BIMATOPROST EG 0,3 mg/ml Collyre sol Fl/3ml

Bimatoprost...................................................................................................................................................0,3 mg

For 1 ml of solution.

One drop contains approximately 7,5 micrograms of bimatoprost.

Excipient with known effect

One millilitre of solution contains 0,05 mg of benzalkonium chloride

For the full list of excipients, see section Composition.

Reduction of elevated intraocular pressure in adult patients with chronic open-angle glaucoma or ocular hypertension (as monotherapy or in combination with beta-blockers).

Dosage

The recommended dose is one drop in the affected eye or eyes once a day, administered in the evening. The dose must not exceed one instillation per day, as more frequent use may reduce the efficacy in lowering intraocular pressure.

Renal or hepatic impairment

Bimatoprost has not been studied in patients with renal impairment or moderate to severe hepatic impairment. Consequently, it should be used with caution in these patients. In patients with a history of benign liver disease or abnormal baseline levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or bilirubin, no deleterious effect on liver function was observed with the eye drops containing 0,3 mg/ml of bimatoprost over 24 months.

Paediatric population

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

Method of administration

If several topical ophthalmic medicinal products are used concomitantly, an interval of at least 5 minutes must be observed between each administration.

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

BIMATOPROST EG 0,3 mg/ml, eye drops in solution is contraindicated in patients who have previously experienced adverse reactions suspected to be related to benzalkonium chloride that led to treatment discontinuation.

Ocular

Before starting treatment, patients must be informed that BIMATOPROST EG may cause prostaglandin analogue-associated periorbitopathy (PAP) and an increase in iris pigmentation, as has been observed during studies in patients treated with BIMATOPROST EG. Some of these changes may be permanent and may lead to visual field alteration and differences in appearance between the eyes if only one eye is treated (see section Adverse effects).

Cases of cystoid macular oedema have been reported uncommonly (≥ 1/1 000 to < 1/100) following treatment with the eye drops containing 0,3 mg/ml of bimatoprost. Consequently, BIMATOPROST EG should be used with caution in patients with known risk factors for macular oedema (for example: aphakic patients, pseudophakic patients with posterior capsule rupture).

Rare cases of reactivation of old corneal infiltrates or old ocular infections have been spontaneously reported with the eye drops containing 0,3 mg/ml of bimatoprost. BIMATOPROST EG should be used with caution in patients with a history of significant viral ocular infections (for example: herpes simplex) or uveitis/iritis.

BIMATOPROST EG has not been studied in patients with ocular inflammation, neovascular and inflammatory glaucoma, angle-closure glaucoma, congenital glaucoma or narrow-angle glaucoma.

Dermatological

An increase in eyelash growth may occur at the sites of repeated contact of the BIMATOPROST EG solution with the skin. It is therefore important to apply BIMATOPROST EG as instructed and to avoid it running onto the cheek or other areas of the skin.

Respiratory

BIMATOPROST EG has not been studied in patients with respiratory insufficiency. Although the available data in patients with a history of asthma or COPD are limited, cases of asthma exacerbation, dyspnoea and COPD, as well as occurrence of asthma attacks, have been reported since marketing. The frequency of these symptoms is unknown. Patients with COPD, asthmatic patients, or patients whose respiratory function is impaired due to other conditions should be treated with caution.

Cardiovascular

BIMATOPROST EG has not been studied in patients with cardiac block more severe than first-degree block or with uncontrolled congestive heart failure. There have been a limited number of spontaneous reports of cases of bradycardia or hypotension with use of the eye drops containing 0,3 mg/ml of bimatoprost. BIMATOPROST EG should be used with caution in patients with predispositions to a slow heart rate or low blood pressure.

Additional information

In studies with bimatoprost 0,3 mg/ml in patients with glaucoma or ocular hypertension, it was shown that more frequent exposure of the eye to bimatoprost (i.e., more than one dose per day) may diminish the intraocular pressure-lowering effect (see section Interactions). Patients in whom BIMATOPROST EG is combined with other prostaglandin analogues should therefore be monitored to observe the course of their intraocular pressure.

