Taflotan

Tafluprost.

Each mL contains 15μg of tafluprost.
Its pH is 5.7 - 6.3 and its osmolar ratio is 1.0 - 1.1.
Excipients/Inactive Ingredients: Polysorbate 80, concentrated glycerin, disodium edetate hydrate, sodium dihydrogen phosphate dihydrate, benzalkonium chloride, sodium hydroxide, hydrochloric acid.

Pharmacology: 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 at the concentration of 0.0005% and higher, compared to 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 to the repeated administration of 0.005% tafluprost ophthalmic solution once daily for 3 to 5 days. Uveoscleral outflow was significantly increased without any change in the aqueous production.
Effect On Ocular Blood Flow: (1) A repeated instillation of 0.0015% tafluprost ophthalmic solution 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 0.0015% tafluprost ophthalmic solution into eyes of open-angle glaucoma patients significantly increased the blood flow rate in the optic disc.
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 0.0015% tafluprost ophthalamic solution was 6.6 mmHg (95% confidence interval: 5.8-7.3 mmHg), which demonstrated non inferiority to the comparator. (See Table 1.)

Click on icon to see table/diagram/image

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 0.0015% tafluprost ophthalmic solution was 4.0 mmHg (95% confidence Interval: 3.5-4.5 mmHg), which showed significant IOP-lowering effect compared with placebo. (See Table 2.)

Click on icon to see table/diagram/image

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 0.0015% tafluprost ophthalmic solution 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. (See figure.)
*Cohort 1: 22-34 mmHg at baseline.
Cohort 2: 16-21 mmHg at baseline.

Click on icon to see table/diagram/image

Reference studies with a tafluprost formulation 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 timepoints 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 24 and 12 months, respectively. 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.

Reduction of intraocular pressure in patients with primary open-angle glaucoma or ocular hypertension.

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

Patients with a history of hypersensitivity to any of the ingredients of Taflotan.

Do not use more than once daily because more frequent administration may lessen the IOP-lowering effect.
Taflotan should be administered with care to the following: Patients with aphakia or pseudophakia [other drugs in this category have been reported to induce macular oedema including cystoid macular oedema and associated with visual acuity reduced].
Patients with bronchial asthma or history of bronchial asthma [Taflotan may aggravate or induce asthmatic attack].
Patient with endophthalmitis (iritis, uveitis) [other drugs in this category have been reported to cause elevation of intraocular pressure].
Pregnant, parturient and lactating women [see Pregnancy & Lactation].
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 cases that 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 the eyes.
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.
Taflotan should be administered with care because there is no clinical experience in patients with closed angle glaucoma.
Effects on the Ability to Drive or Operate Machinery: Temporary blurred vision may develop after administration of Taflotan. Patients should be given instructed to refrain from activities like driving or operating machines until such symptoms disappear.
Pediatric Use: The safety of Taflotan to low birth weight infants, neonates, infants or children has not been established. (No clinical experience.)
Use in the Elderly: Because physiological function is generally reduced in the elderly, caution should be exercised.

Use in Pregnancy: Taflotan 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 10μg/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 (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 dose.]
* Dosage (0.015 μg//kg/day) when one drop (30μL) of this product is instilled into both eyes at a time for a 60 kg patient.
Use in Lactation: 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.]

The following safety data were based on the clinical study result of tafluprost ophthalmic solution 0.0015% containing benzalkonium chloride.
Upon Approval: Adverse drug reactions (including abnormal change in laboratory test values) were reported in 326 of 483 patients (67.5%) in clinical studies in Japan. 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: Adverse drug reactions were reported in 396 of 3,260 patients (12.1%) in post-marketing surveillance in Japan. 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.
Clinically significant adverse drug 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.
Other adverse drug reactions: If an adverse drug reaction is observed, appropriate measures including discontinuing administration should be taken. (See Table 3.)

Click on icon to see table/diagram/image

Precautions concerning Use: Route of administration: For opththalmic use only.
At the time of administration: The following should be instructed to patients: Be careful not to touch the tip of the bottle to the eye directly in order to avoid the contamination of the Taflotan.
Wipe off or wash the face immediately when any excess solution touches the skin around the eye.
When more than one ophthalmic drug is used, at least 5 minutes of intervals should be taken.
Contact lenses should be removed prior to administration as benzalkonium chloride contained may cause discoloration of the lenses. Wait for at least 15 minutes before wearing the contact lenses again.

Store at or below 30°C. Discard contents one month after opening.

Antiglaucoma Preparations

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

POM

Ophth soln 0.0015% (clear, colorless, sterile aqueous solution) x 2.5 mL.