Composition: Active ingredient: tafluprost; 1 ml of eye drops contains 15 mcg of tafluprost; 1 single-dose container (0.3 ml) contains 4.5 mcg of tafluprost; Excipients: glycerin; sodium dihydrogen phosphate dihydrate; disodium edetate; polysorbate 80; sodium hydroxide or hydrochloric acid concentrated; water for injections. Pharmaceutical form. Eye drops. Basic physicochemical properties: clear, colourless solution. Does not contain visible particles. Pharmacotherapeutic group. Medicinal products used in ophthalmology. Anti-glaucoma preparations and miotics. Prostaglandin analogues. Tafluprost. ATC Code S01E E05. Pharmacological properties. Pharmacodynamics. Mechanism of action Tafluprost 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 FP prostaglandin receptor. Tafluprost acid has 12 times greater affinity for the FP receptor than latanoprost. Pharmacodynamic studies in monkeys have shown that tafluprost reduces intraocular pressure by increasing uveoscleral outflow of aqueous humour. Pharmacodynamic effects Tafluprost is a substance that effectively reduces intraocular pressure. In a study evaluating the effect of tafluprost metabolites on intraocular pressure reduction, only tafluprost acid significantly reduced intraocular pressure. In rabbits treated for 4 weeks with 0.0015% ophthalmic solution of tafluprost once daily, blood flow in the optic nerve head significantly (by 15%) increased compared to baseline, as measured by laser speckle flowgraphy on day 14 and day 28. Clinical efficacy Reduction in intraocular pressure begins 2–4 hours after the first administration of the drug, with maximum effect achieved approximately 12 hours after instillation. The duration of effect lasts for at least 24 hours. Core studies of tafluprost containing the preservative benzalkonium chloride demonstrated the efficacy of tafluprost as monotherapy and its additive effect when used as adjunctive therapy with timolol. In a 6-month study, tafluprost showed a significant intraocular pressure-lowering effect of 6–8 mmHg when administered at different times of day, compared to 7–9 mmHg achieved with latanoprost. In another 6-month clinical study, tafluprost reduced intraocular pressure by 5–7 mmHg compared to 4–6 mmHg with timolol. The intraocular pressure-lowering effect of tafluprost was maintained throughout the studies up to 12 months. In a 6-week study comparing the effect of tafluprost versus placebo on intraocular pressure when used concomitantly with timolol, the additional intraocular pressure reduction compared to baseline (measured after a 4-week initial treatment period with timolol) was 5–6 mmHg in the timolol-tafluprost group and 3–4 mmHg in the timolol-placebo group. The formulations of tafluprost with and without preservative showed similar intraocular pressure reduction of over 5 mmHg in a small crossover study with a 4-week treatment period. Furthermore, in a 3-month study conducted in the USA comparing preservative-free tafluprost to preservative-free timolol, the intraocular pressure-lowering effect of tafluprost ranged from 6.2 to 7.4 mmHg at various time points, while the effect of timolol ranged from 5.3 to 7.5 mmHg. Pharmacokinetics. Absorption After a single ocular instillation of one drop of preservative-free tafluprost 0.0015% eye drops in each eye once daily for 8 days, plasma concentrations of tafluprost acid were low and showed similar profiles on day 1 and day 8. Plasma concentrations reached maximum levels 10 minutes after administration and decreased below the lower limit of quantification (10 pg/ml) before the end of the first hour after instillation. Mean values of Cmax (maximum plasma concentration, 26.2 and 26.6 pg/ml) and AUC0-last (area under the concentration-time curve from administration to last quantifiable concentration, 394.3 and 431.9 pg*min/ml) were similar on day 1 and day 8, indicating achievement of steady-state concentrations during the first week of ocular administration. No statistically significant differences in systemic bioavailability were observed between the preserved and preservative-free formulations. In a rabbit study, ocular absorption of tafluprost into aqueous humour was comparable after a single instillation of 0.0015% tafluprost eye drops, either with or without preservative. Distribution In monkeys, no specific distribution of radiolabelled tafluprost was observed in the iris-ciliary body or uvea, including the retinal pigment epithelium, indicating low affinity for melanin pigment. In a whole-body autoradiography study in rats, the highest concentrations of radioactivity were observed in descending order in the cornea, eyelids, sclera, and iris. Outside the eye, radioactivity was distributed in the lacrimal apparatus, palate, oesophagus, gastrointestinal tract, kidneys, liver, gallbladder, and urinary