4.1. Therapeutic indications

Reduction of elevated intraocular pressure in chronic open-angle glaucoma and ocular hypertension in adults (as monotherapy or as adjunctive therapy to beta-blockers).

4.2. Posology and method of administration

Posology

The recommended dose is one drop in the affected eye(s) once daily, administered in the evening. The dose should not exceed once daily as more frequent administration may lessen the intraocular pressure lowering effect.

Paediatric population:

The safety and efficacy of bimatoprost in children aged 0 to 18 years has not yet been established.

Patients with hepatic and renal impairment:

Bimatoprost has not been studied in patients with renal or moderate to severe hepatic impairment and should therefore be used with caution in such patients. In patients with a history of mild liver disease or abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or bilirubin at baseline, bimatoprost 0.3 mg/ml eye drops, solution had no adverse effect on liver function over 24 months.

Method of administration

If more than one topical ophthalmic medicinal product is being used, each one should be administered at least 5 minutes apart.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Bimatoprost Mylan 0.1 mg/ml is contraindicated in patients who have had a suspected previous adverse reaction to benzalkonium chloride that has led to discontinuation.

4.4. Special warnings and precautions for use

Ocular

Before treatment is initiated, patients should be informed of the possibility of prostaglandin analogue periorbitopathy (PAP) and increased iris pigmentation since these have been observed during treatment with bimatoprost. 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).

Cystoid macular oedema has been uncommonly reported (≥1/1000 to <1/100) following treatment with bimatoprost 0.3 mg/ml eye drops, solution. Therefore, bimatoprost should be used with caution in patients with known risk factors for macular oedema (e.g. aphakic patients, pseudophakic patients with a torn posterior lens capsule).

There have been rare spontaneous reports of reactivation of previous corneal infiltrates or ocular infections with bimatoprost 0.3 mg/ml eye drops, solution. Bimatoprost should be used with caution in patients with a prior history of significant ocular viral infections (e.g. herpes simplex) or uveitis/iritis.

Bimatoprost has not been studied in patients with inflammatory ocular conditions, neovascular, inflammatory, angle-closure glaucoma, congenital glaucoma or narrow-angle glaucoma.

Skin

There is a 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 avoid it running onto the cheek or other skin areas.

Respiratory

Bimatoprost has not been studied in patients with compromised respiratory function. While there is limited information available on patients with a history of asthma or COPD, there have been reports of exacerbation of asthma, dyspnoea and COPD, as well as reports of asthma, in post marketing experience. The frequency of these symptoms is not known. Patients with COPD, asthma or compromised respiratory function due to other conditions should be treated with caution.

Cardiovascular

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 0.3 mg/ml eye drops, solution. Bimatoprost should be used with caution in patients predisposed to low heart rate or low blood pressure.

Other Information

In studies of bimatoprost 0.3 mg/ml in patients with glaucoma or ocular hypertension, it has been shown that the more frequent exposure of the eye to more than one dose of bimatoprost daily may decrease the IOP-lowering effect (see section 4.5). Patients using bimatoprost with other prostaglandin analogues should be monitored for changes to their intraocular pressure.

Bimatoprost 0.1 mg/ml contains the preservative benzalkonium chloride (200 ppm), which may be absorbed by soft contact lenses. Eye irritation and discolouration of the soft contact lenses may also occur because of the presence of benzalkonium chloride. Contact lenses should be removed prior to instillation and may be reinserted 15 minutes following administration.

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 Mylan 0.1 mg/ml contains 200 ppm benzalkonium chloride (four times the concentration in bimatoprost 0.3 mg/ml eye drops), it should be used with caution in dry eye patients, in patients where the cornea may be compromised and in patients taking multiple BAK-containing eye drops. In addition, monitoring is required with prolonged use in such patients.

There have been reports of bacterial keratitis associated with the use of multiple dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent ocular disease. Patients with a disruption of the ocular epithelial surface are at greater risk of developing bacterial keratitis.

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 the solution.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

No interactions are anticipated in humans, since systemic concentrations of bimatoprost are extremely low (less than 0.2 ng/ml) following ocular dosing with bimatoprost 0.3 mg/ml eye drops, solution. Bimatoprost is biotransformed by any of multiple enzymes and pathways, and no effects on hepatic drug metabolising enzymes were observed in preclinical studies.

In clinical studies, bimatoprost 0.3 mg/ml, eye drops, solution was used concomitantly with a number of different ophthalmic beta-blocking agents without evidence of interactions.

Concomitant use of bimatoprost and antiglaucomatous 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 (e.g. bimatoprost) to be reduced in patients with glaucoma or ocular hypertension when used with other prostaglandin analogues (see section 4.4).

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of bimatoprost in pregnant women. Animal studies have shown reproductive toxicity at high maternotoxic doses (see section 5.3).

Bimatoprost should not be used during pregnancy unless clearly necessary.

Breast-feeding

It is unknown whether bimatoprost is excreted in human breast milk. Animal studies have shown excretion of bimatoprost in breast milk. A decision must be made whether to discontinue breast- feeding or to discontinue from bimatoprost therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effects of bimatoprost on human fertility.

4.7. Effects on ability to drive and use machines

Bimatoprost has negligible influence on the ability to drive and use machines. As with any ocular treatment, if transient blurred vision occurs at instillation, the patient should wait until the vision clears before driving or using machines.

4.8. Undesirable effects

In a 12-month Phase III clinical study approximately 38 % of patients treated with bimatoprost 0.1 mg/ml eye drops, solution experienced adverse reactions. The most frequently reported adverse reaction was conjunctival hyperaemia (mostly trace to mild and of a non-inflammatory nature) occurring in 29 % of patients. Approximately 4 % of patients discontinued due to any adverse event in the 12-month study.

The following adverse reactions were reported during clinical trials with bimatoprost 0.1 mg/ml eye drops, solution or in the post-marketing period. Most were ocular, mild and none was serious.

Very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon ( ≥1/1,000 to <1/100); rare ( ≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data) adverse reactions are presented according to System Organ Class in Table 1 in order of decreased seriousness within each frequency grouping.

Table 1.

System Organ class

Frequency

Adverse reaction

Nervous system disorders

uncommon

headache

not known

dizziness

Eye disorders

very common

conjunctival hyperaemia, prostaglandin analogue periorbitopathy

common

punctate keratitis, eye irritation, eye pruritus, growth of eyelashes, eye pain, erythema of eyelid, eyelid pruritus

uncommon

asthenopia, blurred vision, conjunctival disorder, conjunctival oedema, iris hyperpigmentation, madarosis, eyelid oedema

not known

macular oedema, blepharal pigmentation, dry eye, eye discharge, eye oedema, foreign body sensation in eyes, lacrimation increased, ocular discomfort, photophobia

Vascular disorders

not known

hypertension

Respiratory, thoracic and mediastinal disorders

not known

asthma, asthma exacerbation, COPD exacerbation and dyspnoea

Gastrointestinal disorders

uncommon

nausea

Skin and subcutaneous tissue disorders

common

skin hyperpigmentation, hypertrichosis

uncommon

dry skin, eyelid margin crusting, pruritus

not known

skin discoloration (periocular)

General disorders and administration site conditions

common

instillation site irritation

Immune system disorders

not known

hypersensitivity reaction including signs and symptoms of eye allergy and allergic dermatitis

In clinical studies, over 1800 patients have been treated with bimatoprost 0.3 mg/ml. On combining the data from phase III monotherapy and adjunctive bimatoprost 0.3 mg/ml usage, the most frequently reported adverse reactions were:

- growth of eyelashes in up to 45 % in the first year with the incidence of new reports decreasing to 7 % at 2 years and 2 % at 3 years.

- conjunctival hyperaemia (mostly trace to mild and thought to be of a non-inflammatory nature) in up to 44 % in the first year with the incidence of new reports decreasing to 13 % at 2 years and 12 % at 3 years.

- ocular pruritus in up to 14 % of patients in the first year with the incidence of new reports decreasing to 3 % at 2 years and 0 % at 3 years. Less than 9 % of patients discontinued due to any adverse event in the first year with the incidence of additional patient discontinuations being 3 % at both 2 and 3 years.

Additional adverse reactions reported with bimatoprost 0.3 mg/ml are presented in Table 2. The table also includes those adverse reactions which occurred with both formulations but at a different frequency. Most were ocular, mild to moderate, and none was serious: With each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2.

System Organ class

Frequency

Adverse reaction

Nervous system disorders

common

headache

uncommon

dizziness

Eye disorders

very common

ocular pruritus, growth of eyelashes

common

corneal erosion, ocular burning, allergic conjunctivitis, blepharitis, worsening of visual acuity, asthenopia, conjunctival oedema, foreign body sensation, ocular dryness, eye pain, photophobia, tearing , eye discharge, visual disturbance/blurred vision, increased iris pigmentation, eyelash darkening

uncommon

retinal haemorrhage, uveitis, cystoid macular oedema, iritis, blepharospasm, eyelid retraction. periorbital erythema

Vascular disorders

common

hypertension

Skin and subcutaneous tissue disorders

uncommon

hirsutism.

General disorders and administration site conditions

uncommon

asthenia

Investigations

common

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% (see section 4.8 Table 2) and did not increase following 3 years treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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

If overdose occurs, treatment should be symptomatic and supportive. If bimatoprost is accidentally ingested, the following information may be useful: in two-week oral rat and mouse studies, doses up to 100 mg/kg/day did not produce any toxicity. This dose expressed as mg/m2 is at least 210 times higher than the accidental dose of one bottle of bimatoprost 0.1 mg/ml eye drops, solution in a 10 kg child.