Consumer medicine information

Bimatoprost Sandoz

Bimatoprost

BRAND INFORMATION

Brand name

Bimatoprost Sandoz

Active ingredient

Bimatoprost

Schedule

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Bimatoprost Sandoz.

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 taking this medicine against the benefits they expect it will have for you.

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

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

WHAT BIMATOPROST SANDOZ IS USED FOR

This medicine is used to lower raised pressure in the eye and to treat glaucoma.

Glaucoma is a condition in which the pressure of fluid in the eye may be high. However, some people with glaucoma may have normal eye pressure. 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.

Bimatoprost Sandoz eye drops lower the pressure in the eye by helping the flow of fluid out of the eye chamber.

Bimatoprost Sandoz eye drops can be used alone or together with other eyedrops/medicines to lower raised pressure within your eyes.

Although Bimatoprost Sandoz eye drops help control your condition, they will not cure it.

Bimatoprost Sandoz eye drops are only available with a doctor's prescription from pharmacies.

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

BEFORE YOU USE BIMATOPROST SANDOZ

When you must not use it

Do not take this medicine if you have an allergy to bimatoprost, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under Product Description

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin

Do not put the eye drops into your eye(s) while you are wearing soft contact lenses.

The preservative in Bimatoprost Sandoz 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 Bimatoprost Sandoz eye drops.

It is not known if Bimatoprost Sandoz eye drops are safe and useful for children and adolescents under 18 years.

These drops are for topical use only.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn 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 taking this medicine, talk to your doctor.

Before you start to use it

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
low blood pressure or heart rate
a disease causing swelling of the back of the eye
an inflammatory eye condition
a history of viral infections in the eye
dry eye or damaged cornea

Tell your doctor if you are pregnant or plan to become pregnant and you are breastfeeding or intend to breast-feed. Like most medicines, Bimatoprost Sandoz eye drops should not be used during pregnancy, unless clearly necessary.

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

During treatment, Bimatoprost Sandoz may cause a loss of fat around the eye, which may cause your eyelid crease to deepen, your eye to appear sunken, your upper eyelid to droop, the skin around your eye to tighten and the lower white part of your eye to become more visible. The changes are typically mild, but if pronounced, they can affect your field of vision. The changes may disappear if you stop taking Bimatoprost Sandoz.

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 affect vision. If you have any concerns, ask your doctor or pharmacist.

Hair may grow where Bimatoprost Sandoz contacts the skin. It is important to use as directed.

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.

It is not expected that Bimatoprost Sandoz will interact with other medicines, however you should always ask your optical practitioner, doctor or pharmacist if you have any concerns about using Bimatoprost Sandoz eye drops as well as other medications.

There is a potential for the eye pressure effect to be reduced if using other glaucoma eye drops of the same type as Bimatoprost Sandoz.

HOW TO USE BIMATOPROST SANDOZ

How much to use

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

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

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how many drops you need to use each day.

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

Use Bimatoprost Sandoz 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 using more than one eye drop product, wait 5 minutes before using the second product.

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.

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

Wait 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.

How long to use it

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it.

It is important to keep using your medicine every day.

If you forget to use it

Take your dose as soon as you remember, and continue to take it as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take 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.

If you think that you or anyone else may have swallowed any or all of the contents of a bottle of Bimatoprost Sandoz eye drops, Immediately telephone your doctor or the Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764766) for advice, or go to Accident and Emergency at the nearest hospital. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

WHILE YOU ARE TAKING BIMATOPROST SANDOZ

Things you must do

Have your eye pressure checked when your eye specialist says, to make sure Bimatoprost Sandoz 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 Bimatoprost Sandoz eye drops because of possible contamination of the old one.

If you become pregnant while using Bimatoprost Sandoz eye drops tell your doctor immediately.

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

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

If you are about to start any new medicine tell your doctor and pharmacist that you are using Bimatoprost Sandoz eye drops.

Things you must not do

Do not use Bimatoprost Sandoz to treat any other complaints unless your doctor tells you to.

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

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

Things to be careful of

Your vision may blur for a short time after you put in your Bimatoprost Sandoz eye drops. If this happens you should wait until you can see well again before you drive or use machinery.

Bimatoprost Sandoz 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 Sandoz eye drops affect you.

SIDE EFFECTS

Tell your doctor optical practitioner, or pharmacist as soon as possible if you do not feel well while you are taking Bimatoprost Sandoz.

Check with your doctor as soon as possible if you have any problems while taking Bimatoprost Sandoz, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

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 and they worry you:

red, congested eyes
growth of eyelashes
itching or irritation of eye/s

More often the following effects have been seen:

loss of fat in the eye region which can lead to deepening of your eyelid crease, sunken eye, drooping eyelid, tightening of the skin around your eye, and the lower white part of your eye to become more visible.

Less often the following effects have been seen:
Other eye-related effects such as discharge from the eye, eye discomfort, eye itchiness, redness in or around the eye, increased tears and inflamed areas around eye/s, small lesions or erosions on the eye surface, allergic effects on eye and surrounding eyelid, deepened eyelids, pain in the eye, feeling of something in the eye, burning of eye and nearby eyelid, dryness, irritation, sensitivity to light, an increase in colouring or pigment of area around eye, blurred vision, visual changes, eyelash darkening, darkening of the coloured part of the eye, swelling of the back of the eye.

Rarely:
Other eye related problems can occur such as spasm of the eye where there is uncontrolled blinking and squeezing of eyelid, swelling of eyelid, inflammation of the coloured part of eye, bleeding in eye chamber, eyelid retraction, deepened eyelid sulcus (sockets sunken), precipitation of calcium salts on corneal surface.

There can also be effects on the body as a whole such as headache, weakness, and very rarely dizziness, hypersensitivity, depression, infection, nausea, high blood pressure, skin pigmentation, asthma, exacerbation of asthma, shortness of breath and abnormal hair growth.

AFTER USING BIMATOPROST SANDOZ

Storage

Keep your medicine in a cool dry place where the temperature stays below 25 °C.

Do not store Bimatoprost Sandoz 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 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

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 taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

PRODUCT DESCRIPTION

What Bimatoprost Sandoz eye drops look like

Clear, colourless, sterile solution.

Ingredients

Active ingredient:

Bimatoprost 300 µg/ml

Inactive ingredients:

benzalkonium chloride (Preservative)
dibasic sodium phosphate heptahydrate
citric acid monohydrate
sodium chloride
purified water
hydrochloric acid and/or sodium hydroxide may be added to adjust pH.

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park
NSW 2113 AUSTRALIA
Tel: 1800 726 369

This leaflet was revised in November 2022.

Australian Register Number

Bimatoprost Sandoz eye drops 300 microgram/mL
AUST R 234901

Published by MIMS January 2023

BRAND INFORMATION

Brand name

Bimatoprost Sandoz

Active ingredient

Bimatoprost

Schedule

1 Name of Medicine

Bimatoprost.

2 Qualitative and Quantitative Composition

Bimatoprost Sandoz 300 microgram/mL is a sterile ophthalmic solution. Each mL of Bimatoprost Sandoz solution contains active ingredient bimatoprost 0.3 mg.
Bimatoprost is a prostamide with potent ocular hypotensive activity. Bimatoprost is a white or almost white crystalline 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 260 to 330 mOsmol/kg.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Bimatoprost Sandoz 300 microgram/mL eye drops sterile solution is packed in plastic dropper bottles with a plastic tamper-proof screw cap. Each bottle has a fill volume of 3 mL.

4 Clinical Particulars

4.1 Therapeutic Indications

Bimatoprost eye drops is indicated for 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

Monotherapy.

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

Adjunctive therapy.

The recommended dose is one drop of bimatoprost eye drops 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 of bimatoprost eye drops, patients should be instructed to apply pressure to the tear duct immediately following administration of the drug.

4.3 Contraindications

Bimatoprost eye drops are contraindicated in patients with hypersensitivity to bimatoprost or to any component 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. Patients with COPD, asthma or compromised respiratory function due to other conditions should be treated with caution. In clinical studies, in those patients with a history of a compromised respiratory function, no significant untoward respiratory effects have been seen. There have been reports of exacerbation of asthma, dyspnoea and COPD, as well as reports of asthma, in post marketing experience.
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.
Before treatment is initiated, patients should be informed of the possibility of prostaglandin analogue periorbitopathy (PAP) and increased iris pigmentation. Some of these changes may be permanent and may lead to impaired field of vision and differences in appearance between the eyes when only one eye is treated (see Section 4.8 Adverse Effects (Undesirable Effects)).
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. There have been rare spontaneous reports of reactivation of previous corneal infiltrates or ocular infections with bimatoprost 0.03% eye drops. Bimatoprost should be used with caution in patients with a prior history of significant ocular viral infections (e.g. herpes simplex) or uveitis/iritis.
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.
Benzalkonium chloride, which is commonly used as a preservative in ophthalmic products, has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Since Bimatoprost Sandoz eye drops contains benzalkonium chloride, monitoring is required with frequent or prolonged use in dry eye patients or where the cornea is compromised.

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 renal impairment.

Bimatoprost has not been studied in patients with renal 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.

Other 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 multiple dose 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.

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 eye drops.
In the two pivotal monotherapy trials (715 patients) the most frequently reported treatment-related adverse events were: conjunctival hyperemia in up to 42%, growth of eyelashes in up to 36% and ocular pruritus in up to 14% of patients. The incidence of conjunctival hyperemia 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 hyperemia 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 hyperemia, growth of eyelashes, ocular pruritus.
Common (< 10%): allergic conjunctivitis, asthenopia, blepharitis, blepharal 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.

In addition to what has been observed in clinical trials, the following adverse reactions have been identified during post-marketing use of bimatoprost eye drops. Because post-marketing reporting is voluntary and from a population of uncertain size, it is not possible to reliably estimate the frequency of these reactions:

Eye disorders.

Prostaglandin analogue periorbitopathy, erythema (periorbital), eyelid oedema, macular oedema, uveitis, 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, COPD exacerbation.

Investigations.

Liver function test abnormal.

Adverse reactions reported in phosphate containing eye drops.

Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas.

Description of selected adverse reactions.

Prostaglandin analogue periorbitopathy (PAP).

Prostaglandin analogues including bimatoprost can induce periorbital lipodystrophic changes which can lead to deepening of the eyelid sulcus, ptosis, enophthalmos, eyelid retraction, involution of dermatochalasis and inferior scleral show. Changes are typically mild, can occur as early as one month after initiation of treatment with bimatoprost, and may cause impaired field of vision even in the absence of patient recognition. PAP is also associated with periocular skin hyperpigmentation or discoloration and hypertrichosis. All changes have been noted to be partially or fully reversible upon discontinuation or switch to alternative treatments.

Iris hyperpigmentation.

Increased iris pigmentation is likely to be permanent. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. The long-term effects of increased iris pigmentation are not known. Iris colour changes seen with ophthalmic administration of bimatoprost may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts become more brownish. Neither naevi nor freckles of the iris appear to be affected by the treatment. At 12 months, the incidence of iris hyperpigmentation with bimatoprost 0.1 mg/mL eye drops, solution was 0.5%. At 12 months, the incidence with bimatoprost 0.3 mg/mL eye drops, solution was 1.5% and did not increase following 3 years treatment.

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.

4.9 Overdose

In case of overdose treatment should be supportive and symptomatic.

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 Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacotherapeutic group: ophthalmologicals; prostaglandin analogues; ATC code: S01EE03.
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 biosynthesized 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 in man 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

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 C_max values were similar on days 7 and 14 at 0.0721 and 0.0822 nanogram/mL respectively. The mean AUC_0-24hr 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.

Metabolism.

Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing in humans. 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 radiolabeled 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.
After twice daily dosing, the mean AUC_0-24hr 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.

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 0.05 mg (preservative); dibasic sodium phosphate heptahydrate; citric acid monohydrate; sodium chloride; purified water. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH.

6.2 Incompatibilities

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

6.3 Shelf Life

36 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. Discard contents 4 weeks after opening the bottle. Contents are sterile if seal is intact.

6.5 Nature and Contents of Container

LDPE bottle.
Pack size: 1 x 3 mL bottle.

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

Chemical structure.

Chemical name: (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[1E,3S)-3-hydroxy-5-phenyl-1-pentenyl] cyclopentyl]-5-N-ethylheptenamide.
Molecular weight: 415.58.
Empirical formula: C₂₅H₃₇NO₄.

CAS number.

155206-00-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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