SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Bimatoprost Pharmathen 0.1 mg/ml eye drops, solution

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

One ml of solution contains 0.1 mg bimatoprost.

Excipient with known effect:

One ml of solution contains 0.2 mg benzalkonium chloride.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Eye drops, solution.

Clear, colourless solution, free from visible particles. pH: 6.8-7.8

Osmolalily: 290 mOsm/kg

4    CLINICAL PARTICULARS

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 Pharmathen 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.

Contraindications

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

Bimatoprost Pharmathen 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 eyelash growth, darkening of the eyelid skin and increased iris pigmentation, since these have been observed during treatment with bimatoprost. Some of these changes may be permanent, and may lead to differences in appearance between the eyes when only one eye is treated. 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. Periorbital tissue pigmentation has been reported to be reversible in some patients.

Cystoid macular oedema has been uncommonly reported (>1/1,000 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 comeal 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 Pharmathen solution comes repeatedly in contact with the skin surface. Thus, it is important to apply Bimatoprost Pharmathen 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 Pharmathen 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 Pharmathen 0.1 mg/ml contains the preservative benzalkonium chloride, 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 Pharmathen 0.1 mg/ml contains benzalkonium chloride, 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 Pharmathen) 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 Pharmathen 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 Pharmathen 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 Pharmathen 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
Eye disorders	very common	conjunctival hyperaemia
	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	blepharal pigmentation, macular oedema, periorbital and lid changes including deepening of the eyelid sulcus, dry eye
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
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 noninflammatory 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 comeal 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

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard.

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Mechanism of action

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_2a (PGF_2a), 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 12-month pivotal study in adults with bimatoprost 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.

Limited experience is available with the use of bimatoprost 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.

Paediatric population

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

5.2 Pharmacokinetic properties

Absorption

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.

Distribution

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 %.

Biotransformation

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.

Elimination

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.

5.3 Preclinical safety data

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 103-times 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 860-times or 1700-times higher than the dose in humans, respectively. These doses resulted in systemic exposures of at least 33- or 97-times 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 41-times the intended human exposure). Neurobehavioural functions of offspring were not affected.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Benzalkonium chloride

Sodium chloride

Sodium phosphate dibasic heptahydrate Citric acid monohydrate

Hydrochloric acid concentrated or sodium hydroxide (to adjust pH) Water for injection

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months.

4 weeks after first opening.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

White opaque low density polyethylene vial for eye drops containing 3 ml of the ophthalmic solution sealed with a white opaque LDPE plug applicator and a white HDPE/LDPE cap with a tamper-proof seal.

The following pack sizes are available: cartons containing 1 or 3 bottles of 3 ml solution.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

MARKETING AUTHORISATION HOLDER

Pharmathen S.A.

6 Dervenakion Street Pallini 15351 Athens, Greece Tel: 0030 210 66 04 300 Fax: 0030 210 66 66 749 Email: info@pharmathen.com

8    MARKETING AUTHORISATION NUMBER(S)

PL 17277/0350

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

22/03/2016

10    DATE OF REVISION OF THE TEXT

22/03/2016