SAFLUTAN® 15 micrograms/ml eye drops, solution, single-dose container

One ml of eye drops, solution, contains 15 micrograms of tafluprost.

One single-dose container (0.3 ml) of eye drops, solution, contains 4.5 micrograms of tafluprost.

For a full list of excipients, see section 6.1.

Eye drops, solution, single-dose container (eye drops).

A clear, colourless solution.

Reduction of elevated intraocular pressure in open angle glaucoma and ocular hypertension.

As monotherapy in patients:

o who would benefit from preservative free eye drops

o insufficiently responsive to first line therapy

o intolerant or contra-indicated to first line therapy.

As adjunctive therapy to beta-blockers.

Posology

The recommended dose is one drop of SAFLUTAN in the conjunctival sac of the affected eye(s) once daily in the evening.

The dose should not exceed once daily as more frequent administration may lessen the intraocular pressure lowering effect.

For single use only, one container is sufficient to treat both eyes. Any unused solution should be discarded immediately after use.

Use in elderly:

No dosage alteration in elderly patients is necessary.

Use in children and adolescents:

Tafluprost is not recommended for use in children or adolescents below age 18 due to a lack of data on safety and efficacy.

Use in renal/hepatic impairment

Tafluprost has not been studied in patients with renal/hepatic impairment and should therefore be used with caution in such patients.

Method of administration

To reduce the risk of darkening of the eyelid skin the patients should wipe off any excess solution from the skin. As with any other eye drops, nasolacrimal occlusion or gently closing the eyelid after administration is recommended. This may reduce the systemic absorption of medicinal products administered via the ocular route.

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

Hypersensitivity to tafluprost or to any of the excipients.

Before treatment is initiated, patients should be informed of the possibility of eyelash growth, darkening of the eyelid skin and increased iris pigmentation. 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. The change in eye colour has predominantly been seen in patients with mixed coloured irises, e.g. blue-brown, grey-brown, yellow-brown and green-brown. The risk of lifelong heterochromia between the eyes in unilateral cases is obvious.

There is no experience with tafluprost in neovascular, angle-closure, narrow-angle or congenital glaucoma. There is only limited experience with tafluprost in aphakic patients and in pigmentary or pseudoexfoliative glaucoma.

Caution is recommended when using tafluprost in aphakic patients, pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema or iritis/uveitis.

There is no experience in patients with severe asthma. Such patients should therefore be treated with caution.

No interactions are anticipated in humans, since systemic concentrations of tafluprost are extremely low following ocular dosing. Therefore, specific interaction studies with other medicinal products have not been performed with tafluprost.

In clinical studies tafluprost was used concomitantly with timolol without evidence of interaction.

Women of childbearing potential/contraception

SAFLUTAN must not be used in women of childbearing age/potential unless adequate contraceptive measures are in place (see section 5.3).

Pregnancy

There are no adequate data from the use of tafluprost in pregnant women. Tafluprost can have harmful pharmacologic effects on pregnancy and/or the fetus/newborn child. Studies in animals have shown reproductive toxicity (see section 5.3). Therefore, SAFLUTAN should not be used during pregnancy unless clearly necessary (in case no other treatment options are available).

Lactation

It is unknown whether tafluprost is excreted in human milk. A study in rats has shown excretion of tafluprost in breast milk after topical administration (see section 5.3). Therefore, tafluprost should not be used during breast-feeding.

Tafluprost has no 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 machinery.

In clinical studies, over 1200 patients have been treated with tafluprost either as monotherapy or as adjunctive therapy to timolol 0.5%. The most frequently reported treatment-related adverse event was ocular hyperaemia. It occurred in approximately 13% of the patients participating in the clinical studies with tafluprost in Europe and the US. It was mild in most cases and led to discontinuation on an average in 0.4% of patients participating in the pivotal studies.

The following undesirable effects related to treatment were reported during clinical trials with tafluprost in Europe and the US after a maximum follow-up of 12 months:

Within each frequency grouping, adverse reactions are presented in order of decreasing frequency.

Eye disorders

Very common (1/10): conjunctival/ocular hyperaemia

Common (1/100 to <1/10): eye pruritus, eye irritation, eye pain, changes in eyelashes (increased length, thickness and number of lashes), dry eye, eyelash discolouration, foreign body sensation in eyes, erythema of eye lid, blurred vision, increased lacrimation, blepharal pigmentation, eye discharge, reduced visual acuity, photophobia, eyelid oedema and increased iris pigmentation.

Uncommon (1/1000 to <1/100): superficial punctate keratitis (SPK), asthenopia, conjunctival oedema, blepharitis, ocular discomfort, anterior chamber flare, conjunctival follicles, allergic conjunctivitis, anterior chamber cell, conjunctival pigmentation and abnormal sensation in eye.

Nervous system disorders

Common (1/100 to <1/10): headache

Skin and subcutaneous tissue disorders

Uncommon (1/1000 to <1/100): hypertrichosis of eyelid

No case of overdose has been reported. Overdose is unlikely to occur after ocular administration.

If overdose occurs, treatment should be symptomatic.

Pharmacotherapeutic group: Antiglaucoma preparations and miotics, prostaglandin analogues

ATC code: S01EE05

Mechanism of action

Tafluprost is a fluorinated analogue of prostaglandin F_2α. Tafluprost acid, the biologically active metabolite of tafluprost, is a highly potent and selective agonist of the human prostanoid FP receptor. Tafluprost acid has a 12-fold higher affinity for the FP receptor than latanoprost. Pharmacodynamic studies in monkeys indicate that tafluprost reduces intraocular pressure by increasing the uveoscleral outflow of aqueous humour.

Clinical effects on intraocular pressure

Reduction of intraocular pressure starts between 2 and 4 hours after the first administration and maximum effect is reached at around 12 hours after instillation. The duration of effect is maintained for at least 24 hours. Pivotal studies with a tafluprost formulation containing the preservative benzalkonium chloride have demonstrated that tafluprost is effective as monotherapy and has an additive effect when administered as adjunctive therapy to timolol: In a 6-month study, tafluprost showed a significant IOP lowering effect of 6 to 8 mmHg at different time points of the day as compared to 7 to 9 mmHg with latanoprost. In a second 6-month clinical study, tafluprost reduced IOP by 5 to 7 mmHg as compared to 4 to 6 mmHg with timolol. The IOP lowering effect of tafluprost was maintained in the extension of these studies up to 12 months. In a 6-week study, the IOP-lowering effect of tafluprost was compared with its vehicle when used adjunctively with timolol. Compared to baseline values (measured after a 4-week run in on timolol), the additional IOP-lowering effects were 5 to 6 mmHg in the timolol-tafluprost group and 3 to 4 mmHg in the timolol-vehicle group. The preserved and the non-preserved formulations of tafluprost showed a similar IOP-lowering effect of over 5 mmHg in a small cross-over study with a 4-week treatment period.

Secondary pharmacodynamics

When rabbits were treated for 4 weeks with a tafluprost 0.0015% ophthalmic solution once daily, the optic nerve head blood flow was significantly increased compared to baseline when measured by the laser speckle flowgraphy on Days 14 and 28.

After once daily ocular administration of one drop of unpreserved tafluprost 0.0015% eye drops in single-dose container to both eyes for 8 days, plasma concentrations were low and had similar profiles on days 1 and 8. The plasma concentrations peaked at 10 minutes after dosing and declined to below the lower limit of detection (10 pg/mL) before one hour after dosing. Mean C_max (26.2 and 26.6 pg/mL) and AUC_0-last (394.3 and 431.9 pg*min/mL) values were similar on days 1 and 8, indicating that a steady drug concentration was reached during the first week of ocular dosing. No statistically significant differences in the systemic bioavailability between the preserved and unpreserved formulation were detected.

In a rabbit study, the absorption of tafluprost into the aqueous humour was comparable after a single ocular instillation of unpreserved or preserved tafluprost 0.0015% ophthalmic solution.

In monkeys, there was no specific distribution of radiolabelled tafluprost in the iris-ciliary body or choroid including retinal pigment epithelium, which suggested low affinity for melanin pigment.

The principle metabolic pathway of tafluprost in humans is the hydrolysis to tafluprost acid and further beta-oxidation to the pharmacologically inactive 1,2-dinor and 1,2,3,4-tetranor tafluprost acids, which may be glucuronated or hydroxylated. Cytochrome P450 (CYP) enzyme system is not involved in the metabolism of tafluprost acid.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, systemic repeated dose toxicity, genotoxicity and carcinogenic potential. As with other PGF2 agonists, repeated dose topical ocular administration of tafluprost to monkeys produced irreversible effects on iris pigmentation and reversible enlargement of the palpebral fissure.

Increased contraction of rat and rabbit uteri in vitro was observed at tafluprost acid concentrations that exceeded 4 to 40 times, respectively, the maximum plasma concentrations of tafluprost acid in humans. Uterotonic activity of tafluprost has not been tested in human uterus preparations.

Reproduction toxicity studies were performed in the rat and rabbit with intravenous administration. In rats, no adverse effects on fertility or early embryonic development were observed at systemic exposure over 12 000 times the maximum clinical exposure based on C_max or greater than 75 times based on AUC.

In conventional embryo-foetal development studies, tafluprost caused reductions in foetal body weights and increases in post-implantation losses. Tafluprost increased the incidence of skeletal abnormalities in rats as well as the incidence of skull, brain and spine malformations in rabbits. In the rabbit study, plasma levels of tafluprost and its metabolites were below the level of quantification.

In a pre- and postnatal development study in rats, increased mortality of newborns, decreased body weights and delayed pinna unfolding were observed in offspring at tafluprost doses greater than 20 times the clinical dose.

The experiments in rats with radiolabelled tafluprost showed that around 0.1% of the topically applied dose on eyes was transferred into milk. As the half-life of active metabolite (tafluprost acid) in plasma is very short (not detectable after 30 minutes in humans), most of the radioactivity probably represented metabolites with little, or no pharmacologic activity. Based on metabolism of the drug and natural prostaglandins, the oral bioavailability is expected to be very low.

Glycerol

Sodium dihydrogen phosphate dihydrate

Disodium edetate

Polysorbate 80

Hydrochloric acid and/or sodium hydroxide for pH adjustment

Water for injections.

Not applicable

3 years.

After first opening a foil pouch: 28 days.

Store in a refrigerator (2°C - 8°C).

After opening the foil pouch:

• Keep the single-dose containers in the original foil pouch

• Do not store above 25°C

• Discard an opened single-dose container with any remaining solution immediately after use.

Low-density polyethylene (LDPE) single-dose containers packed in foil pouch. Each single-dose container has a fill volume of 0.3 ml and there are 10 containers in each foil pouch.

The following pack sizes are available: 30 x 0.3 ml single-dose containers and 90 x 0.3 ml single-dose containers.

Not all pack sizes may be marketed.

No special requirements.

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU, UK

PL 00025/0529

17 October 2008

07/2009

POM

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© Merck Sharp & Dohme Limited 2010. All rights reserved.SPC.SAF.10.UK.3224 IB-02