- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- Legal category
PosologyThe 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 elderlyNo dosage alteration in elderly patients is necessary.
Paediatric populationThe safety and efficacy of tafluprost in children below age 18 has not yet been established. No data are available.
Use in renal/hepatic impairmentTafluprost has not been studied in patients with renal/hepatic impairment and should therefore be used with caution in such patients.
Method of administrationTo 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.
Women of childbearing potential/contraceptionSAFLUTAN must not be used in women of childbearing age/potential unless adequate contraceptive measures are in place (see section 5.3).
PregnancyThere 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).
Breast-FeedingIt is unknown whether tafluprost or its metabolites are excreted in human milk. A study in rats has shown excretion of tafluprost and/or its metabolites in breast milk after topical administration (see section 5.3). Therefore, tafluprost should not be used during breast-feeding.
FertilityIn female and male rats, mating performance and fertility was unaffected by intravenous tafluprost doses up to 100 μg/kg/day.
Nervous system disordersCommon (≥1/100 to <1/10): headache
Eye disordersCommon (≥1/100 to <1/10): eye pruritus, eye irritation, eye pain, conjunctival/ocular hyperaemia, changes in eyelashes (increased length, thickness and number of lashes), dry eye, foreign body sensation in eyes, eyelash discolouration, erythema of eye lid, superficial punctate keratitis (SPK), photophobia, increased lacrimation, blurred vision, reduced visual acuity and increased iris pigmentation.Uncommon (≥1/1000 to <1/100): blepharal pigmentation, eyelid oedema, asthenopia, conjunctival oedema, eye discharge, blepharitis, anterior chamber cells, ocular discomfort, anterior chamber flare, conjunctival pigmentation, conjunctival follicles, allergic conjunctivitis and abnormal sensation in eye.Not known (cannot be estimated from the available data): iritis/uveitisCases 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.
Respiratory disordersNot known (cannot be estimated from the available data): exacerbation of asthma, dyspnea
Skin and subcutaneous tissue disordersUncommon (≥1/1,000 to <1/100): hypertrichosis of eyelidReporting of suspected adverse reactionsReporting 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.
Mechanism of actionTafluprost is a fluorinated analogue of prostaglandin F2α. 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.
Pharmacodynamic effectsThe experiments in normotensive and ocular hypertensive monkeys showed that tafluprost is an effective IOP-lowering compound. In the study investigating IOP-reducing effect of tafluprost metabolites only tafluprost acid reduced IOP significantly.When rabbits were treated for 4 weeks with a tafluprost 0.0015% ophthalmic solution once daily, the optic nerve head blood flow was significantly (15%) increased compared to baseline when measured by the laser speckle flowgraphy on Days 14 and 28.
Clinical efficacyReduction 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. Furthermore, in a 3-month study in the US comparing the non-preserved formulation of tafluprost with the non-preserved formulation of timolol, the IOP-lowering effect of tafluprost was between 6.2 and 7.4 mmHg at different timepoints whereas that of timolol varied between 5.3 and 7.5 mmHg.
AbsorptionAfter 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 of tafluprost acid 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 Cmax (26.2 and 26.6 pg/ml) and AUC0-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.
DistributionIn 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. In a whole body autoradiography study in rats, the highest concentration of radioactivity was observed in the cornea followed by the eyelids, sclera and the iris. Outside the eye radioactivity was distributed to the lacrimal apparatus, palate, oesophagus and gastrointestinal tract, kidney, liver, gall bladder and urinary bladder.The binding of tafluprost acid to human serum albumin in vitro was 99% at 500 ng/ml tafluprost acid.
BiotransformationThe principal metabolic pathway of tafluprost in human, which was tested in vitro, is the hydrolysis to the pharmacologically active metabolite, tafluprost acid, which is further metabolized by glucuronidation or beta-oxidation. Products of beta-oxidation, 1,2-dinor and 1,2,3,4-tetranor tafluprost acids, which are pharmacologically inactive, may be glucuronidated or hydroxylated. Cytochrome P450 (CYP) enzyme system is not involved in the metabolism of tafluprost acid. Based on the study in rabbit corneal tissue and with purified enzymes, the main esterase responsible for the ester hydrolysis to tafluprost acid is carboxyl esterase. Butylcholine esterase but not acetylcholine esterase may also contribute to the hydrolysis.
EliminationFollowing once daily administration of 3H-tafluprost (0.005% ophthalmic solution; 5 μl/eye) for 21 days to both eyes in rats, approximately 87% of the total radioactive dose was recovered in the excreta. Percent of the total dose excreted in urine was approximately 27-38% and approximately 44-58% of the dose was excreted in the faeces.
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