Taflotan® multi

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TAFLONAN® MULTİ

Composition:

Active substance: tafluprost;

1 ml of eye drops, solution, contains 15 mcg of tafluprost;

Excipients: glycerin; sodium dihydrogen phosphate, dihydrate; disodium edetate; polysorbate 80; sodium hydroxide or concentrated hydrochloric acid; water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear, colorless solution. Practically free from visible particles.

Pharmacotherapeutic group. Medicinal products used in ophthalmology. Anti-glaucoma and miotic agents. Prostaglandin analogues. ATC code S01E E05.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Tafluprost is a fluorine-containing analogue of prostaglandin F2α. Tafluprost acid—the biologically active metabolite of tafluprost—is a highly potent and selective agonist of the human prostaglandin FP receptor. Tafluprost acid has 12 times greater affinity for the FP receptor than latanoprost. Pharmacodynamic studies in monkeys indicate that tafluprost reduces intraocular pressure by increasing uveoscleral outflow of aqueous humor.

Pharmacodynamic effects

Tafluprost is a substance that effectively reduces intraocular pressure. In a study evaluating the effects of tafluprost metabolites on intraocular pressure reduction, only tafluprost acid caused a significant decrease in intraocular pressure.

In rabbits, administration of 0.0015 % tafluprost ophthalmic solution once daily for 4 weeks significantly increased (by 15 %) optic nerve head blood flow compared to baseline levels, 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 dose, with maximum effect achieved approximately 12 hours after instillation. The duration of effect lasts for at least 24 hours. Pivotal studies of tafluprost formulation containing the preservative benzalkonium chloride demonstrated efficacy of tafluprost as monotherapy and an additive effect when used concomitantly with timolol.

In a 6-month study, tafluprost demonstrated a significant intraocular pressure reduction of 6–8 mmHg when administered at various times of the 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 continuation of these studies up to 12 months. In a 6-week study comparing the intraocular pressure-lowering effect of tafluprost versus placebo when used concomitantly with timolol, additional intraocular pressure reduction compared to baseline (measured after a 4-week initial treatment period with timolol alone) was 5–6 mmHg in the timolol-tafluprost group and 3–4 mmHg in the timolol-placebo group. Tafluprost formulations with and without preservative showed similar intraocular pressure-lowering effects exceeding 5 mmHg in a small crossover study with a 4-week treatment period. Furthermore, in a 3-month U.S. study 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 ocular administration of one drop of preservative-free tafluprost 0.0015 % ophthalmic solution to 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 concentration peaked 10 minutes after dosing and decreased to levels below the lower limit of quantification (10 pg/mL) before the end of the first hour post-dose. Mean Cmax (maximum plasma concentration) values (26.2 and 26.6 pg/mL) and AUC0-last (area under the concentration-time curve from dosing to the last quantifiable concentration, 394.3 and 431.9 pg*min/mL) were similar on day 1 and day 8, indicating achievement of steady-state concentration within 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 was comparable after single instillation of 0.0015 % tafluprost ophthalmic solution with and without preservative.

Distribution

In monkeys, no specific distribution of radiolabeled tafluprost was observed in the iris-ciliary body or choroid, 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, esophagus, 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 primary metabolic pathway of tafluprost in humans, as analyzed 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, are pharmacologically inactive and 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 primary esterase responsible for hydrolysis of the ester prodrug to tafluprost acid. Butyrylcholinesterase may also participate in hydrolysis, but acetylcholinesterase does not.

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 eliminated from the body. The fraction excreted in urine was approximately 27–38 %, and approximately 44–58 % of the dose was excreted in feces.

Clinical characteristics.

Indications.

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

Used as monotherapy in patients:

• for whom it is desirable to use preservative-free ophthalmic solutions;
• with insufficient response to first-line therapy;
• with intolerance or contraindications to first-line therapy.

As adjunctive treatment in combination with beta-blockers.

The medicinal product is intended for adults (aged 18 years and older).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Interaction in humans is not expected, as systemic concentrations of tafluprost after ocular administration are very low. Therefore, specific studies on tafluprost interaction with other medicinal products have not been conducted.

In clinical trials, tafluprost was used concomitantly with timolol without any signs of interaction.

Special precautions for use.

Before starting treatment, patients should be informed about the possibility of eyelash growth, darkening of the eyelid skin, and increased pigmentation of the iris. Some of these changes may be long-lasting and may lead to differences in the appearance of the eyes if only one eye is treated.

Iris pigmentation changes occur gradually and may go unnoticed for several months. Changes in eye color have mainly been observed in patients with mixed-colored irises, such as blue-brown, gray-brown, yellow-brown, and green-brown. The risk of permanent heterochromia is evident when only one eye is treated.

There is a possible increase in hair growth in areas where the tafloprost solution repeatedly comes into contact with the skin surface.

There is no experience with the use of tafloprost in neovascular, closed-angle, narrow-angle, or congenital glaucoma. Experience with tafloprost use in patients with aphakia, as well as in pigmentary or pseudoexfoliative glaucoma, is limited.

Tafloprost 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 developing cystoid macular edema or iritis/uveitis.

There is no experience with the use of the drug in patients with severe asthma. Therefore, the drug should be used with caution in such patients.

Each drop of TAFLON® MULTIDOSE contains approximately 0.04 mg of phosphates, equivalent to a concentration of 1.2 mg/mL. In patients with severe corneal epithelial defects, phosphates may very rarely cause corneal clouding due to calcium accumulation during treatment.

Use during pregnancy or breastfeeding.

Women of childbearing potential / contraception

The medicinal product should not be used in women of childbearing potential who are not using effective contraception.

Pregnancy

There are no adequate data on the use of tafloprost in pregnant women. Tafloprost may have adverse pharmacological effects on pregnancy and/or the fetus/newborn. Animal studies have shown reproductive toxicity. Therefore, the medicinal product should not be used during pregnancy except in cases of urgent medical need (when no other treatment options are available).

Breastfeeding

It is unknown whether tafloprost and/or its metabolites are excreted in human breast milk. Studies in rats have shown excretion of tafloprost and/or its metabolites in milk after topical administration. Therefore, tafloprost should not be used during breastfeeding.

Fertility

In rats, intravenous administration of tafloprost at doses up to 100 mcg/kg/day had no effect on mating ability or fertilization.

Ability to influence reaction speed when driving or operating machinery.

Tafloprost does not affect the ability to drive or operate machinery. However, 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 dosing may reduce the intraocular pressure-lowering effect.

Use in elderly patients

Dosage adjustment is not required for elderly patients.

Use in patients with renal or hepatic impairment

Studies of tafluprost in patients with renal or hepatic impairment have not been conducted; therefore, it should be used with caution in such patients.

Method of Administration

Patients should be instructed on the proper handling of the bottle. When using the bottle for the first time, the patient should first learn how to use it by gently squeezing the bottle to dispense one drop of the medicinal product. The patient should be able to confidently administer one drop at a time. Otherwise, an alternative formulation of the same medicinal product without a preservative in single-dose packaging may be more suitable.

To prevent potential contamination of the solution, patients must not touch their eyelids, surrounding areas, or any other surfaces with the tip of the dispenser on the bottle. Any residual liquid remaining on the dispenser tip after instillation should be immediately removed by tapping the bottle downward once. The dispenser tip should not be touched or wiped.

To minimize the risk of eyelid skin pigmentation, patients should wipe away any excess solution from the skin. As with any other ophthalmic drops, closure of the nasolacrimal duct or gentle closure of the eyelids after administration is recommended. This may reduce systemic absorption of ophthalmically administered medicinal products.

After 28 days of use at the recommended dosage, approximately 1 mL of solution will remain in the bottle. Patients should not attempt to completely empty the bottle.

If a patient is using more than one ophthalmic medicinal product, the interval between administration of each product should be at least 5 minutes.

Children

The safety and efficacy of tafluprost in children (under 18 years of age) have not been established. Data are lacking.

When using a new bottle

Do not use the bottle if the pouch is damaged or if the plastic ring around the neck of the bottle is missing or damaged. Open the pouch along the dotted line. Record the date you opened the bottle in the space provided for the date on the cardboard carton.

Each time you use Taflotan® Multi

1. Wash your hands.

1. Open the bottle by pulling off the cap.
2. When using the bottle for the first time, press once to release one drop of the medication as waste.

Overdose.

Overdose after ocular administration is unlikely.

In case of overdose, treatment should be symptomatic.

Adverse Reactions.

During clinical studies, over 1400 patients received tafluprost with preservative as monotherapy or as adjunctive therapy to timolol 0.5%. The most frequently reported treatment-related adverse reaction was ocular hyperemia. It occurred in approximately 13% of patients participating in tafluprost with preservative clinical trials in Europe and the United States. In most cases, ocular hyperemia was mild and led to discontinuation of the drug in only an average of 0.4% of patients in the pivotal studies. In a 3-month Phase III study conducted in the United States comparing preservative-free tafluprost to preservative-free timolol, ocular hyperemia was observed in 4.1% (13 out of 320) of patients treated with tafluprost.

During clinical trials of tafluprost in Europe and the United States with a maximum observation period of 24 months, the treatment-related adverse reactions listed below were reported.

Within each frequency group, adverse reactions are listed in order of decreasing severity.

Systemic nervous system 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 hyperemia, eyelash changes (increased length, thickness, and number of eyelashes), dry eye syndrome, foreign body sensation in the eye, eyelash discoloration, 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 edema, asthenopia (eye strain), conjunctival edema, eye discharge, blepharitis, anterior chamber cell disturbances, eye discomfort, inflammatory anterior chamber hyperemia, conjunctival pigmentation, conjunctival follicles, allergic conjunctivitis, and abnormal eye sensations.

Unknown (cannot be estimated from available data): iritis (inflammation of the iris)/uveitis (inflammation of the uvea), deepening of the eyelid sulcus, macular edema/cystoid macular ed游戏副本.

In some patients with significant corneal damage, very rare cases of corneal calcification have been observed associated with the use of ophthalmic solutions containing phosphates.

Respiratory, thoracic and mediastinal disorders

Unknown (cannot be estimated from available data): asthma exacerbation, dyspnea.

Skin and subcutaneous tissue disorders

Uncommon (from ≥ 1/1,000 to < 1/100): eyelid hypertrichosis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization 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.

Shelf life.

3 years.

Use within 28 days after opening the bottle.

Storage conditions.

Store in the original packaging to protect from light at a temperature of 2 to 8°C.

Do not freeze.

Keep out of the reach of children.

After opening, store at a temperature not exceeding 25°C.

Packaging.

3 ml in a bottle with a dropper and a cap with a first-opening indicator. One bottle per cardboard box.

Prescription category.

Prescription only.

Manufacturer. Santen Oy.

Manufacturer's address and location of its operations.

Keltorintie 1, Tampere, 33100, Finland.