BIMATOPROST EG 0,3 mg/ml, eye drops in solution contains a preservative, benzalkonium chloride, which may be absorbed by soft contact lenses. Benzalkonium chloride may cause eye irritation and discolouration of contact lenses. Contact lenses should be removed before instillation and may be reinserted 15 minutes after administration.

Benzalkonium chloride, commonly used as a preservative in ophthalmic products, may cause superficial punctate keratitis and/or toxic ulcerative keratopathy. As BIMATOPROST EG 0,3 mg/ml, eye drops in solution contains benzalkonium chloride, monitoring is required during frequent or prolonged use in patients with dry eye or corneal disorders.

Bacterial keratitis associated with the use of multidose containers of topical ophthalmic products has been reported. These containers had been accidentally contaminated by patients who, in most cases, had an underlying ocular disease.

In patients with damage to the ocular epithelial surface, the risk of developing bacterial keratitis is higher.

Patients should be instructed to avoid contact of the bottle tip with the eye or surrounding structures, to avoid eye injury or contamination of the solution.

No interaction studies have been performed.

No interaction is expected in humans, as systemic concentrations of bimatoprost are extremely low (less than 0,2 ng/ml) after ocular administration of the eye drops containing 0,3 mg/ml of bimatoprost. Bimatoprost is metabolised by various metabolic pathways, but no effect on enzymes involved in hepatic metabolism was observed in preclinical studies.

In clinical studies, bimatoprost was used concomitantly with several ophthalmic beta-blockers without any interactions being identified.

Apart from topical beta-blockers, the combination of BIMATOPROST EG with other antiglaucoma agents has not been studied in the treatment of glaucoma.

The intraocular pressure-lowering effect of prostaglandin analogues (for example BIMATOPROST EG) may be reduced if they are used with other prostaglandin analogues in patients with glaucoma or ocular hypertension (see section Warnings and precautions).

Pregnancy

There are no relevant data on the use of bimatoprost in pregnant women. Animal studies have shown reproductive toxicity at high maternotoxic doses (see section Preclinical safety).

BIMATOPROST EG should not be used during pregnancy, unless absolutely necessary.

Breast-feeding

It is not known whether bimatoprost is excreted in human milk. Animal studies have shown that bimatoprost passes into milk. The decision whether to discontinue breast-feeding or to discontinue therapy with BIMATOPROST EG should take into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.

Fertility

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

BIMATOPROST EG has negligible influence on the ability to drive and use machines. As with any ophthalmic treatment, if transient blurred vision occurs after instillation, the patient should wait until vision is clear before driving or using machines.

In clinical studies, more than 1 800 patients were treated with BIMATOPROST EG 0,3 mg/ml, eye drops in solution. Pooling data from the phase III clinical studies of BIMATOPROST EG 0,3 mg/ml, eye drops in solution as monotherapy or in combination, the most frequent treatment-related adverse events were:

• eyelash growth up to 45% in the first year, with the incidence of new cases reduced to 7% at 2 years and 2% at 3 years;

• conjunctival hyperaemia (mostly minimal to mild and considered non-inflammatory in nature) up to 44% of patients in the first year, with the incidence of new cases reduced to 13% at 2 years and 12% at 3 years;

• ocular pruritus up to 14% of patients in the first year, with the incidence of new cases reduced to 3% at 2 years and 0% at 3 years. Fewer than 9% of patients had to discontinue treatment due to an adverse event in the first year, with an incidence of additional discontinuations of 3% in the second and third years.

The adverse reactions described below were reported during clinical trials with BIMATOPROST EG 0,3 mg/ml, eye drops in solution or after its marketing. Most were ocular, mild in intensity, and none were serious.

Very common adverse effects (≥ 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); frequency not known (cannot be estimated from the available data) are listed in the table below by system organ class. Within each frequency grouping, adverse effects are presented in order of decreasing seriousness.

Table 1.

