Ivermectin (Page 2 of 3)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of ivermectin cream in treating rosacea lesions is unknown.

12.2 Pharmacodynamics

Cardiac Electrophysiology

At therapeutic doses, ivermectin cream is not expected to prolong QTc interval.

12.3 Pharmacokinetics

Absorption

The absorption of ivermectin from ivermectin cream was evaluated in a clinical trial in 15 adult male and female subjects with severe papulopustular rosacea applying 1 g ivermectin cream, 1% once daily. At steady state (after 2 weeks of treatment), the highest mean ± standard deviation) plasma concentrations of ivermectin peaked (Tmax ) at 10 hours ± 8 hours post-dose, the maximum concentration (Cmax ) was 2.10 ng/mL ± 1.04 ng/mL (range: 0.69 ng/mL to 4.02 ng/mL) and the area under the concentration curve (AUC0-24hr ) was 36.14 ng.hr/mL ± 15.56 ng.hr/mL (range: 13.69 ng.hr/mL to 75.16 ng.hr/mL). In addition, systemic exposure assessment in longer treatment duration (Phase 3 studies) showed that there was no plasma accumulation of ivermectin over the 52 week treatment period.

Distribution

An in vitro study demonstrated that ivermectin is greater than 99% bound to plasma proteins and is bound primarily to human serum albumin. No significant binding of ivermectin to erythrocytes was observed.

Metabolism

In vitro studies using human hepatic microsomes and recombinant CYP450 enzymes have shown that ivermectin is primarily metabolized by CYP3A4. In vitro studies show that ivermectin at therapeutic concentrations does not inhibit the CYP450 isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 or 4A11 or induce 1A2, 2B6, 2C9 or 3A4.

Excretion

The apparent terminal half-life averaged 6.5 days (mean ± standard deviation: 155 hours ± 40 hours, range 92 hours to 238 hours) in patients receiving a once daily cutaneous application of ivermectin cream for 28 days.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2 year dermal mouse carcinogenicity study, ivermectin was administered to CD-1 mice at topical doses of 1 mg/kg/day, 3 mg/kg/day and 10 mg/kg/day (0.1%, 0.3% and 1% ivermectin cream applied at 2 ml/kg/day). No drug-related tumors were noted in this study up to the highest dose evaluated in this study of 10 mg/kg/day (747 times the MRHD based on AUC comparison).

In a 2 year oral rat carcinogenicity study, ivermectin was administered to Wistar rats at gavage doses of 1 mg/kg/day, 3 mg/kg/day and 9 mg/kg/day. A statistically significant increase in the incidence of hepatocellular adenoma was noted in males treated with 9 mg/kg/day (1766 times the MRHD based on AUC comparison) ivermectin. The clinical relevance of this finding is unknown. No drug-related tumors were noted in females up to the highest dose evaluated in this study of 9 mg/kg/day (1959 times the MRHD based on AUC comparison). No drug-related tumors were noted in males at doses ≤ 3 mg/kg/day (599 times the MRHD based on AUC comparison).

Ivermectin revealed no evidence of genotoxic potential based on the results of two in vitro genotoxicity tests (the Ames test and the L5178Y/TK+/- mouse lymphoma assay) and one in vivo genotoxicity test (rat micronucleus assay).

In a fertility study, oral doses of 0.1 mg/kg/day, 1 mg/kg/day and 9 mg/kg/day ivermectin were administered to male and female rats. Mortality occurred at 9 mg/kg/day (1027 times the MRHD based on AUC comparison). The precoital period was generally prolonged at 9 mg/kg/day. No treatment related effects on fertility or mating performance were noted at doses ≤ 1 mg/kg/day (68 times the MRHD based on AUC comparison).

14 CLINICAL STUDIES

Ivermectin cream applied once daily at bedtime was evaluated in the treatment of inflammatory lesions of rosacea in two randomized, double-blind, vehicle-controlled clinical trials, which were identical in design. The trials were conducted in 1,371 subjects aged 18 years and older who were treated once daily for 12 weeks with either ivermectin cream or vehicle cream.

Overall, 96% of subjects were Caucasian and 67% were female. Using the 5-point Investigator Global Assessment (IGA) scale (0=clear, 1=almost clear, 2=mild, 3=moderate, 4=severe), 79% of subjects were scored as moderate (IGA=3) and 21% scored as severe (IGA= 4) at baseline.

The co-primary efficacy endpoints in both pivotal trials were the success rate based on the IGA outcome (percentage of subjects “clear” and “almost clear”) and absolute change from baseline in inflammatory lesion counts at Week 12. Table 1 presents the co-primary efficacy results at Week 12. Ivermectin cream was more effective than vehicle cream on the co-primary efficacy endpoints starting from 4 weeks of treatment in both studies, see Figures 1 through 4.

Table 1 Co-Primary Efficacy Results at Week 12
Study 1 Study 2
Ivermectin Cream (N=451) Vehicle Cream (N=232) Ivermectin Cream (N=459) Vehicle Cream (N=229)
Investigator Global Assessment:
Number (%) of Subjects Clear or Almost Clear 173 (38.4%) 27 (11.6%) 184 (40.1%) 43 (18.8%)
Inflammatory Lesion Counts:
Mean Absolute (%) Change from Baseline 20.5 (64.9%) 12 (41.6%) 22.2 (65.7%) 13.4 (43.4%)

Figures 1 and 2:

IGA Success Rates Over Time

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Figures 3 and 4:

Mean Absolute Change in Inflammatory Lesion Counts from Baseline Over Time

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(click image for full-size original)

16 HOW SUPPLIED/STORAGE AND HANDLING

Ivermectin cream, 1% is a white to pale yellow homogeneous cream, supplied in a laminated tube with a child-resistant cap in the following sizes:

30 gram NDC 72578-120-06

45 gram NDC 72578-120-08

60 gram NDC 72578-120-02

Storage

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

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