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.

For single use only, one container is sufficient to treat both eyes. Any unused solution should be discarded immediately after use.

Paediatric population:

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

Patients with hepatic or renal impairment:

This medicine 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 (multi-dose formulation), 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.

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 this medicine. 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 (≥1/1,000 to <1/100) following treatment with bimatoprost 0.3 mg/ml eye drops (multi-dose formulation). Therefore, this medicine 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 (multi-dose formulation). This medicine should be used with caution in patients with a prior history of significant ocular viral infections (e.g. herpes simplex) or uveitis/iritis.

This medicine 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 this medicine comes repeatedly in contact with the skin surface. Thus, it is important to apply this medicine as instructed and avoid it running onto the cheek or other skin areas.

Respiratory

This medicine 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

This medicine 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 (multi-dose formulation). This medicine 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. Patients using this medicine with other prostaglandin analogues should be monitored for changes to their intraocular pressure.

This medicine has not been studied in patients wearing contact lenses.

Contact lenses should be removed prior to instillation and may be reinserted 15 minutes following administration.

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 (mulit-dose formulation). 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 0.3mg/ml eye drops (mulit-dose formulation) was used concomitantly with a number of different ophthalmic beta-blocking agents without evidence of interactions.

Concomitant use of bimatoprost 0.3mg/ml eye drops 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 0.3mg/ml eye drops) 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).

This medicine 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 0.3mg/ml eye drops, solution, in single-dose container 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

This medicine 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 3 month clinical study, approximately 29% of patients treated with bimatoprost 0.3 mg/ml single-dose experienced adverse reactions. The most frequently reported adverse reactions were conjunctival hyperaemia (mostly trace to mild and of a non-inflammatory nature) occurring in 24% of patients, and eye pruritus occurring in 4% of patients. Approximately 0.7% of patients in the bimatoprost 0.3 mg/ml single-dose group discontinued due to any adverse event in the 3 month study.

The following adverse reactions were reported during clinical trials with bimatoprost 0.3 mg/ml single-dose 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) and not known (cannot be estimated from available data) adverse reactions are presented according to System Organ Class in Table 1. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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, foreign body sensation, dry eye, eye pain, eye pruritus, growth of eyelashes, eyelid erythema

uncommon

asthenopia, conjunctival oedema, photophobia, lacrimation increased, iris hyperpigmentation, blurred vision, eyelid pruritus, eyelid oedema

not known

eye discharge, ocular discomfort

Respiratory, thoracic and mediastinal disorders

not known

asthma, asthma exacerbation, COPD exacerbation and dyspnoea

Skin and subcutaneous tissue disorders

common

skin hyperpigmentation (periocular)

uncommon

hair growth abnormal

not known

skin discoloration (periocular)

Immune system disorders

not known

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

Vascular disorders

not known

hypertension

In clinical studies, over 1800 patients have been treated with bimatoprost 0.3 mg/ml (multi-dose formulation). On combining the data from phase III monotherapy and adjunctive bimatoprost 0.3 mg/ml (multi-dose formulation) 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.

Table 2 lists adverse reactions that were seen in a 12 month clinical study with bimatoprost 0.3 mg/ml (multi-dose formulation), but were reported at a higher frequency than with bimatoprost 0.3 mg/ml (single-dose). Most were ocular, mild to moderate, and none were serious.

Table 2

System Organ class

Frequency

Adverse Reaction

Nervous system disorders

common

headache

Eye disorders

very common

ocular pruritus, growth of eyelashes

common

asthenopia, conjunctival oedema, photophobia, tearing, increased iris pigmentation; blurred vision

Skin and subcutaneous tissue disorders

common

eyelid pruritus

In addition to the adverse reactions seen with bimatoprost 0.3 mg/ml single-dose, Table 3 lists additional adverse reactions that were seen with bimatoprost 0.3 mg/ml (multi-dose formulation). Most were ocular, mild to moderate, and none were serious.

Table 3

System Organ class

Frequency

Adverse Reaction

Nervous system disorders

uncommon

dizziness

Eye disorders

common

corneal erosion, ocular burning, allergic conjunctivitis, blepharitis, worsening of visual acuity, eye discharge, visual disturbance, eyelash darkening

uncommon

retinal haemorrhage, uveitis, cystoid macular oedema, iritis, blepharospasm, eyelid retraction

Vascular disorders

common

hypertension

Gastrointestinal disorders

uncommon

nausea

Skin and subcutaneous tissue disorders

not known

periorbital erythema

General disorders and administration site conditions

uncommon

asthenia

Investigations

common

liver function test abnormal

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.

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.

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 (Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store).

4.9. Overdose

No information is available on overdose in humans; overdose is unlikely to occur after ocular administration.

If overdose occurs, treatment should be symptomatic and supportive. If this medicine is accidentally ingested, the following information may be useful: In short term oral (by gavage) mouse and rat studies, doses up to 100 mg/kg/day of bimatoprost did not produce any toxicity. This dose is at least 22 times higher than an accidental dose of the entire content of a pack of this medicine (30 x 0.4 ml single-dose containers; 12 ml) in a 10 kg child.