Description of selected adverse reactions

Periorbitopathy associated with prostaglandin analogues (PAP)

Prostaglandin analogues may cause periorbital lipodystrophic changes that may lead to deepening of the palpebral sulcus, ptosis, enophthalmos, eyelid retraction, involution of dermatochalasis and inferior scleral exposure. These changes are generally mild, may occur as early as one month after starting treatment with bimatoprost and may lead to impairment of the visual field even without recognition by the patient. PAP is also associated with hyperpigmentation or discolouration of the periocular skin and with hypertrichosis. These changes have been found to be partially or fully reversible upon discontinuation of treatment or switching to another treatment.

Iris hyperpigmentation

The increase in iris pigmentation will probably be permanent. The change in pigmentation is due to an increase in melanin content in melanocytes rather than to an increased number of melanocytes. The long-term effects of increased iris pigmentation are not known. Changes in iris colour observed with ophthalmic administration of bimatoprost may not be visible for several months or several years. Usually, brown pigmentation around the pupils extends concentrically towards the periphery of the iris, and all or part of the iris takes on a brownish colour. Treatment does not appear to affect iris naevi and freckles. The incidence of iris hyperpigmentation after 12 months of treatment with an eye drop containing 0,1 mg/ml of bimatoprost was 0,5%. With the eye drop containing 0,3 mg/ml of bimatoprost, the incidence, which was 1,5% at 12 months (see section Adverse effects, Table 2), did not increase during the 3 years of treatment.

Adverse effects reported with phosphate-containing eye drops:

Very rarely, cases of corneal calcification have been reported with the use of phosphate-containing eye drops in some patients with significant corneal damage.

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 national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website:

https://signalement.social-sante.gouv.fr

No cases of overdose have been reported: such incidents are unlikely to occur with ocular instillation.

In case of overdose, symptomatic and supportive treatment should be instituted. If BIMATOPROST is accidentally ingested, the following information may be useful: in two-week oral studies in rats and mice, doses of up to 100 mg/kg/day caused no toxicity. This dose expressed in mg/m² is 70 times higher than the dose corresponding to accidental ingestion of one bottle of BIMATOPROST 0,3 mg/ml, eye drops in solution by a child weighing 10 kg.

Pharmacotherapeutic class: Ophthalmological products, prostaglandin analogues, ATC code: S01EE03.

Mechanism of action

Bimatoprost reduces intraocular pressure in humans by increasing aqueous humour outflow through the trabecular meshwork and by improving uveoscleral outflow. The reduction in intraocular pressure begins approximately 4 hours after the first administration and the maximum effect is achieved at approximately 8 to 12 hours. The action persists for at least 24 hours.

Bimatoprost is a potent ocular hypotensive agent. It is a synthetic prostamide, structurally related to prostaglandin F2α (PGF2α) which does not act through known prostaglandin receptors. Bimatoprost selectively mimics the effects of newly discovered biosynthetic substances called prostamides. However, the structure of prostamide receptors has not yet been identified.

Pharmacodynamic effects

Clinical efficacy and safety

During 12 months of monotherapy with bimatoprost 0,3 mg/ml in adults, versus timolol, the mean change from baseline intraocular pressure in the morning (08h00) ranged from -7,9 to -8,8 mmHg. At each visit, the mean diurnal IOP values measured over the 12-month study period did not differ by more than 1,3 mmHg throughout the day and were never higher than 18,0 mmHg.

In a 6-month clinical study with bimatoprost 0,3 mg/ml, versus latanoprost, a statistically superior mean reduction in morning IOP (ranging from -7,6 to -8,2 mmHg for bimatoprost versus -6,0 to -7,2 mmHg for latanoprost) was observed at each visit during the study. Conjunctival hyperaemia, eyelash growth and ocular pruritus were statistically significantly higher with bimatoprost than with latanoprost; however, discontinuation rates due to adverse events were low, with no statistically significant difference.

Compared with beta-blocker treatment alone, treatment with a beta-blocker and bimatoprost 0,3 mg/ml significantly reduced morning intraocular pressure (08h00) by -6,5 to -8,1 mmHg.

