LUMIGAN 0.1mg / ml ophthalmic drops solution medication leaflet

LUMIGAN 0.1 mg/ml eye drops, solution

One ml of solution contains 0.1 mg bimatoprost.

One ml of solution contains 0.2 mg benzalkonium chloride.

For the full list of excipients, see section 6.1.

Eye drops, solution (eye drops)

Colourless solution.

Reduction of elevated intraocular pressure in chronic open-angle glaucoma and ocular hypertension inadults (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. Thedose should not exceed once daily, as more frequent administration may lessen the intraocular pressurelowering effect.

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

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

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

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

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

Ocular

Before treatment is initiated, patients should be informed of the possibility of prostaglandin analogueperiorbitopathy (PAP) and increased iris pigmentation, since these have been observed duringtreatment with LUMIGAN. Some of these changes may be permanent, and may lead to impaired fieldof vision and differences in appearance between the eyes when only one eye is treated (see section4.8).

Cystoid macular oedema has been uncommonly reported (≥1/1 000 to <1/100) following treatmentwith bimatoprost 0.3 mg/ml eye drops, solution. Therefore, LUMIGAN should be used with caution inpatients with known risk factors for macular oedema (e.g. aphakic patients, pseudophakic patients witha torn posterior lens capsule).

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

LUMIGAN 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 LUMIGAN solution comes repeatedly incontact with the skin surface. Thus, it is important to apply LUMIGAN as instructed and avoid itrunning onto the cheek or other skin areas.

Respiratory

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

LUMIGAN has not been studied in patients with heart block more severe than first degree oruncontrolled congestive heart failure. There have been a limited number of spontaneous reports ofbradycardia or hypotension with bimatoprost 0.3 mg/ml eye drops, solution. LUMIGAN should beused with caution in patients predisposed to low heart rate or low blood pressure.

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

LUMIGAN 0.1 mg/ml contains the preservative benzalkonium chloride (200 ppm), which may beabsorbed by soft contact lenses. Eye irritation and discolouration of the soft contact lenses may alsooccur because of the presence of benzalkonium chloride. Contact lenses should be removed prior toinstillation and may be reinserted 15 minutes following administration.

Benzalkonium chloride, which is commonly used as a preservative in ophthalmic products, has beenreported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Since

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

There have been reports of bacterial keratitis associated with the use of multiple dose containers oftopical 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 epithelialsurface 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 orsurrounding structures, to avoid eye injury and contamination of the solution.

No interaction studies have been performed.

No interactions are anticipated in humans, since systemic concentrations of bimatoprost are extremelylow (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 hepaticdrug metabolising enzymes were observed in preclinical studies.

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

Concomitant use of LUMIGAN and antiglaucomatous agents other than topical beta-blockers has notbeen evaluated during adjunctive glaucoma therapy.

There is a potential for the IOP-lowering effect of prostaglandin analogues (e.g. LUMIGAN) to bereduced in patients with glaucoma or ocular hypertension when used with other prostaglandinanalogues (see section 4.4).

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

LUMIGAN should not be used during pregnancy unless clearly necessary.

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

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

LUMIGAN has negligible influence on the ability to drive and use machines. As with any oculartreatment, if transient blurred vision occurs at instillation, the patient should wait until the vision clearsbefore 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 frequentlyreported adverse reaction was conjunctival hyperaemia (mostly trace to mild and of anon-inflammatory nature) occurring in 29 % of patients. Approximately 4 % of patients discontinueddue to any adverse event in the 12-month study.

The following adverse reactions were reported during clinical trials with LUMIGAN 0.1 mg/ml eyedrops, 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 000to <1/1 000); very rare (<1/10 000); not known (cannot be estimated from available data) adversereactions 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. List of adverse reactions

System Organ class Frequency Adverse reaction

Nervous system disorders Uncommon Headache

Not known Dizziness

Eye disorders Very common Conjunctival hyperaemia,prostaglandin analogueperiorbitopathy

Common Punctate keratitis, eye irritation, eyepruritus, growth of eyelashes,eye pain,erythema of eyelid, eyelid pruritus

Uncommon Asthenopia, blurred vision,conjunctival disorder, conjunctivaloedema, iris hyperpigmentation,madarosis, eyelid oedema

Not known Blepharal pigmentation, macularoedema, dry eye, eye discharge, eyeoedema, foreign body sensation ineyes, lacrimation increased, oculardiscomfort, photophobia

Respiratory, thoracic and Not known Asthma, asthma exacerbation, COPDmediastinal disorders exacerbation and dyspnoea

Gastrointestinal disorders Uncommon Nausea

Skin and subcutaneous tissue Common Skin hyperpigmentation,disorders hypertrichosis

Uncommon Dry skin, eyelid margin crusting,pruritus

Not known Skin discoloration (periocular)

General disorders and Common Instillation site irritationadministration site conditions

Immune system disorders Not known Hypersensitivity reaction includingsigns and symptoms of eye allergy andallergic dermatitis

Vascular disorders Not known Hypertension

Prostaglandin analogue periorbitopathy (PAP)

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

Iris hyperpigmentation

Increased iris pigmentation is likely to be permanent. The pigmentation change is due to increasedmelanin content in the melanocytes rather than to an increase in the number of melanocytes. The longterm effects of increased iris pigmentation are not known. Iris colour changes seen with ophthalmicadministration of bimatoprost may not be noticeable for several months to years. Typically, the brownpigmentation around the pupil spreads concentrically towards the periphery of the iris and the entireiris or parts become more brownish. Neither naevi nor freckles of the iris appear to be affected by thetreatment. At 12 months, the incidence of iris hyperpigmentation with bimatoprost 0.1 mg/ml eyedrops, solution was 0.5%. At 12 months, the incidence with bimatoprost 0.3 mg/ml eye drops, solutionwas 1.5% (see section 4.8 Table 2) and did not increase following 3 years treatment.

