Consumer medicine information

APO-Dorzolamide Eye drops

Dorzolamide

BRAND INFORMATION

Brand name

APO-Dorzolamide Eye drops

Active ingredient

Dorzolamide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Dorzolamide Eye drops.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about dorzolamide. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

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

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with your medicine. You may want to read it again.

What this medicine is used for

The name of your medicine is APO-Dorzolamide eye drops. It contains the active ingredient dorzolamide hydrochloride.

It is used to treat 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 dorzolamide 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 02 9906 6640.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

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

How it works

Dorzolamide is used, either alone or in combination with other eye drops or medicines, to lower raised pressure within your eye(s).

Dorzolamide lowers pressure in the eye by reducing the production of fluid.

Dorzolamide belongs to a family of medicines called carbonic anhydrase inhibitors.

There is no evidence that this medicine is addictive.

Use in children

This medicine should not be used in children.

The safety and effectiveness of dorzolamide in children have not been established.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You are hypersensitive to, or have had an allergic reaction to, dorzolamide or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include: shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.
  • Do not put the eye drops into your eye(s) while you are wearing soft contact lenses.
    The preservative in dorzolamide (benzalkonium chloride) may be deposited in soft contact lenses. You can put soft contact lenses back into your eyes at least 15 minutes after you have used dorzolamide.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • kidney disease
  • liver disease.
  1. You have an allergy to sulfonamide medicines.
    The active ingredient of dorzolamide is a sulfonamide-related compound. Therefore, if you are allergic to sulfonamide medicines you may be allergic to dorzolamide. Check with your doctor or pharmacist if you are not sure whether you are allergic to sulfonamides.
  2. You are currently pregnant or you plan to become pregnant. Do not take this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved.
  3. You are currently breastfeeding or you plan to breast-feed. Do not take this medicine whilst breastfeeding until you and your doctor have discussed the risks and benefits involved.
  4. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Taking other medicines

Some medicines may interact with dorzolamide. These include:

  • tablets used to treat glaucoma
  • large amounts of aspirin or salicylates

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with dorzolamide.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor will tell you how many drops you need to use each day. This will depend on your condition and whether you are taking any other medicines.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

When dorzolamide is used alone, the usual dose for adults is one drop three times a day, in either one or both eyes.

If your doctor has recommended that you use dorzolamide with a beta-blocker eye drop, then the usual dose for adults is one drop of dorzolamide twice a day, in either one or both eyes.

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

How to take 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 seal joining the cap to 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. Unscrew the cap and break it off from the seal.
  3. Place the cap upside 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. Use your finger to gently pull down the lower eyelid of the affected eye.
  5. Tilt your head back and look up.
  6. Place the tip of the bottle close to your lower eyelid. Do not let it touch your eye.
  7. Squeeze the bottle gently so that only drop goes into your eye, then release the lower eyelid.
  8. Close your eye and keep it closed. Do not blink or rub your eye.
  9. 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 or pharmacist for more specific instructions on this technique.
  10. Screw the cap back on the bottle, sealing it tightly. Do not over tighten the cap.
  11. 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 shortly after using the eye drops.

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

When to take it

If you are using dorzolamide three times a day, use the drops first thing in the morning, in the early afternoon and at bedtime (i.e. approximately 8 hours apart). If you are using dorzolamide twice a day, use the drops in the morning and in the evening (i.e. approximately 12 hours apart).

Use dorzolamide 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.

It does not matter if you take it before, with or after food.

How long to take it for

Dorzolamide helps control your condition but does not cure it.

Therefore dorzolamide must be used every day. Continue using dorzolamide for as long as your doctor prescribes.

Make sure you have enough of this medicine to last over weekends and holidays.

If you forget to take it

If it is almost time to take your next dose, skip the missed dose and take your next dose at the usual time. Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses.

This may increase the chance of you experiencing side effects.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Have your eye pressure checked when your eye specialist says, to make sure dorzolamide 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 container of the eye drops because of possible contamination of the old one, or may advise to stop your treatment with the eye drops.

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant
  • you are breastfeeding or are planning to breast-feed
  • you are going to have surgery or going into hospital.

Go to your doctor or eye specialist regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.
    If you stop using the eye drops, your pressures may rise again and damage to the eye may occur.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you.

Dorzolamide generally does not cause any problems with your ability to drive a car or operate machinery. However, it may cause certain side effects in some people, including blurred vision and dizziness. Make sure you know how you react to dorzolamide before you drive a car or operate machinery.

Possible side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking dorzolamide or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not. You may need medical treatment if you get some of the side effects.

