Ivermectin (Page 2 of 3)

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 ± 8 hours post-dose, the maximum concentration (Cmax ) was 2.10 ± 1.04 ng/mL (range: 0.69 to 4.02 ng/mL) and the area under the concentration curve (AUC0-24hr ) was 36.14 ± 15.56 ng.hr/mL (range: 13.69 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± 40 hours, range 92 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, 3, 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 (747X maximum topical human dose (MTHD)).

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 (1766X MTHD) 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 (1959X MTHD). No drug-related tumors were noted in males at doses less than or equal to 3 mg/kg/day (599X MTHD).

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 (1027X MTHD). The precoital period was generally prolonged at 9 mg/kg/day. No treatment related effects on fertility or mating performance were noted at doses less than or equal to 1 mg/kg/day (68X MTHD).

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

Vehicle

Ivermectin

Vehicle

Cream (N=451)

Cream (N=232)

Cream (N=459)

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%)

12.0 (41.6%)

22.2 (65.7%)

13.4 (43.4%)

1
(click image for full-size original)

Figures 1 and 2: IGA Success Rates Over Time

2
(click image for full-size original)

Figures 3 and 4: Mean Absolute Change in Inflammatory Lesion Counts from Baseline Over Time

16 HOW SUPPLIED/STORAGE AND HANDLING

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

45 gram – NDC 0591-4052 -89

Storage

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

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Instructions for Use).

Patients using ivermectin cream should receive the following instruction:

Keep out of reach of children.

Teva Pharmaceuticals USA, Inc.
North Wales, PA 19454

Revised – January 2019

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