5.1 Pigmentation

Tafluprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Pigmentation is expected to increase as long as tafluprost is administered. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of tafluprost, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. The long term effects of increased pigmentation are not known.

Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with tafluprost ophthalmic solution can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly. [See Patient Counseling Information (17.3)].

5.2 Eyelash Changes

Tafluprost ophthalmic solution may gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, color, thickness, shape and number of lashes. Eyelash changes are usually reversible upon discontinuation of treatment.

5.3 Intraocular Inflammation

Tafluprost ophthalmic solution should be used with caution in patients with active intraocular inflammation (e.g., iritis/uveitis) because the inflammation may be exacerbated.

5.4 Macular Edema

Macular edema, including cystoid macular edema, has been reported during treatment with prostaglandin F2α analogs. Tafluprost ophthalmic solution should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.

6.1 Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Preservative-containing or preservative-free tafluprost 0.0015% was evaluated in 905 patients in five controlled clinical studies of up to 24-months duration. The most common adverse reaction observed in patients treated with tafluprost was conjunctival hyperemia which was reported in a range of 4% to 20% of patients. Approximately 1% of patients discontinued therapy due to ocular adverse reactions.

Ocular adverse reactions reported at an incidence of ≥ 2% in these clinical studies included ocular stinging/irritation (7%), ocular pruritus including allergic conjunctivitis (5%), cataract (3%), dry eye (3%), ocular pain (3%), eyelash darkening (2%), growth of eyelashes (2%) and vision blurred (2%).

Nonocular adverse reactions reported at an incidence of 2% to 6% in these clinical studies in patients treated with tafluprost 0.0015% were headache (6%), common cold (4%), cough (3%) and urinary tract infection (2%).

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of tafluprost. Because postapproval adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory disorders: exacerbation of asthma, dyspnea

Eye disorders: iritis/uveitis

In postmarketing use with prostaglandin analogs, periorbital and lid changes including deepening of the eyelid sulcus have been observed.

8.1 Pregnancy

Pregnancy Category C.

Teratogenic effects: In embryo-fetal development studies in rats and rabbits, tafluprost administered intravenously was teratogenic. Tafluprost caused increases in post-implantation losses in rats and rabbits and reductions in fetal body weights in rats. Tafluprost also increased the incidence of vertebral skeletal abnormalities in rats and the incidence of skull, brain and spine malformations in rabbits. In rats, there were no adverse effects on embryo-fetal development at a dose of 3 mcg/kg/day corresponding to maternal plasma levels of tafluprost acid that were 343 times the maximum clinical exposure based on Cmax. In rabbits, effects were seen at a tafluprost dose of 0.03 mcg/kg/day corresponding to maternal plasma levels of tafluprost acid during organogenesis that were approximately 5 times higher than the clinical exposure based on Cmax. At the no-effect dose in rabbits (0.01 mcg/kg/day), maternal plasma levels of tafluprost acid were below the lower level of quantification (20 pg/mL).

In a pre- and postnatal development study in rats, increased mortality of newborns, decreased body weights and delayed pinna unfolding were observed in offsprings. The no observed adverse effect level was at a tafluprost intravenous dose of 0.3 mcg/kg/day which is greater than 3 times the maximum recommended clinical dose based on body surface area comparison.

There are no adequate and well-controlled studies in pregnant woman. Although animal reproduction studies are not always predictive of human response, tafluprost ophthalmic solution should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

Women of childbearing age/potential should have adequate contraceptive measures in place.

8.3 Nursing Mothers

A study in lactating rats demonstrated that radio-labeled tafluprost and/or its metabolites were excreted in milk. It is not known whether this drug or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tafluprost ophthalmic solution is administered to a nursing woman.

8.4 Pediatric Use

Use in pediatric patients is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use.

8.5 Geriatric Use

No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients.

12.1 Mechanism of Action

Tafluprost acid, a prostaglandin analog is a selective FP prostanoid receptor agonist which is believed to reduce intraocular pressure by increasing uveoscleral outflow. The exact mechanism of action is unknown at this time.

12.3 Pharmacokinetics

Absorption

Following instillation, tafluprost is absorbed through the cornea and is hydrolyzed to the biologically active acid metabolite, tafluprost acid. Following instillation of one drop of the 0.0015% solution once daily into each eye of healthy volunteers, the plasma concentrations of tafluprost acid peaked at a median time of 10 minutes on both Days 1 and 8. The mean plasma Cmax of tafluprost acid were 26 pg/mL and 27 pg/mL on Day 1, and Day 8, respectively. The mean plasma AUC estimates of tafluprost acid were 394 pg*min/mL and 432 pg*min/mL on Day 1 and 8, respectively.

Metabolism

Tafluprost, an ester prodrug, is hydrolyzed to its biologically active acid metabolite in the eye. The acid metabolite is further metabolized via fatty acid β-oxidation and phase II conjugation.

Elimination

Mean plasma tafluprost acid concentrations were below the limit of quantification of the bioanalytical assay (10 pg/mL) at 30 minutes following topical ocular administration of tafluprost 0.0015% ophthalmic solution.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Tafluprost was not carcinogenic when administered subcutaneously daily for 24 months at doses up to 30 mcg/kg/day in rats and for 18 months at doses up to 100 mcg/kg/day in mice (over 1600 and 1300 times, respectively, the maximum clinical exposure based on plasma AUC).

Tafluprost was not mutagenic or clastogenic in a battery of genetic toxicology studies, including an in vitro microbial mutagenesis assay, an in vitro chromosomal aberration assay in Chinese hamster lung cells, and an in vivo mouse micronucleus assay in bone marrow.

In rats, no adverse effects on mating performance or fertility were observed with intravenous dosing of tafluprost at a dose of 100 mcg/kg/day (over 14000 times the maximum clinical exposure based on plasma Cmax or over 3600 times based on plasma AUC).

17.1 Nightly Application

Advise patients to not exceed once daily dosing since more frequent administration may decrease the intraocular pressure lowering effect of tafluprost ophthalmic solution.

17.2 Handling the Single-Dose Container

Advise patients that tafluprost ophthalmic solution is a sterile solution that does not contain a preservative. The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be maintained after the individual unit is opened, the remaining contents should be discarded immediately after administration.

17.3 Potential for Pigmentation

Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent. Also inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation of tafluprost ophthalmic solution.

17.4 Potential for Eyelash Changes

Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with tafluprost ophthalmic solution. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment.

17.5 When to Seek Physician Advice

Advise patients that if they develop a new ocular condition (e.g., trauma or infection), experience a sudden decrease in visual acuity, have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician's advice concerning the continued use of tafluprost ophthalmic solution.

17.6 Use with Other Ophthalmic Drugs

If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes between applications.

17.7 Storage Information

Instruct patients on proper storage of cartons, unopened foil pouches, and opened foil pouches [see How Supplied/Storage and Handling (16)]. Recommended storage for cartons and unopened foil pouches is to store refrigerated at 2º to 8°C (36º to 46°F). After the pouch is opened, the single-dose containers may be stored in the opened foil pouch for up to 28 days at room temperature 20º to 25°C (68º to 77°F). Protect from moisture.

Manufactured for:

Ingenus Pharmaceuticals, LLC

Orlando, FL 32811-7193

Made in France

Rx Only