LUMIGAN 0.1 mg/ml eye drops, solution

One ml of solution contains 0.1 mg bimatoprost.

Excipient:

One ml of solution contains 0.2 mg benzalkonium chloride.

For a full list of excipients, see section 6.1.

Eye drops, solution.

Colourless to slightly yellow solution.

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

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.

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

Use in children and adolescents (under the age of 18):

LUMIGAN is not recommended for use in children below 18 years, due to a lack of data on safety and efficacy.

Use in hepatic and renal impairment:

LUMIGAN 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.

Hypersensitivity to the active substance or to any of the excipients.

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

Before treatment is initiated, patients should be informed of the possibility of eyelash growth, darkening of the eyelid skin and increased iris pigmentation since these have been observed during treatment with LUMIGAN. Some of these changes may be permanent, and may lead to differences in appearance between the eyes when only one eye is treated. The change in iris pigmentation occurs slowly and may not be noticeable for several months or years. . At 12 months, there was one report of iris hyperpigmentation with bimatoprost 0.1 mg/ml eye drops, solution (incidence of 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 (see section 4.8). Periorbital tissue pigmentation has been reported to be reversible in some patients.

LUMIGAN 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.

LUMIGAN 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. LUMIGAN should be used with caution in patients predisposed to low heart rate or low blood pressure.

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

Cystoid macular oedema has been uncommonly reported (1/1000 to <1/100) following treatment with bimatoprost 0.3 mg/ml eye drops, solution. Therefore, LUMIGAN 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. LUMIGAN should be used with caution in patients with a prior history of significant ocular viral infections (e.g. herpes simplex) or uveitis/iritis.

LUMIGAN 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 LUMIGAN 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.

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 betablocking agents without evidence of interactions.

Concomitant use of LUMIGAN and antiglaucomatous agents other than topical beta-blockers has not been evaluated during adjunctive glaucoma therapy.

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).

LUMIGAN should not be used during pregnancy unless clearly necessary.

Lactation

It is unknown whether bimatoprost is excreted in human breast milk. Animal studies have shown excretion of bimatoprost in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with LUMIGAN should be made taking into account the benefit of breast-feeding to the child and the benefit of LUMIGAN therapy to the woman.

LUMIGAN 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.

In a 12-month Phase III clinical study approximately 38 % of patients treated with LUMIGAN 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 12month study.

The following adverse reactions were reported during clinical trials with LUMIGAN 0.1 mg/ml eye drops, solution. 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) adverse reactions are presented according to System Organ Class in Table 1 in order of decreased seriousness within each frequency grouping.

Table 1.

In clinical studies, over 1800 patients have been treated with LUMIGAN 0.3 mg/ml. On combining the data from phase III monotherapy and adjunctive LUMIGAN 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 and 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 during clinical trials with LUMIGAN 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, undesirable effects are presented in order of decreasing seriousness.

Table 2.

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 LUMIGAN 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 LUMIGAN 0.1 mg/ml eye drops, solution in a 10 kg child.

Pharmacotherapeutic group: Ophthalmologicals, prostaglandin analogues, ATC code: S01EE03.

The mechanism of action by which bimatoprost reduces intraocular pressure in humans is 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.

Bimatoprost is a potent ocular hypotensive agent. It is a synthetic prostamide, structurally related to prostaglandin F_2α (PGF_2α), that does not act through any known prostaglandin receptors. Bimatoprost selectively mimics the effects of newly discovered biosynthesised substances called prostamides. The prostamide receptor, however, has not yet been structurally identified.

During a 12month pivotal study in adults with LUMIGAN 0.1 mg/ml eye drops, the mean diurnal IOP values measured at any visit over the 12-month study period differed by no more than 1.1 mmHg throughout the day and were never greater than 17.7 mmHg.

LUMIGAN 0.1 mg/ml eye drops contains BAK in a concentration of 200 ppm.

Limited experience is available with the use of LUMIGAN in patients with open-angle glaucoma with pseudoexfoliative and pigmentary glaucoma, and chronic angle-closure glaucoma with patent iridotomy.

No clinically relevant effects on heart rate and blood pressure have been observed in clinical trials.

Bimatoprost penetrates the human cornea and sclera well in vitro. After ocular administration in adults, the systemic exposure of bimatoprost is very low with no accumulation over time. After once daily ocular administration of one drop of 0.3 mg/ml bimatoprost to both eyes for two weeks, blood concentrations peaked within 10 minutes after dosing and declined to below the lower limit of detection (0.025 ng/ml) within 1.5 hours after dosing. Mean C_max and AUC _0-24hrs values were similar on days 7 and 14 at approximately 0.08 ng/ml and 0.09 ng•hr/ml respectively, indicating that a steady bimatoprost concentration was reached during the first week of ocular dosing.

Bimatoprost is moderately distributed into body tissues and the systemic volume of distribution in humans at steady-state was 0.67 l/kg. In human blood, bimatoprost resides mainly in the plasma. The plasma protein binding of bimatoprost is approximately 88 %.

Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing. Bimatoprost then undergoes oxidation, N-deethylation and glucuronidation to form a diverse variety of metabolites.

Bimatoprost is eliminated primarily by renal excretion, up to 67 % of an intravenous dose administered to healthy adult 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 was 1.5 l/hr/kg.

Characteristics in elderly patients:

After twice daily dosing with bimatoprost 0.3 mg/ml eye drops, solution, the mean AUC_0-24hr value of 0.0634 ng•hr/ml bimatoprost in the elderly (subjects 65 years or older) were significantly higher than 0.0218 ng•hr/ml in young healthy adults. However, this finding is not clinically relevant as systemic exposure for both 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.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Monkeys administered ocular bimatoprost concentrations of 0.3 mg/ml daily for 1 year had 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. The increased iris pigmentation appears to be caused by increased stimulation of melanin production in melanocytes and not by an increase in melanocyte number. No functional or microscopic changes related to the periocular effects have been observed, and the mechanism of action for the periocular changes is unknown.

Bimatoprost was not mutagenic or carcinogenic in a series of in vitro and in vivo studies.

Bimatoprost did not impair fertility in rats up to doses of 0.6 mg/kg/day (at least 103times the intended human exposure). In embryo/foetal developmental studies abortion, but no developmental effects were seen in mice and rats at doses that were at least 860times or 1700times higher than the dose in humans, respectively. These doses resulted in systemic exposures of at least 33 or 97times higher, respectively, than the intended human exposure. In rat peri/postnatal studies, maternal toxicity caused reduced gestation time, foetal death, and decreased pup body weights at 0.3 mg/kg/day (at least 41times the intended human exposure). Neurobehavioural functions of offspring were not affected.

Benzalkonium chloride

Sodium chloride

Sodium phosphate dibasic heptahydrate

Citric acid monohydrate

Hydrochloric acid or sodium hydroxide (to adjust pH)

Purified water

Not applicable.

2 years.

4 weeks after first opening.

This medicinal product does not require any special storage conditions.

White opaque low density polyethylene bottles with polystyrene screw cap. Each bottle has a fill volume of 3 ml.

The following pack sizes are available: cartons containing 1 or 3 bottles of 3 ml solution. Not all pack sizes may be marketed.

No special requirements.

Allergan Pharmaceuticals Ireland

Castlebar Road

Westport

Co. Mayo

Ireland

EU/1/02/205/003-004

7^th January 2010

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu