Consumer medicine information

Alphagan Eye Drops

Brimonidine tartrate

BRAND INFORMATION

Brand name

Alphagan

Active ingredient

Brimonidine tartrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Alphagan Eye Drops.

What is in this leaflet

This leaflet answers some common questions about ALPHAGAN® eye drops, including how to use the eye drops. 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 ALPHAGAN® eye drops against the benefits they expect it will have for you.

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

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

What ALPHAGAN® eye drops are used for

ALPHAGAN® eye drops are 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. 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, including total blindness. In fact, untreated glaucoma is one of the most common causes of blindness.

ALPHAGAN® eye drops are used, either alone or in combination with other eye drops/medicines, to lower raised pressure within your eye(s).

Mechanism of action:
ALPHAGAN® eye drops lower the pressure in the eye by decreasing the fluid produced and helping the flow of fluid out of the eye chamber.

Your doctor may have prescribed ALPHAGAN® eye drops for another reason. Ask your doctor if you have any questions about why ALPHAGAN® eye drops have been prescribed for you.

Before you use ALPHAGAN® eye drops

When you must not use it

Do not use ALPHAGAN eye drops if:

  1. you have an allergy to ALPHAGAN® eye drops or any of the ingredients listed at the end of this leaflet, some symptoms of an allergic reaction include skin rash, itching, shortness of breath or swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing
  2. you are taking monoamine oxidase antidepressant medication,

Check with your doctor if:

  1. you are taking other medication for depression, or
  2. you have liver or kidney disease, or
  3. you have a severe, uncontrolled heart condition, or
  4. you are breast-feeding. Your baby may absorb this medicine from breast milk and therefore there is a possibility of harm to the baby.

Do not use ALPHAGAN® eye drops if:

  • the seal around the cap is broken,
  • the bottle/packaging shows signs of tampering,
  • the product does not look quite right,
  • the expiry date on the bottle or carton has passed.

If you use this medicine after the expiry date has passed, it may not work.

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

If you are not sure whether you should start using ALPHAGAN® eye drops, talk to your doctor.

Do not use ALPHAGAN® eye drops in a child or adolescent. Safety and effectiveness in paediatric patients have not been established. It is particularly important that the medicine is not used in children under the age of 2 years.

Before you start to use it.

Tell your doctor if:

  1. you have had an allergy to any other medicines or any other substances, such as foods, preservatives or dyes.
  2. you have or have had any medical conditions, especially the following:
  • severe heart disease
  • disease affecting your blood vessels, including Raynaud’s phenomenon or fainting.

If you have not told your doctor about any of the above, tell them before you use ALPHAGAN® eye drops.

Like most medicines, ALPHAGAN® eye drops are not recommended during pregnancy, unless the benefits outweigh the risk to the baby.

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 ALPHAGAN® eye drops may interfere with each other. These include:

  • medicines for high blood pressure,
  • certain medicines to treat depression, such as monoamine oxidase inhibitors and tricyclics,
  • medicines to relieve strong pain or anesthetics,
  • any sedative-type medicines, including alcohol and antihistamines
  • any sympathomimetic medicines.

Medicines used to treat asthma, severe headaches or coughs and colds may belong in the sympathomimetic group. These medicines may be affected by ALPHAGAN® eye drops, 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 ALPHAGAN® eye drops.

How to use ALPHAGAN® eye drops

How much to use

The usual dosage of eye drops is one drop in the eye(s) every twelve hours. If you are using more than one eye drop product, wait 5 to 10 minutes before using the second product so that the first eye drop is not washed out by, or interacts with the second.

Your doctor will tell you how many drops you need to use each day. Use ALPHAGAN eye drops only when prescribed by your doctor.

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

Use ALPHAGAN® eye drops 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.

If you are being changed from one eye drop to another, follow your doctor’s instructions carefully as to when to stop the old drops and when to start the new drops.

How to use it

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

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

To open a new bottle of ALPHAGAN® eye drops, first tear off the protective seal from the bottle. The seal will break and you can pull it off and then throw it away.

  1. Wash your hands well with soap and water.
  2. Shake the bottle gently.
  3. Remove the cap.
  4. Hold the bottle upside down in one hand between your thumb and forefinger or index finger.
  5. Using your other hand, gently pull down your lower eyelid to form a pouch or pocket.
  6. Tilt your head back and look up.
  7. Put the tip of the bottle close to your lower eyelid. Do not let the tip touch your eye.
  8. Release one drop into the pouch or pocket formed between your eye and eyelid by gently squeezing the bottle.
  9. Close your eye. Do not blink or rub your eye.
  10. While your eye is 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.
  12. Wash your hands again with soap and water to remove any residue.