There are limited data available on the use of BIMATOPROST EG in patients with pseudoexfoliative glaucoma and open-angle pigmentary glaucoma, as well as in patients with chronic angle-closure glaucoma who have undergone iridotomy.

No clinically significant effect on heart rate and blood pressure was observed in clinical studies.

Paediatric population

The safety and efficacy of BIMATOPROST EG in children aged 0 to 18 years have not yet been established.

Absorption

Bimatoprost penetrates well into the cornea and human sclera. in vitro. After ophthalmic administration in adults, systemic exposure to bimatoprost is very low. No accumulation is observed after repeated administration. After administration for two weeks, of one drop per day of bimatoprost 0,3 mg/ml in both eyes, the plasma peak is reached 10 minutes after the last instillation. Circulating plasma concentrations fall below the limit of detection (0,025 ng/ml) after approximately 1 h 30. The mean values of the Cmax and of ASC0-24 h (Area under the curve) were comparable to day 7e day and to day 14e day (approximately 0,08 ng/ml and 0,09 ng•h/ml), indicating that a stable concentration of bimatoprost is reached after the first week of treatment.

Distribution

Bimatoprost distributes moderately into the extravascular compartment. In humans, the steady-state systemic volume of distribution is 0,67 L/kg. In the blood, bimatoprost is found mainly in plasma in a form bound to circulating proteins (approximately 88 %).

Biotransformation

In plasma, bimatoprost is weakly metabolised. The unchanged form represents the majority circulating entity. Bimatoprost undergoes oxidative metabolism (N-deethylation and glucuronidation) resulting in the formation of various metabolites.

Elimination

Bimatoprost is mainly eliminated by renal excretion. Up to 67 % of an intravenous dose administered to healthy adult volunteers is eliminated in the urine and 25 % is excreted in the faeces. The elimination half-life determined after intravenous administration is approximately 45 minutes; the total blood clearance is 1,5 L/h/kg.

Characteristics in elderly subjects

When administered at a rate of 2 instillations per day of eye drops in solution containing bimatoprost at 0,3 mg/ml, systemic exposure to bimatoprost observed in elderly subjects aged 65 years or older (AUC0-24 h : 0,0634 ng•h/ml) is markedly higher than that observed in healthy young adults (AUC0-24 h : 0,0218 ng•h/ml).

However, due to the low systemic passage by the ocular route, this systemic exposure to bimatoprost remains low in both groups and therefore without clinical consequence. Given the absence of accumulation of bimatoprost in the blood, the safety profile would be comparable in elderly and younger patients.

Effects observed in animals at exposures far above the maximum exposure in humans have little clinical significance.

In monkeys, daily ophthalmic administration of bimatoprost at concentrations ≥ 0,3 mg/ml for one year resulted in increased iris pigmentation and reversible, dose-dependent periocular changes characterised by prominence of the upper and/or lower fornices and widening of the palpebral fissure. The process of increased iris pigmentation is due to strong stimulation of melanin production in melanocytes and not to an increase in the number of melanocytes. No functional or microscopic change related to these periocular effects was observed. The mechanism underlying these periocular changes is unknown.

Bimatoprost was not shown to be mutagenic or carcinogenic in the studies in vitro and in vivo.

Bimatoprost had no effect on fertility in rats at doses up to 0,6 mg/kg/day (at least 103 times higher than human exposure). In studies on embryo and foetal development in pregnant mice and rats, abortions were observed, but no developmental effects, at doses at least 860 or 1 700 times higher than the doses administered to humans. These doses represented, respectively in mice and rats, a systemic exposure at least 33 times or 97 times higher than exposure in humans. In perinatal or postnatal studies in rats, maternal toxicity resulted in decreased gestation time, foetal death and decreased weight in the offspring of females given a dose ≥ 0,3 mg/kg/day (at least 41 times higher than human exposure). The neurobehavioural functions of the offspring were not affected.

3 years.

4 weeks after first opening.

No special precautions for storage.

No special requirements for disposal.

• Indication(s) appearing in the marketing authorisation at the date of publication of this decree