Taflotan-S

Tafluprost.

See Table 1.

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Nonproprietary name: Tafluprost
Chemical name: 1-Methylethyl (5Z)-7-{(1R, 2R, 3R, 5S)-2-[(1E)-3,3-difluoro-4-phenoxy-1-butenyl]-3,5-dihydroxycyclopentyl}-5-heptenoate
Molecular formula: C₂₅H₃₄F₂O₅
Molecular weight: 452.53
Tafluprost occurs as a colorless to light yellow, viscous liquid. It is very soluble in ethanol, diethyl ether and acetonitrile, and practically insoluble in water.

Pharmacology: Pharmacodynamics: Intraocular pressure (IOP) lowering effect: Ocular administration of tafluprost ophthalmic solutions ranged from 0.00002% to 0.005% in a single dose to monkeys showed the IOP lowering effect in a concentration-dependent manner. The effect was statistically significant in the groups of the concentration of 0.0005% and higher, compared with the vehicle group. In a repeated dose study in monkeys of tafluprost ophthalmic solutions ranged from 0.001% to 0.005% once daily for 5 days, IOP lowering effect at every concentration was stable and did not attenuate during the administration period.
Mechanism of action: Tafluprost acid form, an active metabolite, showed high affinity for the prostanoid FP receptor (Ki=0.40 nM). Aqueous humor dynamics in monkeys was evaluated using fluorophotometry, two-level constant pressure perfusion and ¹²⁵I-¹³¹I labeled albumin perfusion methods following the repeated administration of 0.005% tafluprost ophthalmic solution once daily for 3 to 5 days. Uveoscleral outflow significantly increased without any change in aqueous production.
Effect on ocular blood flow: 1) A repeated instillation of this product into rabbit eyes once daily for 28 days significantly increased the blood flow in the optic nerve head, measured with laser speckle method.
2) A single dose instillation of this product into eyes of healthy adults significantly increased the blood flow rate in the paraoptic nerve head retinal artery and the blood flow at the paraoptic nerve head retina.
Clinical Studies: In a randomized blind comparative study in 109 patients with primary open angle glaucoma or ocular hypertension using latanoprost ophthalmic solution as a comparator, the decrease in intraocular pressure (IOP) for this product was 6.6 mmHg (95% confidence interval: 5.8-7.3 mmHg), which demonstrated non inferiority to the comparator. (See Table 2.)

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In a randomized blind comparative study in 94 patients with normal tension glaucoma using placebo ophthalmic solution as a comparator, the decrease in IOP for this product was 4.0 mmHg (95% confidence interval: 3.5-4.5 mmHg), which showed significant IOP lowering effect compared with placebo. (See Table 3.)

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In a long-term administration study in 351 patients with open angle glaucoma including normal tension glaucoma, or patients with ocular hypertension, the decrease in IOP for this product remained between 4.9 and 5.7 mmHg for 52 weeks, which demonstrated stable IOP lowering effect in long-term administration. IOP decrease was 6.0-6.9 mmHg in cohort 1* and 3.4-4.0 mmHg in cohort 2 over 52 weeks.
*Cohort 1: 22-34 mmHg at baseline.
Cohort 2: 16-21 mmHg at baseline. (See Figure.)

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Pharmacokinetics: Plasma concentrations: When 0.0025% or 0.005% tafluprost ophthalmic solution was instilled one drop once daily for 7 days in both eyes of 7 healthy adult volunteers, the plasma concentrations of tafluprost and its active metabolite, tafluprost acid form, were below the quantitation limits (tafluprost; 0.2 ng/mL, tafluprost acid form; 0.1 ng/mL) at every time point, except in one volunteer of the 0.0025% group at 15 minutes after instillation on Day 1, with the concentration of tafluprost acid form being 0.144 ng/mL.
(Note: The concentration of this product is 0.0015%.)
Ocular tissue distribution in animals (monkeys): Following a single ocular instillation of 0.005% ³H-tafluprost ophthalmic solution to monkeys, the radioactivity was distributed in the ocular tissues rapidly and reached the maximum radioactive concentrations in the cornea and conjunctiva at 5 to 15 minutes after instillation; in the aqueous humor, iris, ciliary body and lens at 2 hours after instillation, and was eliminated rapidly.

Glaucoma and ocular hypertension.

Instill 1 drop in the affected eye(s) once daily.

Patients with a history of hypersensitivity to any of the ingredients of this product.

Do not use more than once daily because more frequent administration may lessen the IOP lowering effect.
Careful administration (This product should be administered with care to the following patients): 1) Patients with aphakia or pseudophakia [this product may induce macular oedema including cystoid macular oedema, and the associated visual acuity reduced.]
2) Patients with bronchial asthma or a history of bronchial asthma [this product may aggravate or induce asthmatic attack.]
3) Patients with endophthalmitis (iritis, uveitis) [other drugs in this category have been reported to cause elevation of intraocular pressure.]
4) Pregnant, parturient and lactating women [see Use in Pregnancy & Lactation].
Important precautions: 1) Pigmentation in iris and eyelid (increased melanin content), or hypertrichosis around the eyes may occur. These symptoms gradually progress with continued administration, and stop when the treatment is discontinued. The symptoms like blepharal pigmentation and hypertrichosis around the eyes can gradually disappear or diminish after the administration is discontinued, however, there are reports of the cases that the symptom of iris pigmentation persists even after the administration was discontinued. In such cases, iris color change can be detected clearly in patients with mixed-colored irises and even in patients with single-color dark brown irises (seen among most Japanese) as well. The difference in iris color between right and left eyes could be noted particularly in the case of unilateral administration. As long-term observation data about these symptoms are not yet available, doctors are required to closely observe patients through periodic checkups. Patients should be well informed of the possibility of these symptoms and instructed to wipe off any excess solution from the skin around the eye or to wash the face in order to prevent blepharal pigmentation or hypertrichosis around eyes.
2) Corneal epithelium disorder (superficial punctate keratitis, filamentary keratitis or corneal erosion) may occur during the treatment. Instruct patients to consult a doctor immediately if subjective symptoms including smarting pain, itching and eye pain continue.
3) This product should be administered with care because there is no clinical experience in patients with closed angle glaucoma.
4) Temporary blurred vision may develop after administration of this product. Patients should be instructed to refrain from activities like driving or operating machines until the symptom disappears.
Use in children: The safety of this product to low birth weight infants, neonates, infants or children has not been established. (No clinical experience.)
Use in elderly: Because physiological function is generally reduced in the elderly, caution should be exercised.

This product should be used in pregnant women or women who may possibly be pregnant only if the expected therapeutic benefits are judged to outweigh the possible risks associated with the treatment. [The safety of this product for use during pregnancy has not been established. In animal studies, when tafluprost solution was administered intravenously to pregnant rats at a dose of 30 μg/kg/day (2000 times the clinical dose*), teratogenicity and post-implantation embryonic mortality rate increased; at 10 μg/kg/day (about 670 times the clinical dose*) adverse effect on fetal development (low body weight and unossification of breast bone in fetuses) was observed. In an intravenous administration in pregnant rabbits at 0.1 μg/kg/day (about 6.7 times the clinical dose*), miscarriage and mortality rate after implantation increased, and luteal body and implantation decreased; at 0.03 μg/kg/day (2 times the clinical dose*) teratogenicity was observed. In an intravenous administration study in pregnant and lactating rats at a dose level of 1 μg/kg/day (about 67 times the clinical dose*), mal-nursing of dams was observed and 4-day survival rate of new born baby decreased. On the other hand, in the study using uteri isolated from rats, uterine contraction was observed at about 3.3 times the plasma concentration of tafluprost (less than 30 pg/mL), or about 420 times the plasma concentration of unbound tafluprost (less than 0.24 pg/mL), calculated based on protein binding ratio, estimated after ocular administration of the clinical dosage.]
*Dosage (0.015 μg/kg/day) when one drop (30 μL) of this product is instilled into both eyes at a time for a 60 kg patient.
Avoid administration to nursing mothers. If administration is judged to be essential, the patients should be instructed to stop breast-feeding during the treatment. [A study in rats has shown excretion of tafluprost in breast milk after ocular instillation.]

Following safety data were derived from tafluprost ophthalmic solution 0.0015% containing benzalkonium chloride.
At the time of approval: Adverse drug reactions (including abnormal change in laboratory test values) were reported in 326 of 483 patients (67.5%). The major adverse drug reactions were conjunctival hyperaemia in 151 patients (31.3%), abnormality in eyelashes in 93 patients (19.3%), itching in 85 patients (17.6%), eye irritation in 65 patients (13.5%), iris pigmentation in 39 patients (8.1%), etc.
Post-marketing surveillance (Upon issuance of the 5th Periodic Safety Update Report): Adverse drug reactions were reported in 396 of 3,260 patients (12.1%). The major adverse drug reactions were blepharal pigmentation in 93 patients (2.9%), conjunctival hyperaemia in 74 patients (2.3%), corneal epithelium disorder including corneal erosion in 58 patients (1.8%), hypertrichosis of eyelids in 40 patients (1.2%), abnormality in eyelashes in 39 patients (1.2%), etc.
1) Clinically significant adverse reactions: Iris pigmentation (8.1%): Since iris pigmentation may occur, patients should be examined periodically, and administration should be discontinued depending on the clinical status when iris pigmentation is observed.
2) Other adverse reactions: If an adverse drug reaction is observed, appropriate measures including discontinuing administration should be taken. (See Table 4.)

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Incidence was calculated based on the clinical study results up to the approval of tafluprost ophthalmic solution 0.0015% containing benzalkonium chloride.

Precautions concerning use: 1) Route of administration: Ophthalmic use only.
2) At the time of administration: Followings should be instructed to patients. (1) Be careful not to touch the tip of the container to the eye directly in order to avoid the contamination of the drug.
(2) Wipe off or wash the face immediately when any excess solution touches the skin around the eye.
(3) When more than one ophthalmic drug is used, at least 5 minutes of intervals should be taken.
(4) Discard 1 or 2 drops before use (in order to eliminate fragments of container possibly contaminated upon opening the container).
(5) Discard any remaining solution once the eyedropper is opened. This product is a sterilized single-use disposable medical product, and contains no preservative agents for prevention of cross contamination.
Instruction for Handling: After opening the aluminum foil pouch, store in a refrigerator (2-8°C) under protection from light and use within 6 months. If the product is stored below 25°C after opening under protection from light, it should be used within one month. Use the product in the pouch which has been opened first.

Store in a refrigerator (2-8°C) under protection from light.
Indicated on the package and aluminum foil pouch (3 years).

How to apply this ophthalmic solution: 1) Separate one container for one time use.
2) Hold the tip (the part which contains no fluid), twist and remove.
3) Discard 1 or 2 drops before use.
4) Do not allow the eye dropper nozzle to touch the eye.

Antiglaucoma Preparations

S01EE05 - tafluprost ; Belongs to the class of prostaglandin analogues. Used in the treatment of glaucoma.

P₁S₁S₃