bladder. In vitro binding of tafluprost acid to human serum albumin was 99% at a tafluprost acid concentration of 500 ng/ml. Biotransformation The main metabolic pathway of tafluprost in humans, studied in vitro, is hydrolysis to the pharmacologically active metabolite – tafluprost acid – which is further metabolized via glucuronidation or beta-oxidation. The beta-oxidation products – 1,2-dinor- and 1,2,3,4-tetranor-tafluprost acid – which are pharmacologically inactive, may undergo glucuronidation or hydroxylation. The cytochrome P450 (CYP) enzyme system is not involved in the metabolism of tafluprost acid. Based on studies in rabbit corneal tissue using purified enzymes, carboxylesterase is the main esterase responsible for hydrolysis of the ester to tafluprost acid. Butyrylcholinesterase may also participate in hydrolysis, but not acetylcholinesterase. Elimination After daily administration of 3H-tafluprost (0.005% ophthalmic solution; 5 µl/eye) to both eyes of rats for 21 days, approximately 87% of the total radioactive dose was excreted from the body. The fraction excreted in urine was approximately 27–38%, and approximately 44–58% was excreted in faeces. Clinical characteristics. Indications. Reduction of elevated intraocular pressure in open-angle glaucoma and ocular hypertension. Used as monotherapy in patients: - for whom use of preservative-free eye drops is desirable;
- with inadequate response to first-line therapy;
- with intolerance or contraindications to first-line therapy.
As adjunctive therapy in combination with beta-blockers. The drug is intended for adults (≥ 18 years). Contraindications. Hypersensitivity to the active substance tafluprost or to any of the excipients. Interaction with other medicinal products and other forms of interactions. Interactions in humans are not expected, as systemic concentrations of tafluprost after ocular administration are very low. Therefore, specific interaction studies between tafluprost and other medicinal products have not been conducted. In clinical studies, tafluprost was used concomitantly with timolol without any signs of interaction. Special precautions. Before initiating treatment, patients should be informed about the possibility of eyelash growth activation, darkening of eyelid skin, and increased pigmentation of the iris. Some of these changes may be long-lasting and may lead to differences in eye appearance if only one eye is treated. Changes in iris pigmentation occur slowly and may go unnoticed for several months. Eye colour changes were mainly observed in patients with mixed-colour irises, e.g., blue-brown, grey-brown, yellow-brown, and green-brown. The risk of permanent heterochromia between eyes when treating only one eye is evident. There is a potential for hair growth in areas where tafluprost solution repeatedly contacts the skin surface. There is no experience with tafluprost in neovascular, closed-angle, narrow-angle, or congenital glaucoma. Experience with tafluprost in patients with aphakia, or in pigmentary or pseudoexfoliative glaucoma, is limited. Tafluprost should be used with caution in patients with aphakia, pseudophakia with posterior lens capsule rupture or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema or iritis/uveitis. There is no experience with the use of tafluprost in patients with severe asthma. Therefore, the drug should be used with caution in such patients. Use during pregnancy or breastfeeding. Women of childbearing potential/contraception The drug should not be used in women of childbearing potential who are not using appropriate contraceptive measures. Pregnancy Adequate data on the use of tafluprost in pregnant women are lacking. Tafluprost may have an adverse pharmacological effect on pregnancy and/or the foetus/newborn. Animal studies have shown reproductive toxicity. Therefore, the drug should not be used during pregnancy except in cases of urgent need (if no other treatment options are available). Breastfeeding It is unknown whether tafluprost or its metabolites are excreted in breast milk. Studies in rats have shown excretion of tafluprost and/or its metabolites in milk after topical administration. Therefore, tafluprost should not be used during breastfeeding. Fertility In rats, intravenous administration of tafluprost at doses up to 100 mcg/kg/day did not affect mating ability or fertility. Ability to affect reaction speed when driving or operating machinery. Tafluprost does not affect the ability to drive or operate machinery. However, as with any ophthalmic preparation, if transient blurred vision occurs after instillation, patients should wait for vision to clear before driving or operating machinery. Method of administration and dosage. Dosage The recommended dose is 1 drop of the medicinal product into the conjunctival sac of the affected eye(s) once daily in the evening. Administration more frequently than once daily is not recommended, as more frequent use may reduce the intraocular pressure-lowering effect. For single use: one package (single-dose container) is sufficient for instillation into both eyes. Any unused solution residue must be discarded immediately after use. Use in elderly patients No dose adjustment is required for elderly patients. Use in patients with renal/hepatic impairment Studies with tafluprost in patients with renal/hepatic impairment have not been conducted; therefore, it should be used with caution in such patients. Method of administration To reduce the risk of eyelid skin darkening, patients should wipe off excess solution from the skin. As with any other eye drops, occlusion of the nasolacrimal duct or gentle closure of the eyelids is recommended after instillation. This may reduce systemic absorption of ophthalmically administered drugs. If a patient uses more than one topical ophthalmic medicinal product, intervals between administration of each product should be at least 5 minutes. Children. Safety and efficacy of tafluprost in children (under 18 years of age) have not been established. Data are lacking. Overdose. Overdose after ocular administration is unlikely. In case of overdose, symptomatic treatment should be administered. Adverse reactions. Over 1400 patients used tafluprost as monotherapy or as adjunctive therapy to 0.5% timolol in clinical studies. The most common treatment-related adverse reaction was ocular hyperaemia, occurring in approximately 13% of patients in tafluprost clinical trials in Europe and the USA. In most cases, ocular hyperaemia was mild and led to discontinuation in only about 0.4% of patients in core studies. In a 3-month Phase III study conducted in the USA comparing preservative-free tafluprost to preservative-free timolol, ocular hyperaemia was observed in 4.1% (13 out of 320) of patients using tafluprost. During clinical studies of tafluprost in Europe and the USA with a maximum observation period of 24 months, the following treatment-related adverse reactions were reported. Within each frequency group, adverse reactions are listed in order of decreasing frequency. Frequency is defined as: very common (≥ 1/10), common (≥ 1/100–<1/10), uncommon (≥ 1/1000–< 1/100), rare (≥1/10000 –< 1/1000), very rare (<1/10000), not known (cannot be estimated from available data). Systemic disorders Common (from ≥ 1/100 to < 1/10): headache. Eye disorders Common (from ≥ 1/100 to < 1/10): eye pruritus, eye irritation, eye pain, conjunctival/ocular hyperaemia, eyelash changes (increased length, thickness, and number of eyelashes), dry eye syndrome, foreign body sensation in the eye, eyelash discolouration, eyelid redness, superficial punctate keratitis (SPK), photophobia, increased lacrimation, blurred vision, decreased visual acuity, and increased iris pigmentation. Uncommon (from ≥ 1/1,000 to < 1/100): eyelid pigmentation, eyelid oedema, asthenopia, conjunctival oedema, eye discharge, blepharitis, anterior chamber cell abnormalities, eye discomfort, inflammatory hyperaemia of the anterior chamber of the eye, conjunctival pigmentation, conjunctival follicles, allergic conjunctivitis, and abnormal eye sensations. Not known (cannot be estimated from available data): iritis/uveitis, deepening of eyelid sulcus, macular oedema/cystoid macular oedema. In some patients with significant corneal damage, rare cases of tissue calcification have been observed with the use of eye drops containing phosphates. Respiratory system disorders Not known (cannot be estimated from available data): asthma exacerbation, breathing difficulty. Skin and subcutaneous tissue disorders Uncommon (from ≥ 1/1,000 to < 1/100): eyelid hypertrichosis. Reporting suspected adverse reactions It is important to report suspected adverse reactions after marketing authorisation. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions. Shelf life. 3 years. Use within 4 weeks after opening the package. Storage conditions. Store in the original packaging at 2–8 °C. Keep out of reach of children. After opening the package of single-dose containers:
- eye drops should be used within 4 weeks after opening the package;
- the single-dose container should be stored at a temperature not exceeding 25 °C;
- after single use, the single-dose container should be discarded together with any remaining content.
Packaging. 0.3 ml of eye drops in a single-dose container. 10 single-dose containers in foil pouches. 3 foil pouches (10 single-dose containers each) in a cardboard box. Prescription status. Prescription only. Manufacturer. Santen Oy / Santen Oy. Manufacturer's address and location of operations. Kelloportinkatu 1, Tampere, 33100, Finland / Kelloportinkatu 1, Tampere, 33100, Finland. |
