Ivermectin (Page 2 of 3)

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 ± 8 hours post dose, the maximum concentration (Cmax ) was 2.10 ± 1.04 ng/mL (range: 0.69 — 4.02 ng/mL) and the area under the concentration curve (AUC0-24hr ) was 36.14 ± 15.56 ng.hr/mL (range: 13.69-75.16 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.

ExcretionThe apparent terminal half-life averaged 6.5 days (mean ± standard deviation: 155± 40 hours, range 92-238 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, 3, 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 ≤ 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, 1 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 ≤ 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 1371 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 VehicleCream (N=451) Cream (N=232)

Ivermectin VehicleCream (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%)

Figures 1 and 2: IGA Success Rates Over Time

figure_IGA_Success_Rate
(click image for full-size original)

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

Figure_3and4_Change_inInflmmatory_Lesion_count
(click image for full-size original)

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 66993-948-48

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.

Marketed by:
Prasco Laboratories Mason, OH 45040 USA

Made in Canada.

20102-0819

Instructions for Use

Ivermectin cream, 1%

Important: Ivermectin cream is for use on the face only. Do not use Ivermectin cream in your eyes, mouth or vagina.

Read and follow the steps below so that you use Ivermectin cream correctly:

1. Open the tube of Ivermectin cream by gently pressing down on the child resistant cap and twist in the direction of the arrow (counterclockwise) as shown below. See Figures A and B. To avoid spilling, do not squeeze the tube while opening or closing.

ivermectin-fig-a-fig-b
(click image for full-size original)

2. To apply Ivermectin cream to your face, squeeze a pea-sized amount of Ivermectin cream from the tube onto your fingertip. See Figure C.

ivermectin-fig-c
(click image for full-size original)

3. Apply Ivermectin to the affected areas of your face once a day. Use a pea-sized amount of Ivermectin cream for each area of your face (forehead, chin, nose, each cheek) that is affected. Spread the cream smoothly and evenly in a thin layer. Avoid contact with your eyes and lips.

4. To close Ivermectin cream, gently press down on the child resistant cap and twist to the right (clockwise). See Figure D.

ivermectin-fig-d
(click image for full-size original)

How should I store Ivermectin cream?
Store Ivermectin cream at room temperature between 68°F to 77°F (20°C to 25°C).

Keep Ivermectin cream out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Marketed by:
Prasco Laboratories Mason, OH 45040 USA

Made in Canada.

Issued: August 2019

20102-0819

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