This information is intended for use by health professionals

1. Name of the medicinal product

Eyreida 0.3mg/ml eye drops, solution

2. Qualitative and quantitative composition

1 ml of solution contains 0.3mg of bimatoprost.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Eye drops, solution.

Clear, colourless, eye drops.

Osmolality: 261-319 mOsm/Kg

pH: 6.8 – 7.8

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.

Eyreida eye drops solution is a sterile solution that does not contain a preservative.

Paediatric population:

The safety and efficacy of Eyreida in children aged 0 to 18 years has not yet been established. No data are currently available.

Hepatic or renal impairment

Eyreida 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 (preserved 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.

Before instillation of the eye drops

- Users should be instructed to wash their hands before opening the bottle.

- Users should also be instructed to not use this medicine if they notice that the tamper-proof seal on the bottle neck is broken before they first use it.

- When used for the first time, before delivering a drop to the eye, the patient should practise using the dropper bottle by squeezing it slowly to deliver one drop away from the eye.

- When the patient is confident they can deliver one drop at a time, the patient should adopt a position that is the most comfortable for the instillation of the drops (the patient can sit down, lie on their back, or stand in front of a mirror).

Instillation

1. The bottle should be held directly below the cap and the cap should be turned to open the bottle. To avoid contamination of the solution, the tip of the bottle must not touch anything.

2. The patient should tilt their head backwards and hold the bottle above their eye.

3. The patient should pull the lower eyelid down and look up. The bottle should be squeezed gently in the middle and a drop should be allowed to fall into the patient's eye. Please note that there might be a few seconds delay between squeezing and the drop coming out. The bottle must not be squeezed too hard.

Patients should be instructed to seek advice from their doctor, pharmacist or nurse if they are not sure how to administer their medicine.

4. The patient should blink a few times so that the drop spreads over their eye.

5. Instructions 2. – 4. should be repeated for delivery into the other eye, if required. The patient should be clearly instructed if one eye only requires treatment, and if so, which eye is affected.

6. After each use and prior to recapping, the bottle should be shaken once in a downwards direction, without touching the dropper tip, in order to remove any residual liquid on the tip. This is necessary in order to ensure delivery of subsequent drops.

7. At the end of the 28-day in-use shelf life of the medicine, there will be some Eyreida left in the bottle. Using the excess medicine remaining in the bottle after the patient has completed the course of treatment should not be attempted. Patients must not use the eye drops for longer than 28 days after first opening the bottle.

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 eyelash growth, darkening of the eyelid skin and increased iris pigmentation since these have been observed during treatment with Eyreida. 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 3 months, the incidence of iris hyperpigmentation with bimatoprost 0.3 mg/ml (preservative free formulation) was 0.3%. At 12 months, the incidence of iris pigmentation with bimatoprost 0.3 mg/ml (preserved formulation) was 1.5% (see section 4.8) 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 (preserved formulation). Therefore, Eyreida 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 (preserved formulation). Eyreida should be used with caution in patients with a prior history of significant ocular viral infections (e.g. herpes simplex) or uveitis/iritis.

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

Respiratory

Eyreida 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

Eyreida 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. Eyreida 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 Eyreida with other prostaglandin analogues should be monitored for changes to their intraocular pressure.

Eyreida 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.

Patients with a history of contact hypersensitivity to silver should not use this product as dispensed drops may contain traces of silver.

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, this medicine was used concomitantly with a number of different ophthalmic beta-blocking agents without evidence of interactions.

Concomitant use of Eyreida 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. Eyreida) 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).

Eyreida 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 Eyreida 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

Eyreida 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 (preservative free formulation) 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 (preservative free formulation) 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 (preservative free formulation) 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

Eye disorders

very common

conjunctival hyperaemia

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

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

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 (preserved formulation). On combining the data from phase III monotherapy and adjunctive bimatoprost 0.3 mg/ml (preserved 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 (preserved formulation), but were reported at a higher frequency than with bimatoprost 0.3 mg/ml ((preservative free formulation)). 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 (preservative free formulation), Table 3 lists additional adverse reactions that were seen with bimatoprost 0.3 mg/ml (preserved 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

not known

periorbital and lid changes including deepening of the eyelid sulcus

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

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.

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 Eyreida 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.

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 F2α (PGF2α), 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.

Clinical efficacy

A 12 week (double-masked, randomized, parallel group) clinical study compared the efficacy and safety of bimatoprost 0.3 mg/ml (preservative free formulation) with bimatoprost 0.3 mg/ml (preserved formulation). bimatoprost 0.3 mg/ml (preservative free formulation) achieved non-inferior IOP-lowering efficacy to bimatoprost 0.3 mg/ml (preserved formulation) for worse eye IOP change from baseline in patients with glaucoma or ocular hypertension. bimatoprost 0.3 mg/ml (preservative free formulation) also achieved equivalent IOP lowering efficacy with bimatoprost 0.3 mg/ml (preserved formulation) in average eye IOP at each follow-up timepoint at weeks 2, 6 and 12.

During 12 months' monotherapy treatment with bimatoprost 0.3 mg/ml (preserved formulation) in adults, versus timolol, mean change from baseline in morning (08:00) intraocular pressure ranged from -7.9 to -8.8 mmHg. At any visit, the mean diurnal IOP values measured over the 12-month study period differed by no more than 1.3 mmHg throughout the day and were never greater than 18.0 mmHg.

In a 6-month clinical study with bimatoprost 0.3 mg/ml (preserved formulation), versus latanoprost, a statistically superior reduction in morning mean IOP (ranging from -7.6 to -8.2 mmHg for bimatoprost versus –6.0 to -7.2 mmHg for latanoprost) was observed at all visits throughout the study. Conjunctival hyperaemia, growth of eyelashes, and eye pruritus were statistically significantly higher with bimatoprost than with latanoprost, however, the discontinuation rates due to adverse events were low with no statistically significant difference.

Compared to treatment with beta-blocker alone, adjunctive therapy with beta-blocker and bimatoprost 0.3 mg/ml (preserved formulation) lowered mean morning (08:00) intraocular pressure by -6.5 to -8.1 mmHg.

Limited experience is available 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 Eyreida in children aged 0 to 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 bimatoprost 0.3 mg/ml 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 Cmax 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 of bimatoprost 0.3 mg/ml, the mean AUC0-24hr 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 were 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

Sodium chloride

Disodium hydrogen phosphate heptahydrate

Citric acid monohydrate

Sodium hydroxide or hydrochloric acid (for pH adjustment)

Water for injection

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

After first opening, the product may be stored for a maximum of 28 days. No special storage conditions are required.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions. For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Eyreida is presented as a clear, colorless aqueous solution in a white opaque 5 ml LDPE bottle and white Novelia nozzle (HDPE and silicone) and sealed with a white HDPE cap.

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 and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Aspire Pharma Ltd

Unit 4, Rotherbrook Court

Bedford Road

Petersfield

Hampshire, GU32 3QG

UK

8. Marketing authorisation number(s)

PL35533/0107

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 18/12/2017

10. Date of revision of the text

18/12/2017