LATISSE (Page 3 of 5)

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]-N -ethyl-5-heptenamide, and its molecular weight is 415.58. Its molecular formula is C25 H37 NO4 .Its chemical structure is:

chemical structure
(click image for full-size original)

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.

Elimination

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.

Excretion

Following an intravenous dose of radiolabeled bimatoprost (3.12 mcg/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

Carcinogenesis

Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage for 104 weeks at doses up to 2 mg/kg/day and 1 mg/kg/day, respectively (192 and 291 times the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily based on blood AUC levels).

Mutagenesis

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

Impairment of Fertility

Bimatoprost did not impair fertility in male or female rats up to doses of 0.6 mg/kg/day (103 times the human systemic exposure following topical ophthalmic administration of bimatoprost 0.03% to the cornea or conjunctival sac bilaterally once daily based on blood AUC levels).

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 2. Number (%) of subjects with at least a 1-grade increase from baseline in Global Eyelash Assessment (Primary Efficacy Endpoint – Week 16)
Week LATISSE ® N=137N (%) Vehicle N=141N (%)
1 7 (5%) 3 (2%)
4 20 (15%) 11 (8%)
8 69 (50%) 21 (15%)
12 95 (69%) 28 (20%)
16 107 (78%) 26 (18%)
20 103 (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 3
Efficacy endpoint at Week 16(Mean Change from Baseline) LATISSE ® Vehicle
Eyelash growth (length) (mm; % increase) N=1371.4; 25% N=1410.1; 2%
Fullness/thickness (mm2 ; % 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%

* a negative value is representative of eyelash darkening

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.

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