LATISSE Eyes drops, solution Ref.[10860] Active ingredients: Bimatoprost

5.1 Effects on Intraocular Pressure

Bimatoprost ophthalmic solution (LUMIGAN) lowers intraocular pressure (IOP) when instilled directly to the eye in patients with elevated IOP. In clinical trials, in patients with or without elevated IOP, LATISSE lowered IOP, however, the magnitude of the reduction was not cause for clinical concern.

In ocular hypertension studies with LUMIGAN, it has been shown that exposure of the eye to more than one dose of bimatoprost daily may decrease the intraocular pressure lowering effect. In patients using LUMIGAN or other prostaglandin analogs for the treatment of elevated intraocular pressure, the concomitant use of LATISSE may interfere with the desired reduction in IOP. Patients using prostaglandin analogs including LUMIGAN for IOP reduction should only use LATISSE after consulting with their physician and should be monitored for changes to their intraocular pressure.

5.2 Iris Pigmentation

Increased iris pigmentation has occurred when bimatoprost solution was administered. Patients should be advised about the potential for increased brown iris pigmentation which is likely to be permanent [see Adverse Reactions (6.2)].

The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. The long term effects of increased pigmentation are not known. Iris color changes seen with administration of bimatoprost ophthalmic solution 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. Treatment with LATISSE solution can be continued in patients who develop noticeably increased iris pigmentation.

5.3 Lid Pigmentation

Bimatoprost has been reported to cause pigment changes (darkening) to periorbital pigmented tissues and eyelashes. The pigmentation is expected to increase as long as bimatoprost is administered, but has been reported to be reversible upon discontinuation of bimatoprost in most patients.

5.4 Hair Growth Outside the Treatment Area

There is the potential for hair growth to occur in areas where LATISSE solution comes in repeated contact with the skin surface. It is important to apply LATISSE only to the skin of the upper eyelid margin at the base of the eyelashes using the accompanying sterile applicators, and to carefully blot any excess LATISSE from the eyelid margin to avoid it running onto the cheek or other skin areas.

5.5 Intraocular Inflammation

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

5.6 Macular Edema

Macular edema, including cystoid macular edema, has been reported during treatment with bimatoprost ophthalmic solution (LUMIGAN) for elevated IOP. LATISSE 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.

5.7 Contamination of LATISSE or Applicators

The LATISSE bottle must be kept intact during use. It is important to use LATISSE solution as instructed, by placing one drop on the single-use-per-eye applicator. The bottle tip should not be allowed to contact any other surface since it could become contaminated. The accompanying sterile applicators should only be used on one eye and then discarded since reuse of applicators increases the potential for contamination and infections. There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products [see Patient Counseling Information (17)].

5.8 Use with Contact Lenses

LATISSE contains benzalkonium chloride, which may be absorbed by and cause discoloration of soft contact lenses. Contact lenses should be removed prior to application of solution and may be reinserted 15 minutes following its administration.

The following adverse reactions are described elsewhere in the labeling:

• Effects on Intraocular Pressure [see Warnings and Precautions (5.1)]
• Iris Pigmentation [see Warnings and Precautions (5.2)]
• Lid Pigmentation [see Warnings and Precautions (5.3)]
• Hair Growth Outside the Treatment Area [see Warnings and Precautions (5.4)]
• Intraocular Inflammation [see Warnings and Precautions (5.5)]
• Macular Edema [see Warnings and Precautions (5.6)]
• Hypersensitivity [see Contraindications (4)]

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

The following information is based on clinical trial results from a multicenter, double-masked, randomized, vehicle-controlled, parallel study including 278 adult patients for four months of treatment.

The most frequently reported adverse reactions were eye pruritus, conjunctival hyperemia, skin hyperpigmentation, ocular irritation, dry eye symptoms, and periorbital erythema. These reactions occurred in less than 4% of patients. Additional adverse reactions seen in clinical trials experience include foreign body sensation, hair growth abnormal, and iris hyperpigmentation.

Additional adverse reactions reported with bimatoprost ophthalmic solution (LUMIGAN) for the reduction of intraocular pressure include, ocular dryness, visual disturbance, ocular burning, eye pain, blepharitis, cataract, superficial punctate keratitis, eye discharge, tearing, photophobia, allergic conjunctivitis, asthenopia, conjunctival edema, iritis, infections (primarily colds and upper respiratory tract infections), headaches, and asthenia.

The following adverse reactions have been identified during postapproval use of LATISSE. Because these 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. The reactions include: dry skin of the eyelid and/or periocular area, eye swelling, eyelid edema, hordeolum, hypersensitivity (local allergic reactions), lacrimation increased, madarosis and trichorrhexis (temporary loss of a few lashes to loss of sections of eyelashes, and temporary eyelash breakage, respectively), periorbital and lid changes associated with a deepening of the eyelid sulcus, rash (including macular and erythematous), skin discoloration (periorbital), trichiasis, and vision blurred.

Risk Summary

There are no adequate and well-controlled studies of LATISSE (bimatoprost ophthalmic solution) 0.03% administration in pregnant women. There is no increase in the risk of major birth defects or miscarriages based on bimatoprost postmarketing experience.

In embryofetal development studies, administration of bimatoprost to pregnant mice and rats during organogenesis, resulted in abortion and early delivery at oral doses at least 33 times (mice) or 94 times (rats) the human exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on the area under the curve (AUC). These adverse effects were not observed at 2.6 times (mice) and 47 times (rats) the human exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC.

In pre/postnatal development studies, administration of bimatoprost to pregnant rats from organogenesis to the end of lactation resulted in reduced gestation length and fetal body weight, and increased fetal and pup mortality at oral doses at least 41 times the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC. No adverse effects were observed in rat offspring at exposures estimated at 14 times the human exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC.

Because animal reproductive studies are not always predictive of human response LATISSE 0.03% should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Data

Animal Data

In an embryofetal development rat study, abortion was observed in pregnant rats administered bimatoprost orally during organogenesis at 0.6 mg/kg/day (94 times the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC). The No Observed Adverse Effect Level (NOAEL) for abortion was 0.3 mg/kg/day (estimated at 47 times the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily based on AUC). No abnormalities were observed in rat fetuses at doses up to 0.6 mg/kg/day.

In an embryofetal development mouse study, abortion and early delivery were observed in pregnant mice administered bimatoprost orally during organogenesis at doses greater than or equal to 0.3 mg/kg/day (33 times the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC). The NOAEL for abortion and early delivery was 0.1 mg/kg/day (2.6 times the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC) . No abnormalities were observed in mouse fetuses at doses up to 0.6 mg/kg/day (72 times the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC).

In a pre/postnatal development study, treatment of pregnant rats with bimatoprost orally from gestation day 7 to lactation day 20 resulted in reduced gestation length, increased late resorptions, fetal deaths, and postnatal pup mortality, and reduced pup body weight at doses greater than or equal to 0.3 mg/kg/day. These effects were observed at exposures at least 41 times the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC. The NOAEL for postnatal development and mating performance of the offspring was 0.1 mg/kg/day (estimated at 14 times the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily, based on AUC).

Risk Summary

It is not known whether topical ocular treatment with LATISSE 0.03% could result in sufficient systemic absorption to produce detectable quantities in human milk. In animal studies, bimatoprost has been shown to be present in breast milk of lactating rats at an intravenous dose (i.e., 1 mg/kg) 324 times the recommended human ophthalmic dose (on a mg/m² basis), however no animal data is available at clinically relevant doses.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LATISSE 0.03% and any potential adverse effects on the breastfed child from LATISSE 0.03%.

Use of LATISSE was evaluated in a sixteen week double-masked, randomized, vehicle-controlled study conducted in pediatric patients who were post-chemotherapy or had alopecia areata, and adolescents who had hypotrichosis with no associated medical condition. No new safety issues were observed. The results of the Global Eyelash Assessment are provided in Table 1.

Table 1. Number (%) of subjects with at least a 1-grade increase from baseline at month 4 in Global Eyelash Assessment:

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