Wait 15 minutes before replacing your contact lenses.

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.

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.

How long to use it

ALPHAGAN® eye drops help control your condition but does not cure it. Therefore ALPHAGAN® eye drops must be used every day. Continue using ALPHAGAN® eye drops for as long as your doctor prescribes.

For some people ALPHAGAN® eye drops may have been prescribed for a short time before or after eye surgery.

If you forget to use it

If it is almost time for your next dose, skip the dose you missed and use your next dose when you are meant to. Otherwise, use the drops as soon as you remember, and then go back to using/taking 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 use too much (overdose)

If you accidentally put several drops in your eye(s), immediately rinse your eye(s) with warm water.

If you think that you or anyone else may have swallowed any or all of the contents of a bottle of ALPHAGAN® eye drops, immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, or go to casualty at your nearest hospital. In New Zealand call the National Poisons Information Centre (telephone 0800 POISON or 0800 764 766)

Do this even if there are no signs of discomfort or poisoning.

While you are using ALPHAGAN® eye drops

Things you must do

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

If you become pregnant while using ALPHAGAN® eye drops tell your doctor immediately.

If you are about to be started on any new medicine tell your doctor and pharmacist that you are using ALPHAGAN® eye drops.

Things you must not do

Do not give ALPHAGAN® eye drops to anyone else, even if they have the same condition as you.

Do not stop using ALPHAGAN® eye drops without first talking to your doctor. If you stop using your eye drops, your eye pressures 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 ALPHAGAN® eye drops affect you.

ALPHAGAN® eye drops generally do not cause any problems with your ability to drive a car or operate machinery. However, ALPHAGAN® eye drops may cause blurred vision/ dizziness/ drowsiness/ tiredness in some people. Make sure you know how you react to ALPHAGAN® eye drops 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 ALPHAGAN® eye drops.

ALPHAGAN® eye drops help 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.

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

  • redness and swelling of the eye (s)
  • redness and swelling of the eyelids and surrounding area
  • discomfort
  • watering of the eye(s)
  • feeling of something in the eye(s)
  • itching
  • conjunctivitis (discharge with itching of the eye and crusty eyelids)
  • dry eyes
  • blurred vision
  • irritation of the eye(s)
  • burning and stinging of the eye(s)
  • excessive sensitivity to bright light
  • eye ache/pain
  • whitening of the eye(s)
  • abnormal vision
  • headache
  • dizziness
  • fatigue/drowsiness
  • nasal dryness
  • oral dryness
  • abnormal taste
  • upper respiratory symptoms
  • systemic allergic reactions
  • gastro-intestinal symptoms
  • depression
  • weakness

These are usually mild side effects that may occur occasionally.

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

  • dizziness and light-headedness, which may be due to low blood pressure,
  • fast or irregular heart beat, also called palpitations

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

After using ALPHAGAN® eye drops

Storage

Keep your eye drops in a cool place where the temperature stays below 25°C. Do not freeze the eye drops.

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 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 top/lid 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

What it looks like

The eye drops come in a 5 mL sterile plastic bottle.

Ingredients

Active ingredient: brimonidine tartrate.

Inactive ingredients:
benzalkonium chloride, polyvinyl alcohol, sodium chloride, sodium citrate, citric acid, and purified water.

Manufacturer/Supplier

Allergan Australia Pty Ltd
810 Pacific Highway
Gordon, NSW 2072
Allergan New Zealand Ltd,
Auckland

ARTG number: AUST R 60297

For more information about glaucoma, contact Glaucoma Australia on 1800 500 880 or Glaucoma New Zealand on 09 373 8779.

Date of preparation: January 2017

®Marks owned by Allergan, Inc

Published by MIMS July 2017

BRAND INFORMATION

Brand name

Alphagan

Active ingredient

Brimonidine tartrate

Schedule

S4

 

1 Name of Medicine

Brimonidine tartrate.

2 Qualitative and Quantitative Composition

Each mL of Alphagan eye drops contains 2.0 mg brimonidine tartrate (equivalent to 1.32 mg as brimonidine free base).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Eye drops, solution.
Alphagan 0.2% is a sterile ophthalmic solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Alphagan eye drops are effective in lowering elevated intraocular pressure in patients with chronic open angle glaucoma or ocular hypertension. Alphagan eye drops can be used in the treatment of glaucoma as either monotherapy or in combination with topical beta-blockers.

4.2 Dose and Method of Administration

Monotherapy.

The recommended dose is one drop of Alphagan eye drops in the affected eye(s) twice daily, approximately 12 hours apart.

Combination therapy.

The recommended dose is one drop of Alphagan eye drops in the affected eye(s) twice daily, approximately 12 hours apart.
In order to minimise systemic absorption of Alphagan eye drops, apply pressure to the tear duct immediately following administration of the drug.
As with all eye drops containing benzalkonium chloride as a preservative, there is potential for incompatibility with other topical ophthalmic medications. If more than one topical ophthalmic drug is to be used, other eye drops should not be used within five to ten minutes of using Alphagan eye drops.

4.3 Contraindications

Alphagan eye drops are contraindicated in patients with hypersensitivity to brimonidine tartrate or any component of this medication. This product is also contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy.
Alphagan eye drops are also contraindicated in neonates and infants (children under the age of 2 years).

4.4 Special Warnings and Precautions for Use

Identified precautions.

Brimonidine eye drops should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension or thromboangiitis obliterans.
During the studies there was a loss of effect in some patients. The IOP lowering efficacy observed with brimonidine eye drops during the first month of therapy may not always reflect the long-term level of IOP reduction. Patients prescribed IOP lowering medication should be routinely monitored for IOP.

Cardiovascular disease.

Although brimonidine eye drops had minimal effect on blood pressure and heart rate of patients in clinical studies, caution should be observed in treating patients with severe, uncontrolled cardiovascular disease.

Hypersensitivity.

Delayed ocular hypersensitivity reactions have been reported with Alphagan, with some reported to be associated with an increase in IOP.

Use in hepatic or renal impairment.

Brimonidine eye drops have not been studied in patients with hepatic or renal impairment; caution should be used in treating such patients.

Use in the elderly.

No data available.

Paediatric use.

Symptoms of bradycardia, coma, hypotension, lethargy, pallor, respiratory depression, somnolence, hypothermia, hypotonia and apnoea have been reported in neonates, infants and children receiving brimonidine either for congenital glaucoma or by accidental oral ingestion. [See Section 4.3 Contraindications].
Children 2 years of age and above, especially those weighing ≤ 20 kg, should be treated with caution and closely monitored due to the high incidence and severity of somnolence.

Information for patients.

The preservative in brimonidine eye drops, benzalkonium chloride, may be absorbed by and cause discoloration of soft contact lenses. Patients wearing soft contact lenses should be instructed to wait at least 15 minutes after using brimonidine eye drops to insert soft contact lenses.
Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures to avoid eye injury and contamination of eye drops.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Specific drug interaction studies have not been conducted with brimonidine eye drops. The possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered. Because brimonidine eye drops may reduce pulse and blood pressure, caution using concomitant drugs such as beta-blockers (ophthalmic and systemic), antihypertensives and/or cardiac glycosides is advised.
Caution is advised when initiating or changing the dose of a concomitant systemic agent which may interact with alpha-adrenergic agonists or interfere with their activity (i.e. sympathomimetic agents, agonists or antagonists of the adrenergic receptor).
Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with brimonidine can lead to an interference in IOP lowering effect. No data on the level of circulating catecholamines after brimonidine eye drops are instilled are available. Caution, however, is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines.
As brimonidine is metabolised primarily by the liver, most likely by cytochrome P450 and aldehyde oxidase, this may affect the metabolism of other drugs that utilise the cytochrome P450 pathway.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Brimonidine did not have a significant effect on fertility in a reproductive performance study in rats at oral doses of up to 0.66 mg/kg/day.
(Category B3)
There are no studies of brimonidine in pregnant women, but in rats the drug crosses the placenta and enters the foetal circulation.
Because animal reproductive studies are not always predictive of human response, Alphagan should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus.
In pregnant rats, brimonidine was associated with maternotoxicity and increased early resorptions/ post-implantation losses and decreased pup viability and bodyweights at exposures (based on AUC) of 180 times greater than expected exposures in humans treated therapeutically. The drug was also maternotoxic in rabbits and caused abortions at exposures about 12 times greater than those expected in humans. In both rats and rabbits, brimonidine was not teratogenic.
It is not known whether brimonidine is excreted in human milk. Therefore a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. In lactating rats, levels of the drug in milk were up to 12 times higher than those in maternal plasma; and in a peri- and postnatal study in rats, brimonidine was associated with decreased pup viability and pup weights during lactation at maternal plasma exposures of about 55 times greater than those expected in humans.

4.7 Effects on Ability to Drive and Use Machines

As with other alpha-agonists, brimonidine can potentially cause fatigue and/or drowsiness in some patients. Patients who engage in hazardous activities requiring mental alertness, such as driving and operating machinery, should be cautioned of the potential for a decrease in mental alertness.
Alphagan may also cause blurred vision or visual disturbance in some patients. The patient should wait until these symptoms have cleared before driving or using machinery.

4.8 Adverse Effects (Undesirable Effects)

A. Clinical trials - frequency of adverse events occurring in pivotal monotherapy studies.

See Table 1.
Brimonidine eye drops - adverse events occurring at 1-5%.

Ocular.

Eyelid oedema, abnormal vision, blepharitis, ocular irritation, conjunctival blanching, conjunctival discharge.

Systemic.

Dizziness, gastrointestinal symptoms, asthenia, abnormal taste.
Brimonidine eye drops - adverse events occurring at < 1%.

Ocular.

Conjunctival papillae, tearing.

Systemic.

Depression, systemic allergic reaction, nasal dryness, palpitations.

B. Clinical trials - frequency of adverse events occurring in combination therapy studies.

As adjunctive therapy, assigning causality of adverse events cannot be reliable because both agents are administered concurrently. However, the most common adverse events are shown in Table 2.

Postmarketing experience.

During post-marketing surveillance, apnoea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in neonates, infants, and children receiving brimonidine either for congenital glaucoma or by accidental ingestion.
The following adverse reactions have been identified during postmarketing use of Alphagan 0.2% in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Eye disorders.

Iritis, iridocyclitis (anterior uveitis), miosis, conjunctivitis, eyelids pruritus.

Immune system disorders.

Hypersensitivity, skin reaction (including erythema, face oedema, pruritus, rash, and vasodilatation).

Cardiac disorders.

Palpitations/ arrhythmias (including bradycardia or tachycardia).

Psychiatric disorders.

Depression.

Vascular disorders.

Hypotension, syncope.

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

Ophthalmic overdose.

In those cases received, the events reported have generally been those already listed as adverse reactions.

Systemic overdose resulting from accidental ingestion.

There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained. Symptoms of brimonidine overdose such as apnaea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in neonates, infants, and children receiving Alphagan as part of medical treatment of congenital glaucoma or by accidental oral ingestion.
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.

Brimonidine tartrate is an alpha2-adrenergic agonist that is 1000-fold more selective for the alpha2-adrenoreceptor than the alpha1-adrenergic receptor. Affinity at human alpha1 and alpha2-adrenoreceptors are ≈2000 nanoM and ≈2 nanoM, respectively. This selectivity results in no mydriasis and the absence of vasoconstriction in microvessels associated with human retinal xenografts.
Topical administration of brimonidine solution decreases intraocular pressure (IOP) in humans. When used as directed, brimonidine eye drops have the action of reducing elevated IOP with minimal effect on cardiovascular parameters.
Brimonidine has a rapid onset of action, with the peak ocular hypotensive effect occurring at two hours postdosing. The duration of effect is 12 hours or greater.
Fluorophotometric studies in animals and humans suggest that brimonidine solution has a dual mechanism of action. Brimonidine lowers IOP by reducing aqueous humor production and enhancing uveoscleral outflow.

Clinical trials.

Elevated IOP presents a major risk factor in glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss. Brimonidine has the action of lowering intraocular pressure with minimal effect on cardiovascular and pulmonary parameters.

Monotherapy.

The efficacy of Alphagan eye drops was demonstrated in two multicentre studies comparative with timolol 0.5% lasting up to one year in subjects with glaucoma or ocular hypertension. A total of 513 subjects received Alphagan eye drops in the two studies.
The overall mean decrease (± SD) in IOP from baseline at 12 months, as measured at peak response, was 6.20 ± 4.08 mmHg for brimonidine monotherapy and 5.56 ± 3.65 mmHg for timolol monotherapy. At trough response, these figures were 3.74 ± 3.83 mmHg for brimonidine and 5.80 ± 3.35 mmHg for timolol.
These results represent approximately 16%-26% mean reduction from baseline measurements. IOP decreases were maintained for up to one year; no tachyphylaxis was observed. 9.4% of subjects treated with Alphagan eye drops and 5.1% of subjects treated with timolol 0.5% were discontinued because of inadequately controlled intraocular pressure. 30% of these patients withdrew during the first month of therapy.

Adjunctive therapy.

The ability of Alphagan eye drops to lower IOP when used in combination with other antiglaucoma agents has been evaluated in two large scale multicentre randomised studies involving 321 patients, 150 of which received brimonidine.
In the first study, brimonidine 0.2% twice daily as an adjunct to β-blocker therapy was compared with pilocarpine 2% administered three times daily, as an adjunct to β-blocker therapy. The overall mean decrease (± SD) in IOP from baseline at 3 months, as measured at peak response, was 4.92 ± 3.02 mmHg for brimonidine adjunctive therapy and 5.52 ± 3.08 mmHg for pilocarpine adjunctive therapy. At trough response, these figures were 3.95 ± 2.67 mmHg for brimonidine adjunctive therapy and 3.81 ± 2.75 mmHg for pilocarpine adjunctive therapy. These results represent a mean additional decrease in IOP for Alphagan adjunctive therapy of 17%-22%.
The second study was an 8 month comparison of the additive IOP lowering effect to an already established β-blocker eye drop regimen, of Alphagan 0.2% eye drops or dipivefrine 0.1% eye drops. Adjunctive Alphagan eye drops was shown to be superior to adjunctive dipivefrine 0.1% at peak effect and equivalent in efficacy to adjunctive dipivefrine at trough at most time points.
The overall mean decrease (± SD) in IOP from baseline at 3 months, as measured at peak response, was 3.26 ± 3.16 mmHg for Alphagan adjunctive therapy and 2.33 ± 3.13 mmHg for dipivefrine adjunctive therapy. At trough response, these figures were 2.89 ± 3.14 mmHg for Alphagan adjunctive therapy and 3.31 ± 3.69 mmHg for dipivefrine adjunctive therapy. These results represent a mean additional decrease in IOP for brimonidine adjunctive therapy of 12%-15%.

5.2 Pharmacokinetic Properties

Absorption.

After ocular administration of a 0.2% solution twice daily in normal healthy subjects for 10 days, plasma concentrations were measured as (mean) Cmax 0.06 nanogram/mL. Plasma concentrations peaked within 1 to 4 hours and declined with a systemic half-life of approximately 3 hours.

Metabolism.

Brimonidine is metabolised primarily by the liver.

Excretion.

Urinary excretion is the major route of elimination of the drug and its metabolites. Approximately 87% of the radioactivity following an orally administered radioactive dose was eliminated within 120 hours, with 74% found in the urine.

5.3 Preclinical Safety Data

Genotoxicity.

Brimonidine was non-genotoxic in assays for chromosomal damage (Chinese hamster cells in vitro, in vivo bone marrow cytogenetic assay and a dominant lethal assay). In assays for gene mutations in S. typhimurium and E. coli, brimonidine gave a positive response in one S. typhimurium strain without metabolic activation. Other strains gave negative results.

Carcinogenicity.

No compound related carcinogenic effects were observed in 21 month and 2 year studies in mice and rats given oral doses of 2.5 and 1 mg/kg/day, respectively, as the free base. Plasma concentrations of brimonidine in mice and rats in the high-dose groups were ≥ 60 times greater than those expected in humans dosed therapeutically.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each mL of Alphagan 0.2% solution contains:
Active: brimonidine tartrate 2.0 mg (equivalent to 1.32 mg as brimonidine free base).
Preservative: benzalkonium chloride 0.05 mg.
Inactives: polyvinyl alcohol; sodium chloride; sodium citrate dihydrate; citric acid monohydrate; and purified water. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH (6.3-6.5).

6.2 Incompatibilities

As with all eye drops containing benzalkonium chloride as a preservative, there is potential for incompatibility with other topical ophthalmic medications. If more than one topical ophthalmic drug is to be used, other eye drops should not be used within five to ten minutes of using Alphagan eye drops.
The preservative in brimonidine eye drops, benzalkonium chloride, may be absorbed by and cause discoloration of soft contact lenses. Patients wearing soft contact lenses should be instructed to wait at least 15 minutes after using brimonidine eye drops to insert soft contact lenses.

6.3 Shelf Life

30 months.

6.4 Special Precautions for Storage

Store below 25°C.
To avoid contamination of the solution, keep container tightly closed. Do not touch dropper tip to any surface. Contents are sterile if seal is intact.

6.5 Nature and Contents of Container

Alphagan (brimonidine tartrate ophthalmic solution) 0.2% sterile solution is supplied in white opaque plastic dropper bottles. Each bottle has a fill volume of 5 mL.
AUST R 60297.

6.6 Special Precautions for Disposal

Discard contents 4 weeks after opening the bottle.

6.7 Physicochemical Properties

Brimonidine tartrate (Alphagan ophthalmic solution 0.2%) is an alpha2-selective adrenergic agonist for ophthalmic use. Brimonidine tartrate is an off white, pale yellow to pale pink powder and is water soluble (34 mg/mL). In solution, brimonidine tartrate has a clear, greenish-yellow colour.

Chemical structure.


Chemical name: 5-bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate.
Molecular weight: 442.24 as the tartrate salt.
Empirical formula: C11H10BrN5, C4H6O6.

CAS number.

79570-19-7.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes