the eyelids
  • difficulty thinking or working because of:
    - headache
    - tiredness, weakness
    - ringing or buzzing in the ears
    - difficulty sleeping, nightmares
    - changes in mood such as depression, memory loss
  • mouth or stomach problems
    - feeling sick (nausea), upset stomach, stomach pain
    - diarrhoea
    - bitter or abnormal taste, dry mouth
  • respiratory problems
    - cough
    - sore throat and discomfort when swallowing
    - cold or flu-like symptoms such as sneezing, runny nose, cough, red or infected throat
    - feeling of tension or fullness in the nose, cheeks and behind your eyes, sometimes with a throbbing ache, also called sinusitis
  • changes in the way your hands and feet feel such as:
    - cold hands or feet
    - numbness, tingling and colour change (white, blue then red) in fingers when exposed to the cold (Raynaud's Phenomenon)
    - numbness or tingling in the fingers or toes
  • symptoms of a urinary tract infection including an urge to urinate frequently and in small amounts, or painful burning when passing urine
  • back pain
  • nose bleeds
  • hair loss or thinning
  • less desire for sex

These are usually mild side effects.

Tell your doctor immediately if you notice any of the following:

  • fast or irregular heartbeats, also called palpitations
  • slow or irregular heart beats
  • dizziness and light-headedness, which may be due to low blood pressure
  • skin rash, itching
  • swelling of the hands, feet or ankles

These may be serious side effects. You may need urgent medical attention.

Serious side effects are rare.

If any of the following happen, stop using COSOPT and tell your doctor immediately or go to accident and emergency at your nearest hospital:

  • wheezing, difficulty in breathing, shortness of breath
  • very slow pulse, chest pain
  • fainting
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in breathing or swallowing
  • severe and sudden onset of pinkish, itchy swellings on the skin, also called hives or nettle rash

These are serious side effects. You may need urgent medical attention. These side effects are rare.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice any other effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using COSOPT

Storage

Keep your eye drops in a cool place where the temperature stays below 30°C.

Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills.

Do not carry the eye drops in pockets of your clothes.

Heat and dampness can destroy some medicines.

Keep the eye drops away from light.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Do not leave the cap off the bottle for any length of time to avoid contaminating the eye drops.

Disposal

Write the date on the bottle when you open the eye drops and throw out any remaining solution after four weeks. Eye drops contain a preservative which helps prevent germs growing in the solution for the first four weeks after opening the bottle. After this time there is a greater risk that the drops may become contaminated and cause an eye infection. A new bottle should be opened.

If your doctor tells you to stop using the eye drops or they have passed their expiry date, ask your pharmacist what to do with any remaining solution.

Product description

How does it come?

COSOPT comes as eye drops in a 5mL bottle.

Ingredients

Active ingredients:

  • dorzolamide hydrochloride, equivalent to dorzolamide 2% w/v
  • timolol maleate, equivalent to timolol 0.5% w/v

Inactive ingredients:

  • sodium citrate
  • hydroxyethylcellulose
  • sodium hydroxide
  • mannitol
  • water for injections
  • benzalkonium chloride as preservative

Supplier

COSOPT is supplied in Australia by:

Mundipharma Pty Limited
10 Carrington Street
Sydney NSW 2000
Phone: 1800 188 009

This leaflet was prepared in April 2022

Australian Register Number:
AUST R 66103.

COSOPT-CMI-v1-(WPC-MK0507A-OS-022014)

Published by MIMS July 2022

BRAND INFORMATION

Brand name

Cosopt

Active ingredient

Dorzolamide; Timolol

Schedule

S4

 

1 Name of Medicine

Dorzolamide hydrochloride and timolol maleate.

2 Qualitative and Quantitative Composition

Cosopt is supplied as a sterile, isotonic, buffered, slightly viscous, aqueous solution. Each millilitre of Cosopt contains 20.00 mg (2.0% w/v) dorzolamide (22.26 mg of dorzolamide hydrochloride) and 5.00 mg (0.5% w/v) timolol (6.83 mg of timolol maleate) as the active ingredients.
List of excipient(s) with known effect: benzalkonium chloride.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Eye drops, solution.
Clear, colourless to nearly colourless, slightly viscous solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Cosopt is indicated in the treatment of elevated intraocular pressure (IOP) in patients with ocular hypertension or open-angle glaucoma when concomitant therapy is appropriate.

4.2 Dose and Method of Administration

The dose is one drop of Cosopt in the affected eye(s) two times daily.
When substituting Cosopt for another ophthalmic antiglaucoma agent(s), discontinue the other agent(s) after proper dosing on one day, and start Cosopt on the next day.
If another topical ophthalmic agent is being used, Cosopt and the other agent should be administered at least ten minutes apart.
Efficacy in paediatric patients has not been established. Safety in paediatric patients below the age of 2 years has not been established. (For information regarding safety in paediatric patients ≥ 2 and < 6 years of age, see Section 4.4 Special Warnings and Precautions for Use, Paediatric use.)

4.3 Contraindications

Cosopt is contraindicated in patients with:
reactive airway disease, bronchial asthma or a history of bronchial asthma, or severe chronic obstructive pulmonary disease;
sinus bradycardia, sino-atrial block, second or third degree atrioventricular block, overt cardiac failure, cardiogenic shock;
hypersensitivity to any component of this product.
The above are based on the components and are not unique to the combination.

4.4 Special Warnings and Precautions for Use

The timolol component is a beta-blocker and, although administered topically, is absorbed systemically. Therefore, the same types of adverse reactions found with systemic administration of beta-blockers may occur with topical administration.

Cardiorespiratory reactions.

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-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of cardiac failure, Cosopt should be discontinued.
Because of the timolol maleate component, cardiac failure should be adequately controlled before beginning therapy with Cosopt. Patients with a history of cardiovascular disease, including cardiac failure, should be watched for signs of deterioration of these diseases and pulse rates should be checked.
Due to its negative effect on conduction time, beta-blockers should be given with caution to patients with first degree heart block.
Because of potential effects of beta-adrenergic blocking 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 Cosopt, alternative therapy should be considered.
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 ophthalmic solution.
In patients with mild/moderate chronic obstructive pulmonary disease (COPD), Cosopt should be used with caution, and only if the potential benefit outweighs the potential risk.

Vascular disorders.

Patients with severe peripheral circulatory disturbance/disorders (e.g. severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.

Masking of hypoglycemic symptoms in patients with diabetes mellitus.

Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic blocking agents may mask the signs and symptoms of acute hypoglycemia.

Masking of thyrotoxicosis.

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

Surgical anesthesia.

The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial. If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of adrenergic agonists such as isoproterenol, dopamine, dobutamine or levarterenol (see Section 4.9 Overdose).

Immunology and hypersensitivity.

The dorzolamide component is a sulfonamide and, although administered topically, is absorbed systemically. Therefore, the same types of adverse reactions found with systemic administration of sulfonamides may occur with topical administration such as Stevens-Johnson syndrome and toxic epidermal necrolysis. If signs of serious reactions or hypersensitivity occur, discontinue use of this preparation.
In clinical studies, local ocular adverse effects, primarily conjunctivitis and lid reactions, were reported with chronic administration of dorzolamide hydrochloride ophthalmic solution. Some of these reactions had the clinical appearance and course of an allergic type reaction that resolved upon discontinuation of drug therapy. Similar reactions have been reported with Cosopt. If such reactions are observed, discontinuation of treatment with Cosopt should be considered.
While taking β-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 adrenaline (epinephrine) used to treat anaphylactic reactions.

Concomitant therapy.

There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving oral and topical carbonic anhydrase inhibitors concomitantly. The concomitant administration of Cosopt and oral carbonic anhydrase inhibitors has not been studied and is not recommended.
Patients who are already receiving a beta-adrenergic blocking agent systemically and who are given Cosopt should be observed for a potential additive effect either on the intraocular pressure or on the known systemic effects of beta-blockade. The use of two topical beta-adrenergic blocking agents is not recommended.

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.
Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide, dorzolamide) after filtration procedures.
There is an increased potential for developing corneal oedema in patients with low endothelial cell counts. Precautions should be used when prescribing Cosopt to this group of patients.
Beta-adrenergic blockade has been reported to increase muscle weakness consistent with certain myasthenic symptoms (e.g. diplopia, ptosis and generalised weakness). Timolol has been reported rarely to increase muscle weakness in some patients with myasthenic symptoms.
There have been reports of bacterial keratitis associated with the use of multiple dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface. Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.
Patients should be advised that if they develop an intercurrent ocular condition (e.g. trauma, ocular surgery or infection) or any ocular reactions, particularly conjunctivitis and lid reactions, they should immediately seek their physician's advice concerning the continued use of the product.
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.

Contact lens use.

Cosopt contains the preservative benzalkonium chloride, which may be deposited in soft contact lenses; therefore, Cosopt should not be administered while wearing these lenses. The lenses should be removed before application of the drops and not be reinserted earlier than 15 minutes after use.

Use in hepatic impairment.

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

Use in renal impairment.

Cosopt has not been studied in patients with severe renal impairment (CrCl < 30 mL/min). Because dorzolamide hydrochloride and its metabolite are excreted predominantly by the kidney, Cosopt is not recommended in such patients.

Use in the elderly.

Of the total number of patients in clinical studies of Cosopt, 49% were 65 years of age and over, while 13% were 75 years of age and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Paediatric use.

The safety and usage of 2% dorzolamide hydrochloride ophthalmic solution has been tested in a clinical study of three months' duration in children under the age of 6 years. In this study, patients under 6 and greater than 2 years of age whose IOP was not controlled with monotherapy with dorzolamide or 0.5% timolol gel forming solution received Cosopt. Nineteen of 66 patients randomised to dorzolamide monotherapy and 11 of 35 patients randomised to timolol monotherapy were transferred to Cosopt. Of those 30 patients transferred to preserved Cosopt, three patients had the following drug related adverse events: cough, burning/ stinging eye and ocular injection.

Effects on laboratory tests.

Cosopt was not associated with clinically meaningful electrolyte disturbances.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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, nonsteroidal 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 calcium channel blockers, catecholamine depleting drugs, antiarrhythmics, parasympathomimetics or beta-adrenergic blocking agents.
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 Cosopt 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 Cosopt.
Although Cosopt used alone has little or no effect on pupil size, mydriasis resulting from concomitant use of timolol maleate and adrenaline has been reported occasionally.
β-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. Caution should be exercised in patients using these drugs concomitantly. There have been no reports of exacerbation of rebound hypertension with ophthalmic timolol maleate.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Dorzolamide hydrochloride.

In reproduction studies of dorzolamide hydrochloride in rats, there were no adverse effects on the reproductive capacity of males or females at oral doses up to 15 and 7.5 mg/kg/day, respectively.

Timolol maleate.

Reproduction and fertility studies in rats demonstrated no adverse effect on male or female fertility at doses of up to 100 mg/kg/day.
(Category C)
Beta-adrenergic blocking agents may cause pharmacological effects, such as bradycardia in the foetus and newborn infant.
Developmental toxicity studies with dorzolamide hydrochloride in rabbits at oral doses of ≥ 2.5 mg/kg/day (foetal red blood cell Cmax was approximately twice the maternal red blood cell Cmax after the recommended human ophthalmic dose) revealed malformations of the vertebral bodies. These malformations occurred at doses that caused metabolic acidosis with decreased bodyweight gain in dams and decreased foetal weights. No treatment related malformations were seen at 1.0 mg/kg/day. There were no treatment related foetal malformations in developmental toxicity studies with dorzolamide hydrochloride in rats at oral doses up to 10 mg/kg/day.
Developmental studies with timolol in mice, rats and rabbits at oral doses up to 50 mg/kg/day demonstrated 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 the offspring. Doses of 1000 mg/kg/day were maternotoxic in mice and resulted in an increased number of foetal resorptions. Increased foetal resorptions were also seen in rabbits at oral doses of 100 mg/kg/day, in this case without apparent maternotoxicity.
There are no adequate and well controlled studies in pregnant women. Cosopt should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
 Dorzolamide was excreted in the milk of lactating rats and decreases in the bodyweight gain of the offspring were seen during lactation after an oral dose of 7.5 mg/kg/day. A slight delay in postnatal development (incisor eruption, vaginal canalisation and eye openings), secondary to lower foetal bodyweight, was noted. It is not known whether this drug is excreted in human milk.
Timolol has been detected in human milk following oral and ophthalmic drug administration. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cosopt, 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.

4.7 Effects on Ability to Drive and Use Machines

There are side effects associated with Cosopt that may affect some patients' ability to drive and/or operate machinery. See Section 4.8 Adverse Effects (Undesirable Effects).

4.8 Adverse Effects (Undesirable Effects)

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.
The most frequently reported drug related adverse effects were: ocular burning and stinging, taste perversion, corneal erosion, conjunctival injection, blurred vision, tearing and ocular itching. Urolithiasis was reported rarely.

Clinical adverse experiences in ≥ 1% of patients receiving combination therapy in phase III studies.

Body as a whole.

Abdominal pain.

Cardiovascular.

Hypertension.

Digestive.

Dyspepsia, nausea.

Musculoskeletal.

Back pain.

Nervous/psychiatric.

Dizziness, headache, paraesthesia.

Respiratory.

Bronchitis, cough, upper respiratory infection, influenza, pharyngitis, sinusitis.

Special senses.

Blepharitis, blurred vision, burning or stinging of the eye, conjunctivitis, visual field defect, eye discharge, eyelid oedema, corneal erosion, foreign body sensation, conjunctival injection, eye itching, lens opacity, eye pain, taste perversion, corneal staining, eye tearing.

Urogenital.

Urinary tract infection.
The following adverse reactions have been reported in postmarketing experience: dyspnea, respiratory failure, contact dermatitis, bradycardia, heart block, choroidal detachment following filtration surgery, nausea, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
Additional side effects that have been seen with one of the components and may be potential side effects of Cosopt are:

Dorzolamide hydrochloride.

Headache; eyelid inflammation; eyelid irritation; eyelid crusting; asthenia/fatigue; iridocyclitis; rash; dizziness; paresthesia; superficial punctate keratitis; transient myopia (which resolved upon discontinuation of therapy); signs and symptoms of local reactions including palpebral reactions and systemic allergic reactions including angioedema, bronchospasm, urticaria and pruritus; contact dermatitis, epistaxis, throat irritation, dry mouth. Choroidal detachment has been reported with administration of dorzolamide after filtration procedures.

Timolol maleate (topical formulation).

Signs and symptoms of ocular irritation, including conjunctivitis, blepharitis, keratitis, and decreased corneal sensitivity, dry eyes; visual disturbances, including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia and ptosis; choroidal detachment following filtration surgery; tinnitus; bradycardia; arrhythmia; hypotension; syncope; heart block; cerebrovascular accident; cerebral ischaemia; congestive heart failure; palpitation; cardiac arrest; oedema, claudication, Raynaud's phenomenon, cold hands and feet; bronchospasm (predominantly in patients with pre-existing bronchospastic disease); cough; respiratory failure; dyspnoea; headache; asthenia; fatigue; chest pain; alopecia; psoriasiform rash or exacerbation of psoriasis; signs and symptoms of allergic reactions including anaphylaxis, angioedema, urticaria, localised and generalised rash; dizziness; depression, insomnia, nightmares, memory loss; increase in signs and symptoms of myasthenia gravis, paraesthesia; diarrhoea, dyspepsia, dry mouth, abdominal pain; decreased libido, Peyronie's disease, sexual dysfunction; systemic lupus erythematosus, myalgia.

Timolol maleate (systemic formulation).

Extremity pain; decreased exercise tolerance; A-V block (2nd or 3rd degree); sinoatrial block; pulmonary oedema; worsening of arterial insufficiency; worsening of angina pectoris; vasodilation; vomiting; diarrhoea, hyperglycaemia; hypoglycaemia; pruritus; sweating; exfoliative dermatitis; arthralgia; vertigo; local weakness; diminished concentration; increased dreaming; nonthrombocytopenic purpura; rales; impotence; micturition difficulties.
Clinically important changes in standard laboratory parameters were rarely associated with the administration of systemic timolol maleate. Slight increases in serum urea, serum potassium, serum uric acid and triglycerides; and slight decreases in haemoglobin, haematocrit and HDL-cholesterol occurred but were not progressive or associated with clinical manifestations.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

No data are available with regard to human overdosage by accidental or deliberate ingestion of Cosopt.
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.
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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Cosopt is comprised of two components: dorzolamide hydrochloride and timolol maleate. It is the first combination of a topical carbonic anhydrase inhibitor and a topical beta-adrenergic receptor blocking agent. 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 nonselective beta-adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant or local anaesthetic (membrane stabilising) activity. 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 its 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 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. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous visual field loss and optic nerve damage. Cosopt reduces intraocular pressure without the common side effects of miotics, such as night blindness, accommodative spasm and pupillary constriction.

Clinical trials.

Clinical studies of up to 15 months duration (double masked phase of up to 3 months, followed by up to 12 months open label treatment with Cosopt) 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 is appropriate. This includes both untreated patients and patients inadequately controlled with timolol monotherapy. 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 approximately 1 mmHg less than that of concomitant therapy with 2% dorzolamide t.i.d. and 0.5% timolol b.i.d.

A. Comparison to concomitant therapy (patients initiated on timolol therapy).

In a 3 month randomised, double masked, parallel clinical study, patients receiving Cosopt b.i.d. (n = 151) were compared to patients receiving 0.5% timolol b.i.d. plus 2.0% dorzolamide b.i.d. concomitantly (n = 148). At morning trough (hour 0) and morning peak (hour 2), patients receiving Cosopt experienced IOP lowering that was equivalent to that seen in the patients receiving the individual components concomitantly. (Equivalence was defined as a 90% confidence that the absolute difference between mean change in IOP for the 2 treatments was less than 1.5 mmHg.) The following reductions in IOP were observed relative to the baseline value obtained after 2 weeks of 0.5% timolol b.i.d. monotherapy. (See Table 1.)
Four 3 month randomized, double masked parallel clinical studies were conducted to compare Cosopt b.i.d. to 0.5% timolol b.i.d. monotherapy and 2.0% dorzolamide t.i.d. monotherapy. Two studies (n = 685) were conducted in patients with baseline IOP ≤ 24 mmHg after a washout of all previous ocular hypotensive therapies. The other two studies (n = 500) were conducted in patients with elevated IOP ≤ 22 mmHg inadequately controlled after 3 weeks of 0.5% timolol b.i.d. monotherapy. Based upon post hoc analyses of the combined washout studies data and the combined timolol run in studies data, the estimated difference between the IOP lowering effects of Cosopt and dorzolamide was 1.9-2.4 mmHg (7.8-8.9%) at morning trough (hour 0) and 2.3-2.7 mmHg (9.9%) at morning peak (hour 2), while the estimated difference between the IOP lowering effects of Cosopt and timolol was 0.8-0.9 mmHg (2.9-3.5%) at morning trough (hour 0) and 1.8-2.3 mmHg (6.9-9.0%) at morning peak (hour 2). These differences are statistically significant in favor of the combination.

Long-term studies.

Open label extensions of two studies were conducted for up to 12 months. During this period, the IOP lowering effect of Cosopt b.i.d. was demonstrated throughout the day and this effect was maintained during the follow-up period.

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 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 nonlinearly, resulting in a rapid decline of drug concentration initially, followed by a slower elimination phase with a half-life of about four months.
To simulate maximum exposure after long-term topical ocular administration, dorzolamide was given orally to eight healthy subjects for up to 20 weeks. The oral dose of 4 mg/day closely approximates the maximum amount of drug delivered by topical ocular administration of dorzolamide 2% t.i.d. 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 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 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 nanogram/mL and following afternoon dosing was less than the lower limit of quantification of the assay, 0.375 nanogram/mL.

5.3 Preclinical Safety Data

Genotoxicity.

Dorzolamide hydrochloride.

Dorzolamide showed no mutagenic potential in a series of standard assays for gene mutations, chromosomal damage and DNA damage.

Timolol maleate.

In vitro and in vivo studies (Ames test, neoplastic cell transformation assay, cytogenetic assay and micronucleus test in mice) showed no genotoxicity of timolol.

Carcinogenicity.

Dorzolamide hydrochloride.

In a two year study of dorzolamide hydrochloride administered orally to male and female Sprague-Dawley rats, urinary bladder papillomas were seen in male rats in the highest dosage group of 20 mg/kg/day. No treatment related tumours were seen in a 21 month study in male and female mice given oral doses up to 75 and 37.5 mg/kg/day, respectively.
The increased incidence of urinary bladder papillomas seen in the high dose male rats appears to be a class effect of carbonic anhydrase inhibitors in rats. Rats are particularly prone to developing papillomas in response to foreign bodies, compounds causing crystalluria and diverse sodium salts.
No changes in bladder urothelium were seen in dogs given oral dorzolamide hydrochloride for one year at 2 mg/kg/day or monkeys dosed topically to the eye at 0.4 mg/kg/day for one year.

Timolol maleate.

In a 2 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. Similar differences were not observed in rats administered oral doses of 100 mg/kg/day.
In a lifetime oral study in mice, there were statistically significant increases in the incidence of benign and malignant pulmonary tumours, benign uterine polyps and mammary adenocarcinomas in female mice at 500 mg/kg/day, but not at 50 mg/kg/day. 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 tumours 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, but not at doses of 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 tumours 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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium citrate dihydrate, hyetellose, sodium hydroxide, mannitol, and water for injections. Benzalkonium chloride (0.0075%) is added as preservative.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Protect from light.
Discard 28 days after opening.

6.5 Nature and Contents of Container

Cosopt eye drops is available in a translucent ophthalmic dispensing bottle with a controlled dropper tip and an opaque, white cap; pack size 1 x 5 mL bottles.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Dorzolamide hydrochloride has a molecular weight of 360.91. It is a white to off white, free flowing crystalline powder, which is soluble in water and slightly soluble in methanol and ethanol.
Timolol maleate has a molecular weight of 432.50. It is a white, odourless, crystalline powder which is soluble in water, methanol and alcohol.

Chemical structure.

Dorzolamide hydrochloride.

Dorzolamide hydrochloride is described chemically as: (4S-trans)-4-(ethylamino)-5,6-dihydro-6-methyl-4H-thieno [2,3-b]thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride.
Its empirical formula is C10H17N2O4S3Cl and its structural formula is:

Timolol maleate.

Timolol maleate is described chemically as: (S)-1-[(1,1-dimethylethyl) amino]-3-[[4-(4-morpholinyl) -1,2,5-thiadiazol -3-yl]oxy]-2-propanol, (Z)-2-butenedioate (1:1) (salt). Timolol maleate possesses an asymmetric carbon atom in the structure and is provided as the levo isomer.
The empirical formula is C13H24N4O3S*C4H4O4 and the structural formula is:

CAS number.

130693-82-2 dorzolamide hydrochloride.
26921-17-5 timolol maleate.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (S4).

Summary Table of Changes