Tell your doctor or pharmacist if you notice any of the following:

  • eye problems such as burning, stinging, itching, conjunctivitis, watering of the eye(s), redness of the eye(s), swelling or crusting of the eyelid(s), eye pain, blurred vision
  • feeling sick
  • bitter taste, dry mouth
  • nose bleeds
  • throat irritation
  • headache, dizziness
  • tiredness, weakness
  • kidney stone
  • numbness or tingling in fingers or toes

Other side effects not listed above may occur in some patients.

Allergic reactions

If you think you are having an allergic reaction to dorzolamide, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 30°C. Protect from light.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine 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.

Dorzolamide contains 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 taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Dorzolamide Eye Drops looks like

Dorzolamide eye drop is slightly opalescent, colourless to nearly colourless, slightly viscous solution.

The eye drops come in a 5 mL plastic bottle with a dropper and screw cap.

Ingredients

Each 1 mL contains 20 mg of dorzolamide (as hydrochloride) as the active ingredient.

It also contains the following inactive ingredients:

  • hyetellose
  • mannitol
  • sodium citrate dihydrate
  • benzalkonium chloride
  • Sodium hydroxide
  • water for injections

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes

Australian Registration Numbers

APO-Dorzolamide 20 mg/mL eye drops (bottle): AUST R 267119

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO and APOTEX are registered trade marks of Apotex Inc.

This leaflet was last updated in:
December 2016

BRAND INFORMATION

Brand name

APO-Dorzolamide Eye drops

Active ingredient

Dorzolamide

Schedule

S4

 

1 Name of Medicine

Dorzolamide hydrochloride.

2 Qualitative and Quantitative Composition

Dorzolamide eye drops contain 20 mg/mL dorzolamide (as hydrochloride) as the active ingredient.

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.
Each bottle contains 5 mL of a sterile, slightly opalescent, colourless to nearly colourless, slightly viscous, aqueous solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Dorzolamide eye drops are indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

4.2 Dose and Method of Administration

APO-Dorzolamide Eye Drops are intended for ophthalmic administration and is for individual patient use only.

Dosage.

When used as monotherapy, the dose is one drop of dorzolamide hydrochloride 2% eye drops in the affected eye(s) three times daily.
When used as adjunctive therapy with an ophthalmic beta-blocker, the dose is one drop of dorzolamide hydrochloride in the affected eye(s) two times daily.
When substituting dorzolamide hydrochloride eye drops for another ophthalmic anti-glaucoma agent, discontinue the other agent after usual dosing on one day, and start dorzolamide hydrochloride eye drops on the next day.
If more than one topical ophthalmic drug is being used, the drugs should be administered at least ten minutes apart.
Systemic absorption of drugs from ophthalmic solutions may be minimised by pressure on the tear-duct immediately after application.

4.3 Contraindications

Dorzolamide hydrochloride 2% eye drops is contraindicated in patients who are hypersensitive to any component of this product.

4.4 Special Warnings and Precautions for Use

The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. Dorzolamide hydrochloride eye drops has not been studied in patients with acute angle-closure glaucoma.
Dorzolamide hydrochloride is a sulphonamide and although administered topically, is absorbed systemically. Therefore the same types of adverse reactions that are attributable to sulphonamides may occur with topical administration, including severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. The safety of dorzolamide hydrochloride has not been demonstrated in patients with known hypersensitivity to sulphonamides. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation.
In clinical studies, local ocular adverse effects, primarily conjunctivitis and lid reactions, were reported with chronic administration of dorzolamide. Some of these reactions had the clinical appearance and course of an allergic-type reaction that resolved upon discontinuation of drug therapy. If such reactions are observed, discontinuation of treatment with dorzolamide hydrochloride eye drops should be considered.
There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and dorzolamide. The concomitant administration of dorzolamide eye drops and oral carbonic anhydrase inhibitors has not been studied and is not recommended.
Choroidal detachment has been reported with administration of dorzolamide after filtration procedures.
APO-Dorzolamide eye drops contains the preservative benzalkonium chloride, which may be absorbed by soft contact lenses. Therefore, this product should not be administered while wearing soft contact lenses. The contact lenses should be removed before application of the drops and not be reinserted earlier than 15 minutes after use.
There is an increased potential for developing corneal oedema in patients with low endothelial cell counts. Precautions should be used when prescribing dorzolamide to this group of patients.
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 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 also 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.
If more than one topical ophthalmic drug is being utilised, the drugs should be administered at least ten minutes apart.

Contact lens use.

Dorzolamide hydrochloride eye drops contains the preservative benzalkonium chloride, which may be absorbed by soft contact lenses. Therefore, dorzolamide hydrochloride eye drops should not be administered while wearing soft contact lenses. The contact lenses should be removed before application of the drops and not be reinserted earlier than 15 minutes after use.

Use in hepatic impairment.

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

Use in renal impairment.

Dorzolamide hydrochloride 2% eye drops 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, dorzolamide hydrochloride is not recommended in such patients.

Use in the elderly.

Of the total number of patients in clinical studies of dorzolamide hydrochloride 2% eye drops, 44% were 65 years of age and over, while 10% 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 to the product cannot be ruled out.

Paediatric use.

Safety and effectiveness in children have not been established as there have been no trials in children.

Effects on laboratory tests.

Dorzolamide 2% eye drops 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 dorzolamide hydrochloride eye drops. In clinical studies, dorzolamide eye drops was used concomitantly with the following medications without evidence of adverse interactions: timolol ophthalmic solution, betaxolol ophthalmic solution and systemic medications, including ACE-inhibitors, calcium channel blockers, diuretics, non-steroidal anti-inflammatory drugs including aspirin, and hormones (e.g. oestrogen, insulin, thyroxine).
Dorzolamide hydrochloride is a carbonic anhydrase inhibitor and although administered topically, is absorbed systemically. Dorzolamide hydrochloride should not be used concomitantly with oral carbonic anhydrase inhibitors.
In clinical studies, dorzolamide hydrochloride 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 eye drops.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

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.
(Category B3)
There are no adequate and well controlled studies in pregnant women. Dorzolamide hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
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 body weight gain in dams and decreased foetal weights. No treatment-related malformations were seen at 1 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. There are no adequate and well controlled studies in pregnant women.
Dorzolamide eye drops should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
In a study of dorzolamide hydrochloride in lactating rats, decreases in body weight gain in offspring were seen during lactation after an oral dose of 7.5 mg/kg/day. A slight delay in postnatal development (incisor eruption, vaginal canalization and eye opening), secondary to lower foetal body weight, was noted.
It is not known whether this drug is excreted in human milk. 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 potential side effects of dorzolamide hydrochloride eye drops that may affect some patients' ability to drive and use machines. (See Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Dorzolamide hydrochloride 2% eye drops was evaluated in more than 1400 individuals in controlled and uncontrolled clinical studies. In long term studies of 1108 patients treated with dorzolamide eye drops as monotherapy or as adjunctive therapy with an ophthalmic beta-blocker, the most frequent cause of discontinuation (approximately 3%) from treatment with dorzolamide eye drops was drug-related ocular adverse effects consistent with allergic-type reactions, primarily conjunctivitis and lid reactions (see Section 4.4 Special Warnings and Precautions for Use). Such reactions occurred approximately 7% overall in the clinical trials.
In clinical studies, the most common ocular complaints were burning and stinging, blurred vision, itching and tearing. Bitter taste was also frequently reported. Local symptoms considered clinically important by investigators appear as adverse experiences in the listing below.
Adverse experiences reported during clinical studies as drug-related (possibly, probably, or definitely) in 1-5% of patients on dorzolamide 2% eye drops were (in decreasing order of frequency).

Ocular.

Burning and stinging, conjunctivitis, eyelid inflammation, eye itching, eyelid irritation.

Systemic.

Headache, bitter taste, nausea, asthenia/fatigue.
In addition, iridocyclitis and rash were each reported rarely. Also, there was one report of urolithiasis.
The following adverse reactions have been reported in post-marketing experience.

Hypersensitivity.

Signs and symptoms of local reactions including palpebral reactions and systemic allergic reactions including angioedema, bronchospasm, urticaria and pruritus.

Nervous system.

Dizziness, paraesthesia.

Ocular.

Pain, redness, transient myopia (which resolved upon discontinuation of therapy), superficial punctate keratitis, eyelid crusting, choroidal detachment following filtration surgery.

Skin/mucous membranes.

Contact dermatitis, epistaxis, throat irritation, dry mouth, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Respiratory.

Dyspnoea.

Urogenital.

Urolithiasis.
Dorzolamide 2% eye drops was not associated with clinically meaningful electrolyte disturbances.

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 and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Symptoms.

Significant lethality was observed in female rats and mice after single oral doses of dorzolamide hydrochloride of 11,369 mg/m2 (1927 mg/kg) and 3960 mg/m2 (1320 mg/kg), respectively.

Treatment.

Treatment should be symptomatic and supportive. Electrolyte imbalance, development of an acidotic state, and possible central nervous system effects may occur. Serum electrolyte levels particularly potassium) and blood pH levels should be monitored.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Dorzolamide hydrochloride is a novel carbonic anhydrase inhibitor formulated for topical ophthalmic use. Unlike oral carbonic anhydrase inhibitors, dorzolamide hydrochloride, which is administered topically, exerts its effects directly in the eye.
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.

Mechanism of action.

Carbonic anhydrase (CA) is an enzyme found in many tissues of the body including the eye. It catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid. In humans, carbonic anhydrase exists as a number of isoenzymes, the most active being carbonic anhydrase II (CA-II) found primarily in red blood cells (RBCs) but also in other tissues. 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. The result is a reduction in intraocular pressure (IOP).
Dorzolamide hydrochloride is a potent inhibitor of human carbonic anhydrase II. Following topical ocular administration, dorzolamide 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. Dorzolamide does not cause pupillary constriction and reduces intraocular pressure without the side effects such as night blindness and accommodative spasm. Dorzolamide hydrochloride has minimal or no effect on pulse rate or blood pressure.
Topically applied beta-adrenergic blocking agents also reduce IOP by decreasing aqueous humour secretion but by a different mechanism of action. Studies have shown that when dorzolamide hydrochloride is added to a topical beta-blocker, additional reduction in IOP is observed; this finding is consistent with the reported additive effects of beta-blockers and oral carbonic anhydrase inhibitors.

Clinical trials.

In clinical studies for up to one year in patients with glaucoma or ocular hypertension (baseline IOP ≥ 23 mmHg), the IOP-lowering effect of dorzolamide hydrochloride was approximately 3 to 5 mmHg throughout the day. However, as with other IOP lowering drugs, diminished responsiveness after prolonged therapy has been observed in some patients.

5.2 Pharmacokinetic Properties

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 the maximum systemic 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, and the following observations were noted:
in plasma, concentrations of dorzolamide and metabolite were generally below the assay limit of quantitation (15 nanoM) indicating almost no free drug or metabolite;
in RBCs, dorzolamide concentrations approached the binding capacity of CA-II (20-25 microM) and metabolite concentrations approached 12-15 microM, well below the binding capacity of CA-I (125-155 microM);
in RBCs, CA-II activity was inhibited 94-96% and total carbonic anhydrase activity was inhibited 81-88%. This was below the > 99% inhibition of CA-II activity and 96% inhibition of total carbonic anhydrase activity in RBCs that are anticipated to be necessary for a pharmacological effect on renal function and respiration, respectively.
In a subset of 71 patients in a large clinical study (N=333) of dorzolamide 2% eye drops t.i.d. in patients with elevated IOP, dorzolamide and metabolite concentrations and carbonic anhydrase inhibition in RBCs were measured after approximately six and twelve months of treatment. The pharmacokinetic results were consistent with those observed at steady state in the oral pharmacokinetic study in terms of CA-II inhibition. Although in this study several patients 65 years of age and older with renal impairment (estimated CrCl 30 - 60 mL/min) had higher metabolite concentrations in RBCs, no meaningful differences in carbonic anhydrase inhibition and no clinically significant systemic side effects were directly attributable to this finding.

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

In a 2 year study of dorzolamide administered orally to male and female 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 1 year at doses of 2 mg/kg/day or in monkeys given 20 microL of 3% dorzolamide hydrochloride topically to the eye bid for 1 year.

6 Pharmaceutical Particulars

6.1 List of Excipients

Hyetellose, mannitol, sodium citrate dihydrate, benzalkonium chloride, sodium hydroxide and water for injections.

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.
Store in original container.
Discard product 4 weeks after opening.

6.5 Nature and Contents of Container

APO-Dorzolamide eye drops.

Bottle (translucent LDPE bottle with nozzle and white cap).
Pack size: 5 mL.
AUST R 267119.
APO and APOTEX are registered trade marks of Apotex Inc.

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 is a white to off-white, free flowing crystalline powder, which is soluble in water and slightly soluble in methanol and ethanol. It has a melting point of about 275°C.
Dorzolamide hydrochloride is optically active.
The specific rotation is α25 405° (C=1, water) = ~ -17°.

Chemical structure.


Chemical Name: (4S, 6S)-4- ethylamino-5, 6-dihydro-6 -methyl-4H-thieno[2,3-b] thiopyran-2- sulfonamide 7,7-dioxide monohydrochloride.
Molecular Formula: C10H17N2O4S3Cl.
Molecular Weight: 360.9.

CAS number.

130693-82-2.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes