Consumer medicine information

APO-Bimatoprost Eye Drops

Bimatoprost

BRAND INFORMATION

Brand name

APO-Bimatoprost

Active ingredient

Bimatoprost

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Bimatoprost Eye Drops.

What is in this leaflet

This leaflet answers some common questions about bimatoprost. 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 this medicine 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 want to read it again.

What this medicine is used for

Bimatoprost 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 higher than normal. It 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, causing the pressure 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.

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.

How it works

Bimatoprost belongs to a group of medicines called prostaglandin analogues. It lowers the pressure in the eye by helping the flow of fluid out of the eye chamber.

Bimatoprost eye drops can be used alone or together with other medicines to lower the pressure within your eyes.

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.

This medicine is not addictive.

There is not enough information to recommend the use of this medicine in children.

Before you use this medicine

When you must not use it

Do not use this medicine if you have an allergy to:

  • bimatoprost
  • any of the ingredients listed at the end of this leaflet.

Do not use the medicine after the expiry date printed on the bottle or if the seal around the bottle is broken or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

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

Before you start to use it

Before you start using bimatoprost eye drops your doctor should tell you that some changes to your eyes may occur which may be permanent.

Eyelashes may grow longer and thicker, and eyelashes, the skin around the eye and the coloured part of the eye may become darker. If only one eye is being treated the cosmetic differences between the eyes may be noticeable. None of these changes should affect vision. If you have any concerns, ask your doctor.

Do not put the eye drops into your eye(s) while you are wearing soft contact lenses. The preservative in bimatoprost eye drops (benzalkonium chloride) may be deposited in soft contact lenses. Remove soft contact lenses before using eye drops and wait 15 minutes before reinserting lenses.

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • breathing problems
  • liver or kidney problems
  • hypotension (low blood pressure)
  • bradycardia (low heart rate)
  • other heart conditions
  • eye disorders

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Do not use this medicine until you and your doctor have discussed the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you start using this medicine.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

How to use this medicine

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

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How much to use

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

The usual dose is one drop in the affected eye(s) once daily, given in the evening.

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 bimatoprost eye drops, break off the protective seal from the bottle and place in the bin. The contents are sterile if the seal is intact.

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

Wait 5 minutes before using any other topical eye medication.

Wait 15 minutes before replacing your contact lenses.

Be careful not to touch the bottle tip against your eye, eyelid or anything else to avoid contaminating the eye drops.

When to use it

Use bimatoprost eye drops at about the same time each day. Using your eye drops at the same time each day will have the best effect. It will also help you remember when to use your eye drops.

How long to use it

Continue bimatoprost eye drops for as long as your doctor tells you.

Bimatoprost eye drops help to control your condition, but do not cure it.

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 them as you would normally.

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

Do not administer 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 use your medicine, ask your pharmacist for some hints.

If you use too much (overdose)

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

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accidental and Emergency at your nearest hospital, if you think that you or anyone else may have swallowed any or all of the contents of a bottle of bimatoprost eye drops. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using this medicine

Things you must do

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

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

Tell your doctor if you develop an eye infection, receive an eye injury, or have eye surgery. Your doctor may tell you to use a new bottle of bimatoprost eye drops because of possible contamination of the old bottle.

If you become pregnant, tell your doctor immediately.

Hair may grow where bimatoprost contacts the skin.

If you wear soft contact lenses, remove them before using bimatoprost eye drops. Leave your lenses out for at least 15 minutes after putting in the eye drops.

Keep all of your doctor's appointments so that your progress can be checked.

Tell your doctor if your condition gets worse or does not get better while using bimatoprost eye drops.

Things you must not do

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

Do not use your medicine to treat any other complaint unless your doctor tells you to.

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

Things to be careful of

Your vision may blur for a short time after you put in your eye drops. If this happens you should wait until you can see well again before you drive or use machinery. Bimatoprost eye drops are not expected to cause any problems with your ability to drive a car or operate machinery. However, as a general precaution, be careful driving or operating machinery until you know how bimatoprost eye drops affect you.

Side effects

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

This medicine helps most people, 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 attention if you get some of the side effects.

