Latisse (Page 2 of 4)

8.3 Nursing Mothers

It is not known whether LATISSE® solution is excreted in human milk, although in animal studies, bimatoprost has been shown to be excreted in breast milk. Because many drugs are excreted in human milk, caution should be exercised when LATISSE® is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

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

11 DESCRIPTION

LATISSE™ (bimatoprost ophthalmic solution) 0.03% is a synthetic prostaglandin analog. Its chemical name is (Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-N-ethylheptenamide, and its molecular weight is 415.58. Its molecular formula is C25 H37 NO4. Its chemical structure is:

image of chemical structure

Bimatoprost is a powder, which is very soluble in ethyl alcohol and methyl alcohol and slightly soluble in water. LATISSE™ is a clear, isotonic, colorless, sterile ophthalmic solution with an osmolality of approximately 290 mOsmol/kg.

Contains: Active: bimatoprost 0.3 mg/mL; Preservative: benzalkonium chloride 0.05 mg/mL; Inactives: sodium chloride; sodium phosphate, dibasic; citric acid; and purified water. Sodium hydroxide and/or hydrochloric acid may be added to adjust pH. The pH during its shelf life ranges from 6.8 — 7.8.

12 CLINICAL PHARMACOLOGY


12.1 Mechanism of Action

Bimatoprost is a structural prostaglandin analog. Although the precise mechanism of action is unknown the growth of eyelashes is believed to occur by increasing the percent of hairs in, and the duration of the anagen or growth phase.

12.3 Pharmacokinetics

Absorption

After one drop of bimatoprost ophthalmic solution 0.03% was administered once daily into both eyes (cornea and/or conjunctival sac) of 15 healthy subjects for two weeks, blood concentrations peaked within 10 minutes after dosing and were below the lower limit of detection (0.025 ng/mL) in most subjects within 1.5 hours after dosing. Mean Cmax and AUC0-24hr values were similar on days 7 and 14 at approximately 0.08 ng/mL and 0.09 ng•hr/mL, respectively, indicating that steady state was reached during the first week of ocular dosing. There was no significant systemic drug accumulation over time.

Distribution

Bimatoprost is moderately distributed into body tissues with a steady-state volume of distribution of 0.67 L/kg. In human blood, bimatoprost resides mainly in the plasma. Approximately 12% of bimatoprost remains unbound in human plasma.

Metabolism

Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation. Bimatoprost then undergoes oxidation, N-deethylation, and glucuronidation to form a diverse variety of metabolites.

Elimination

Following an intravenous dose of radiolabeled bimatoprost (3.12 μg/kg) to six healthy subjects, the maximum blood concentration of unchanged drug was 12.2 ng/mL and decreased rapidly with an elimination half-life of approximately 45 minutes. The total blood clearance of bimatoprost was 1.5 L/hr/kg. Up to 67% of the administered dose was excreted in the urine while 25% of the dose was recovered in the feces.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 2 mg/kg/day and 1 mg/kg/day respectively (approximately 192 and 291 times the recommended human exposure based on blood AUC levels after topical corneal and/or conjunctival sac administration respectively) for 104 weeks.

Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo mouse micronucleus tests.

Bimatoprost did not impair fertility in male or female rats up to doses of 0.6 mg/kg/day.

14 CLINICAL STUDIES

LATISSE™ solution was evaluated for its effect on overall eyelash prominence in a multicenter, double-masked, randomized, vehicle-controlled, parallel study including 278 adult patients for four months of treatment. The primary efficacy endpoint in this study was an increase in overall eyelash prominence as measured by at least a 1-grade increase on the 4-point Global Eyelash Assessment (GEA) scale, from baseline to the end of the treatment period (week 16). LATISSE™ was more effective than vehicle as measured by the GEA score, with statistically significant differences seen at 8-week, 12-week, and 16-week (primary endpoint) treatment durations.

Table 1 Number (%) of subjects with at least a 1-grade increase from baseline in Global Eyelash Assessment (Primary Efficacy Endpoint – Week 16)
WeekLATISSE™ N=137N (%)VehicleN=141N (%)
17 (5%)3 (2%)
420 (15%)11 (8%)
869 (50%)21 (15%)
1295 (69%)28 (20%)
16 107 (78%) 26 (18%)
20103 (79%)27 (21%)

In this study, patients were also evaluated for the effect of LATISSE™ solution on the length, thickness and darkness of their eyelashes. Improvements from baseline in eyelash growth as measured by digital image analysis assessing eyelash length, fullness/thickness, and darkness were statistically significantly more pronounced in the bimatoprost group at weeks 8, 12, and 16.

Table 2
Efficacy endpoint at Week 16LATISSE ® Vehicle
(Mean Change from Baseline)
Eyelash growth (length)(mm; % increase)N=1371.4; 25%N=1410.1; 2%
Fullness/thicknessmm2 ; % increase)N=1360.7; 106%N=1400.1; 12%
Eyelash darkness (intensity*; % increase in darkness)N=135-20.2; -18%N=138-3.6; -3%

After the 16-week treatment period, a 4-week post-treatment period followed during which the effects of bimatoprost started to return toward baseline. The effect on eyelash growth is expected to abate following longer term discontinuation.

16 HOW SUPPLIED/STORAGE AND HANDLING

LATISSE™ (bimatoprost ophthalmic solution) 0.03% is supplied sterile in opaque white low density polyethylene dispenser bottles and tips with turquoise polystyrene caps accompanied by 60 sterile, disposable applicators:

3 mL in a 5 mL bottle NDC 54868-6053-0

Storage: LATISSE™ should be stored at 2° to 25°C (36° to 77°F).

17 PATIENT COUNSELING INFORMATION


17.1 Nightly Application

Patients should be informed that LATISSE® (bimatoprost ophthalmic solution) should be applied every night using only the accompanying sterile applicators. They should start by ensuring their face is clean, all makeup is removed, and their contact lenses removed (if applicable). Then carefully place one drop of LATISSE® solution on the disposable sterile applicator and brush cautiously along the skin of the upper eyelid margin at the base of the eyelashes. If any LATISSE® solution gets into the eye proper, it will not cause harm. The eye should not be rinsed.

Additional applications of LATISSE® will not increase the growth of eyelashes.

Patients should be informed not to apply to the lower eyelash line. Any excess solution outside the upper eyelid margin should be blotted with a tissue or other absorbent material.

The onset of effect is gradual but is not significant in the majority of patients until 2 months. Patients should be counseled that the effect is not permanent and can be expected to gradually return to the original level upon discontinuation of treatment with LATISSE® .

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