In clinical studies, over 1 800 patients have been treated with LUMIGAN 0.3 mg/ml. On combiningthe data from phase III monotherapy and adjunctive LUMIGAN 0.3 mg/ml usage, the most frequentlyreported adverse reactions were:

* growth of eyelashes in up to 45 % in the first year with the incidence of new reports decreasingto 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 yearsand 12 % at 3 years

* ocular pruritus in up to 14 % of patients in the first year with the incidence of new reportsdecreasing to 3 % at 2 years and 0 % at 3 years. Less than 9 % of patients discontinued due toany adverse event in the first year with the incidence of additional patient discontinuations being3 % at both 2 and 3 years.

Additional adverse reactions reported with LUMIGAN 0.3 mg/ml are presented in Table 2. The tablealso includes those adverse reactions which occurred with both formulations but at a differentfrequency. 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. List of additional adverse reactions

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 bodysensation, ocular dryness, eye pain,photophobia, tearing, eye discharge,visual disturbance/blurred vision,increased iris pigmentation, eyelashdarkening

Uncommon Retinal haemorrhage, uveitis, cystoidmacular oedema, iritis,blepharospasm, eyelid retraction,periorbital erythema

Vascular disorders Common Hypertension

Skin and subcutaneous tissue Uncommon Hirsutismdisorders

General disorders and Uncommon Astheniaadministration site conditions

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 phosphatecontaining eye drops in some patients with significantly damaged corneas.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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 accidentallyingested, the following information may be useful: in two-week oral rat and mouse studies, doses up to100 mg/kg/day did not produce any toxicity. This dose expressed as mg/m2 is at least 210 times higherthan the accidental dose of one bottle of LUMIGAN 0.1 mg/ml eye drops, solution in a 10 kg child.

Pharmacotherapeutic group: Ophthalmologicals - antiglaucoma preparations and miotics -prostaglandin analogues - bimatoprost - ATC code: S01EE03.

The mechanism of action by which bimatoprost reduces intraocular pressure in humans is byincreasing aqueous humour outflow through the trabecular meshwork and enhancing uveoscleraloutflow. Reduction of the intraocular pressure starts approximately 4 hours after the firstadministration and maximum effect is reached within approximately 8 to 12 hours. The duration ofeffect is maintained for at least 24 hours.

Bimatoprost is a potent ocular hypotensive agent. It is a synthetic prostamide, structurally related toprostaglandin F2 (PGF2), that does not act through any known prostaglandin receptors. Bimatoprostselectively mimics the effects of newly discovered biosynthesised substances called prostamides. Theprostamide receptor, however, has not yet been structurally identified.

During a 12-month 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 mmHgthroughout 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 withpseudoexfoliative and pigmentary glaucoma, and chronic angle-closure glaucoma with patentiridotomy.

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

The safety and efficacy of LUMIGAN in children aged 0 to less than 18 years has not beenestablished.

Bimatoprost penetrates the human cornea and sclera well in vitro. After ocular administration inadults, the systemic exposure of bimatoprost is very low with no accumulation over time. After oncedaily ocular administration of one drop of 0.3 mg/ml bimatoprost to both eyes for two weeks, bloodconcentrations peaked within 10 minutes after dosing and declined to below the lower limit ofdetection (0.025 ng/ml) within 1.5 hours after dosing. Mean Cmax and AUC 0-24hrs values were similaron days 7 and 14 at approximately 0.08 ng/ml and 0.09 ng*hr/ml respectively, indicating that a steadybimatoprost concentration was reached during the first week of ocular dosing.

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

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

Bimatoprost is eliminated primarily by renal excretion, up to 67 % of an intravenous doseadministered to healthy adult volunteers was excreted in the urine, 25 % of the dose was excreted viathe faeces. The elimination half-life, determined after intravenous administration, was approximately45 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 AUC0-24hr value of0.0634 ng*hr/ml bimatoprost in the elderly (subjects 65 years or older) were significantly higher than0.0218 ng*hr/ml in young healthy adults. However, this finding is not clinically relevant as systemicexposure for both elderly and young subjects remained very low from ocular dosing. There was noaccumulation of bimatoprost in the blood over time and the safety profile was similar in elderly andyoung patients.

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

Monkeys administered ocular bimatoprost concentrations of 0.3 mg/ml daily for 1 year had anincrease in iris pigmentation and reversible dose-related periocular effects characterised by aprominent upper and/or lower sulcus and widening of the palpebral fissure. The increased irispigmentation appears to be caused by increased stimulation of melanin production in melanocytes andnot by an increase in melanocyte number. No functional or microscopic changes related to theperiocular effects have been observed, and the mechanism of action for the periocular changes isunknown.

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 103-times theintended human exposure). In embryo/foetal developmental studies abortion, but no developmentaleffects were seen in mice and rats at doses that were at least 860-times or 1700-times higher than thedose in humans, respectively. These doses resulted in systemic exposures of at least 33- or 97-timeshigher, respectively, than the intended human exposure. In rat peri/postnatal studies, maternal toxicitycaused reduced gestation time, foetal death, and decreased pup body weights at  0.3 mg/kg/day (atleast 41-times the intended human exposure). Neurobehavioural functions of offspring were notaffected.

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 fillvolume of 3 ml.

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

No special requirements for disposal.

AbbVie Deutschland GmbH & Co. KG

Knollstrasse67061 Ludwigshafen

Germany

EU/1/02/205/003

EU/1/02/205/004

Date of first authorisation: 07 January 2010

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.