Do not be alarmed by the following lists of 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:

  • red, congested eyes
  • darkening or growth of eyelashes
  • itching, pain or irritation of eye/s
  • discharge from the eye, discomfort or dryness
  • tears, inflamed areas around eye/s
  • allergic effects or burning feeling on eye and surrounding eyelid
  • feeling of something in the eye
  • sensitivity to light
  • an increase in colouring or pigment of area around eye (sometimes reversible)
  • blurred vision, visual changes
  • darkening of the coloured part of the eye
  • swelling of the back of the eye
  • other eye related problems such as spasm of the eye where there is uncontrolled blinking and squeezing of the eyelid, swelling of the eyelid, inflammation of the coloured part of eye, bleeding in the eye chamber, eyelid retraction, small lesions or erosions on the eye surface
  • difficult or laboured breathing, coughing, wheezing and tightening of chest
  • effects on the body such as headache, weakness, dizziness, depression, infection, nausea, high blood pressure, skin pigmentation and abnormal hair growth.

The above list includes some side effects that may require medical attention.

If you think you are having an allergic reaction to bimatoprost, stop using this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

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

Storage and disposal

Storage

Keep your eye drops in a cool dry place where the temperature will stay below 25°C.

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

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.

Disposal

Throw out any remaining solution after four weeks from the date of opening. 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 medicine left over.

Product description

What it looks like

Clear, colourless solution in bottles containing 3 mL of solution.

AUST R 204398

Ingredients

APO- Bimatoprost eye drops contain 0.3 mg/mL of bimatoprost.

They also contain the following:

  • benzalkonium chloride
  • anhydrous citric acid
  • sodium chloride
  • dibasic anhydrous sodium phosphate
  • purified water
  • sodium hydroxide or hydrochloric acid for pH adjustment

This medicine does not contain lactose, gluten, sucrose, tartrazine or any other azo dyes.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park, NSW 2113
Australia

APO and APOTEX are registered trademarks of Apotex Inc.

This leaflet was prepared in July 2019.

Published by MIMS September 2019

BRAND INFORMATION

Brand name

APO-Bimatoprost

Active ingredient

Bimatoprost

Schedule

S4

 

1 Name of Medicine

Bimatoprost.

2 Qualitative and Quantitative Composition

Bimatoprost 0.3 mg/mL.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

APO-Bimatoprost 0.3 mg/mL eye drops are a sterile, clear, colourless solution supplied in a plastic dropper bottle with a plastic screw cap.

4 Clinical Particulars

4.1 Therapeutic Indications

The reduction of elevated intraocular pressure, or open angle glaucoma, as first line therapy or monotherapy or as adjunctive therapy to topical beta-blockers.

4.2 Dose and Method of Administration

APO-Bimatoprost is not intended for oral administration and is for individual patient use only.

Dosage.

Monotherapy.

The recommended dose is one drop in the affected eye(s) once daily, administered in the evening.

Adjunctive therapy.

The recommended dose is one drop in the affected eye(s) once daily, administered in the evening.
More frequent administration has not been shown to provide increased efficacy.
If more than one topical ophthalmic medication is to be used, the other medication should not be used within 5 minutes of using bimatoprost eye drops.
In order to minimise systemic absorption, patients should be instructed to apply pressure to the tear duct immediately following administration of the drug.
To avoid contamination of the solution, keep container tightly closed. Do not touch dropper tip to any surface. Discard contents 4 weeks after opening the bottle. Contents are sterile if seal is intact.

4.3 Contraindications

Patients with known hypersensitivity to bimatoprost or any of the excipients of the medication.

4.4 Special Warnings and Precautions for Use

General.

Bimatoprost has not been studied in patients with heart block more severe than first degree or uncontrolled congestive heart failure. There have been a limited number of spontaneous reports of bradycardia or hypotension with bimatoprost eye drops. Bimatoprost should be used with caution in patients predisposed to low heart rate or low blood pressure.
Bimatoprost has not been studied in patients with compromised respiratory function and should therefore be used with caution in such patients. In clinical studies, in those patients with a history of a compromised respiratory function, no significant untoward respiratory effects have been seen.
During treatment with bimatoprost, darkening of the eyelid skin and gradual increased eyelash growth (lengthening, darkening and thickening) with no consequent untoward ocular effects have been observed. Increased iris pigmentation has also been reported. The change in iris pigmentation occurs slowly and may not be noticeable for several months to years. Neither naevi nor freckles of the iris appear to be affected by treatment. The effect has been seen in up to 2% of patients treated with bimatoprost for up to 6 months. The long term effects of increased iris pigmentation are not known.
Before treatment is initiated, patients should be informed of the possibility of eyelash growth, darkening of the eyelid skin and increased iris pigmentation. Some of these changes may be permanent and may lead to differences in appearance between the eyes when only one eye is treated. Periorbital tissue pigmentation has been reported to be reversible in some patients.
There is the potential for hair growth to occur in areas where bimatoprost solution comes repeatedly in contact with the skin surface. Thus, it is important to apply bimatoprost as instructed and to avoid it running onto the cheek or other skin areas.
In bimatoprost studies in patients with glaucoma or ocular hypertension, it has been shown that more frequent exposure of the eye to more than one dose of bimatoprost daily may decrease the IOP-lowering effect. Patients using bimatoprost with other prostaglandin analogues should be monitored for changes to their intraocular pressure.
Bimatoprost should be used with caution in patients with active intraocular inflammations (e.g. uveitis) because the inflammation may be exacerbated.
Macular oedema, including cystoid macular oedema, has been reported during treatment with bimatoprost 0.03% ophthalmic solution for elevated IOP. Bimatoprost should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular oedema (e.g. intraocular surgery, retinal vein occlusions, ocular inflammatory disease and diabetic retinopathy).
Bimatoprost has not been studied in patients with inflammatory ocular conditions, neovascular, inflammatory, angle-closure glaucoma, congenital glaucoma or narrow-angle glaucoma.

Information for patients.

Bimatoprost eye drops contain the preservative benzalkonium chloride, which may be absorbed by and cause discolouration of soft (hydrophilic) contact lenses. Patients wearing soft contact lenses should be instructed to remove their contact lenses prior to instillation of bimatoprost and wait at least 15 minutes following administration before reinserting the contact lenses. Bimatoprost should not be administered while wearing contact lenses.
There have been reports of bacterial keratitis associated with the use of multidose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent ocular disease. Patients with a disruption of the ocular epithelial surface are at greater risk of developing bacterial keratitis.
The tip of the bottle should not be allowed to contact the eye, surrounding structures, fingers or any other surface in order to avoid eye injury and contamination of the solution.

Use in renal impairment.

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

Use in hepatic impairment.

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

Use in the elderly.

No dosage adjustment in elderly patients is necessary.

Paediatric use.

Safety and effectiveness in patients below 18 years of age have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed.
No drug-drug interactions are anticipated in humans since systemic concentrations of bimatoprost are extremely low (less than 0.2 nanogram/mL) following ocular dosing. No effects on hepatic drug metabolising enzymes were observed in pre-clinical studies. Therefore, specific interaction studies with other medicinal products have not been performed with bimatoprost.
In clinical studies, bimatoprost was used concomitantly with a number of different ophthalmic beta-blocking agents without evidence of drug interactions.
Concomitant use of bimatoprost and anti-glaucoma agents other than topical beta-blockers has not been evaluated during adjunctive glaucoma therapy.
There is a potential for the IOP-lowering effect of prostaglandin analogues to be reduced in patients with glaucoma or ocular hypertension when used with other prostaglandin analogues.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Bimatoprost did not affect fertility in male or female rats at oral doses up to 0.6 mg/kg/day corresponding to 30 - 50 times the expected human exposure (based on blood AUC calculated from total blood concentration).
(Category B3)
Bimatoprost and/or its metabolites crossed the placenta in rats. In embryo/foetal developmental studies in pregnant mice and rats, abortion was observed at oral doses of bimatoprost of 0.3 and 0.6 mg/kg/day, respectively, resulting in exposures 15 and 34 times the expected human exposure (based on blood AUC calculated from total blood concentration). Bimatoprost was not teratogenic at up to 0.6 mg/kg/day in mice or rats. At doses of ≥ 0.3 mg/kg/day PO in rats, approximately 20 times the expected human exposure, the gestation length was reduced, embryofoetal losses and peri- and postnatal pup mortality were increased, and pup body weights were reduced.
There are no adequate and well-controlled studies in pregnant women. Bimatoprost should not be used during pregnancy unless clearly necessary.
 Bimatoprost was excreted in rat milk following PO administration. Increased pup mortality and depressed pup growth occurred when dams were treated PO with bimatoprost from gestation day 7 to lactation day 20 at ≥ 0.3 mg/kg/day, corresponding to exposures approximately 20 times the expected human exposure (based on blood AUC calculated from total blood concentration).
There are no data on the excretion of bimatoprost into human milk or on the safety of bimatoprost exposure in infants. Because many drugs are excreted in human milk, nursing women who use bimatoprost should stop breast feeding.

4.7 Effects on Ability to Drive and Use Machines

Based on the pharmacodynamic profile, bimatoprost is not expected to affect the ability to drive and use machines. As with any ocular medication, if transient blurred vision occurs at instillation, the patient should wait until the vision clears before driving or using machinery.

4.8 Adverse Effects (Undesirable Effects)

In clinical studies, over 1,700 patients have been treated with bimatoprost.
In the two pivotal monotherapy trials (715 patients) the most frequently reported treatment-related adverse events were: conjunctival hyperaemia in up to 42%, growth of eyelashes in up to 36% and ocular pruritus in up to 14% of patients. The incidence of conjunctival hyperaemia at baseline was 25.1% and 17.8% in patients allocated to treatment with bimatoprost once daily and timolol twice daily, respectively. At 6 months, the incidence of patients with a greater than mild increase in conjunctival hyperaemia was 6.2% and 0.4% in patients treated with bimatoprost once daily and timolol twice daily, respectively. Less than 7% of patients discontinued due to any adverse event.
The following undesirable effects definitely, probably or possibly related to treatment were reported during clinical trials with bimatoprost. Most were ocular, mild to moderate, and none was serious:

Eye disorders.

Very common (> 10%): conjunctival hyperaemia, growth of eyelashes, ocular pruritus.
Common (< 10%): allergic conjunctivitis, asthenopia, blepharitis, blepheral pigmentation, conjunctival oedema, corneal erosion, eye discharge, eyelash darkening, eyelid erythema, eyelid pruritus, eye pain, foreign body sensation, increased iris pigmentation, lacrimation increased, ocular burning, ocular dryness, ocular irritation, photophobia, pigmentation of periocular skin, superficial punctate keratitis, tearing, visual disturbance, blurred vision and worsening of visual acuity.
Uncommon (< 1%): blepharospasm, eyelid oedema, eyelid retraction, iritis, retinal haemorrhage.

Nervous system disorders.

Common (< 10%): headache.
Uncommon (< 1%): depression, vertigo.

Musculoskeletal and connective tissue disorders.

Common (< 10%): asthenia.

Respiratory, thoracic and mediastinal disorders.

Uncommon (< 1%): infection (primarily colds and upper respiratory tract infections).

Skin and subcutaneous tissue disorders.

Common (< 10%): skin hyperpigmentation.
Uncommon (< 1%): hirsutism.

Post-marketing experiences.

Eye disorders.

Deepened lid sulcus (enophthalmos), erythema (periorbital), macular oedema, ocular discomfort.

Skin and subcutaneous tissue disorders.

Hair growth abnormal, skin discolouration.

Gastrointestinal disorders.

Nausea.

Nervous system disorders.

Dizziness.

Immune system disorders.

Hypersensitivity reaction including signs and symptoms of eye allergy and allergic dermatitis.

Vascular disorders.

Hypertension.

Respiratory, thoracic and mediastinal disorders.

Asthma, exacerbation of asthma, dyspnoea.

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 http://www.tga.gov.au/reporting-problems and contact Apotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

If overdosage occurs, treatment should be symptomatic and supportive.

Ophthalmic overdose.

No case of overdose has been reported, and is unlikely to occur after ocular administration.

Systemic overdose resulting from accidental ingestion.

If bimatoprost is accidentally ingested, the following information may be useful: in two-week oral rat and mouse studies, doses up to 250 mg/kg/day did not produce any toxicity. This dose expressed as mg/kg is 1,100 times higher than the accidental dose of one bottle (7.5 mL) of bimatoprost in a 10 kg child.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Bimatoprost is a novel synthetic prostamide analogue with potent ocular hypotensive activity. It selectively mimics the effects of a newly discovered naturally occurring substance, prostamide. Prostamide is biosynthesised from anandamide by a pathway involving COX-2 but not COX-1, suggesting a new pathway that leads to the synthesis of endogenous lipid amides that lower intraocular pressure (IOP). Bimatoprost and prostamides differ from prostaglandins (PGs) in that prostamides are biosynthesised from a different precursor, anandamide; bimatoprost does not stimulate any previously described prostanoid receptor; it is not mitogenic; it does not contract the human uterus; and it is electrochemically neutral.
Bimatoprost reduces intraocular pressure by increasing aqueous humour outflow through the trabecular meshwork and enhancing uveoscleral outflow. Reduction of the intraocular pressure starts approximately 4 hours after the first administration and maximum effect is reached within approximately 8 to 12 hours. The duration of effect is maintained for at least 24 hours.
Clinical studies have shown mean intraocular pressure decreases of up to 9 mmHg.

Clinical trials.

Elevated IOP presents a major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of optic nerve damage and glaucomatous visual field loss. Bimatoprost has the action of lowering intraocular pressure with no clinically relevant effects on heart rate and blood pressure observed in clinical trials.

Monotherapy.

The efficacy of bimatoprost eye drops was demonstrated in two multi-centre studies compared with timolol 0.5% after 6 months treatment in subjects with chronic glaucoma or ocular hypertension. In each, both once daily and twice daily bimatoprost was compared to twice daily timolol 0.5%. A total of 1198 patients were enrolled in the two studies with 474 receiving bimatoprost once daily, 483 receiving bimatoprost twice daily and 241 receiving timolol. See Table 1.
Bimatoprost eye drops administered once daily as monotherapy, have consistently shown clinically and statistically superior IOP reduction vs timolol 0.5% twice daily over a six month period. Mean IOP changes from baseline for bimatoprost once daily ranged from 6.88 to 7.88 mmHg in study 1 and 7.14 to 8.69 mmHg in study 2. These were superior to the decreases seen in the timolol group (4.17 to 6.27 mmHg and 4.96 to 6.63 mmHg respectively). Twice daily dosing did not show any increased efficacy compared to once daily dosing.
In addition to mean change from baseline, a frequency analysis of the IOP recorded at hour 0 at each visit was performed. In the two studies 46% and 52.5% of patients achieved an IOP of 17 mmHg or less (a commonly agreed 'target IOP') with bimatoprost once daily over the time period studied, compared to 25.4% and 29% in the timolol group. These results corroborate the statistical and clinical superiority of the once daily regimen over timolol seen at all visits.

Adjunctive therapy.

The ability of bimatoprost 0.03% eye drops to lower IOP when used as adjunctive therapy to topical beta-blocker monotherapy has been evaluated in two large scale multi-centre, randomised 3 month studies, involving 722 patients of which 489 received bimatoprost. The numbers and proportions of the different topical beta-blocking agents used in the studies were representative of clinical practice. See Table 2.
Overall at month 3 in study 1, the mean decreases from baseline IOP at hours 0, 2 and 8 in patients treated with bimatoprost once daily/beta-blocker ranged from 6.03 to 7.95 mmHg. These were non-inferior to the decreases seen in the latanoprost/beta-blocker group (5.89 to 7.35 mmHg) at all time points.
Overall at month 3 in study 2, the mean decreases from baseline IOP at hours 0, 2 and 8 in patients treated with bimatoprost once daily/beta-blocker ranged from 6.39 to 7.38 mmHg. These were superior to the decreases seen in the vehicle/beta-blocker group (2.62 to 3.59 mmHg) at all time points. Bimatoprost once daily/beta-blocker showed superiority to vehicle/beta-blocker at all time points at all visits.

5.2 Pharmacokinetic Properties

After twice daily dosing, the mean AUC0-24hr value of 0.0634 nanogram.hr/mL for bimatoprost in the elderly (subjects 65 years or older) was statistically significantly higher than that of 0.0218 nanogram.hr/mL in young healthy adults, suggesting the existence of an age effect. However, this finding is not clinically relevant as systemic exposure for elderly and young subjects remained very low from ocular dosing. There was no accumulation of bimatoprost in the blood over time and the safety profile was similar in elderly and young patients.

Absorption.

Bimatoprost penetrates the human cornea and sclera in vitro.
After once daily ocular administration of one drop of 0.03% bimatoprost to both eyes of 15 healthy subjects for two weeks, blood concentrations peaked within 10 minutes after dosing and declined to below the lower limit of detection (0.025 nanogram/mL) within 1.5 hours after dosing. Mean bimatoprost Cmax values were similar on days 7 and 14 at 0.0721 and 0.0822 nanogram/mL respectively. The mean AUC0-24hr values were also similar on days 7 and 14 at 0.0742 and 0.096 nanogram.hr/mL respectively, indicating that a steady systemic exposure to bimatoprost was reached during the first week of ocular dosing. The systemic exposure of bimatoprost is very low with no accumulation over time.

Distribution.

Bimatoprost is moderately distributed into body tissues with a steady state systemic volume of distribution in humans of 0.67 L/kg. In human blood, bimatoprost resides mainly in the plasma. The plasma protein binding of bimatoprost is approximately 90%.
Data from in vitro studies showed that the overall extent of melanin binding was not dependent on concentration and the binding was reversible.
Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing in humans.

Metabolism.

Bimatoprost then undergoes oxidation, N-deethylation and glucuronidation to form a diverse variety of metabolites.

Excretion.

Bimatoprost is eliminated primarily by renal excretion. Up to 67% of an intravenous dose of radiolabelled bimatoprost administered to healthy volunteers was excreted in the urine, 25% of the dose was excreted via the faeces. The elimination half-life, determined after intravenous administration, was approximately 45 minutes, the total blood clearance of unchanged bimatoprost was 1.5 L/hr/kg.

5.3 Preclinical Safety Data

Ocular administration of bimatoprost in monkeys at concentrations of 0.03% or 0.1% once or twice daily for 1 year caused an increase in iris pigmentation and reversible dose-related periocular effects characterised by a prominent upper and/or lower sulcus and widening of the palpebral fissure. No associated increase in melanocyte number was observed with the pigmentation. It appears that the mechanism of increased iris pigmentation is due to increased stimulation of melanin production in melanocytes and not to an increase in melanocyte number.
Periocular effects were also observed in an intravenous toxicity study at systemic exposures at least 235-fold higher than that observed in humans after ocular administration. No functional or microscopic changes related to the periocular effects were observed. The mechanism of action for the observed periocular changes is unknown.

Genotoxicity.

Bimatoprost was not mutagenic or clastogenic in a bacterial mutation assay, in a mouse lymphoma test in vitro or in a mouse micronucleus test.

Carcinogenicity.

Long-term studies in mice and rats revealed no evidence of carcinogenicity following oral (by gavage) administration of bimatoprost at doses up to 2 and 1 mg/kg/day, respectively. These doses resulted in systemic bimatoprost levels 85 - 95 times the maximum anticipated human exposure (based on blood AUC). In the rat carcinogenicity study, a dose-related increase in vacuolated corpora lutea was observed. The clinical relevance of this ovarian effect is unclear.

6 Pharmaceutical Particulars

6.1 List of Excipients

Benzalkonium chloride; anhydrous citric acid; sodium chloride; dibasic anhydrous sodium phosphate; purified water; sodium hydroxide or hydrochloric acid for pH adjustment.

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 25°C. Discard contents 4 weeks after opening the bottle.

6.5 Nature and Contents of Container

APO-Bimatoprost eye drops.

Bottle containing 3 mL of solution: AUST R 204398.
Apotex Pty Ltd is the licensee of the registered trademarks APO and APOTEX from the registered proprietor, Apotex Inc.
Contents are sterile if seal is intact.

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

Bimatoprost is a prostamide with potent ocular hypotensive activity. It is a white to off-white powder and is very soluble in ethyl alcohol and methyl alcohol and slightly soluble in water. Bimatoprost is a clear, isotonic, colourless, sterile ophthalmic solution with an osmolality of approximately 300 mOsmol/kg.
Chemical Name: (Z)-7-[(1R, 2R, 3R, 5S)-3,5-Dihydroxy-2-[(1E, 3S)-3-hydroxy-5-phenylpent-1- enyl] cyclopentyl]-N-ethylhept-5-enamide. Molecular Formula: C25H37NO4. Molecular Weight: 415.58.

Chemical structure.


CAS number.

155206-00-1.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes