SOOLANTRA (Page 2 of 3)

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Cardiac Electrophysiology
At therapeutic doses, SOOLANTRA cream is not expected to prolong QTc interval.

12.3 Pharmacokinetics

Absorption
The absorption of ivermectin from SOOLANTRA cream was evaluated in a clinical trial in 15 adult male and female subjects with severe papulopustular rosacea applying 1 g SOOLANTRA 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 SOOLANTRA 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

SOOLANTRA 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 SOOLANTRA 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. SOOLANTRA 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

SOOLANTRA VehicleCream (N=451) Cream (N=232)

SOOLANTRA 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 Baseline20.5 (64.9%) 12.0 (41.6%)22.2 (65.7%) 13.4 (43.4%)

Figures 1 and 2: IGA Success Rates Over Time

ivermectin-fig-1-fig-2
(click image for full-size original)

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

ivermectin-fig-3-fig-4
(click image for full-size original)

16 HOW SUPPLIED/STORAGE AND HANDLING

SOOLANTRA (ivermectin) cream, 1% is a white to pale yellow cream, supplied in a laminated tube with a child resistant cap in the following sizes:
30 gram NDC 0299-3823-30
45 gram NDC 0299-3823-45
60 gram NDC 0299-3823-60

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 SOOLANTRA cream should receive the following instruction:

Keep out of reach of children.

Marketed by:
GALDERMA LABORATORIES, L.P.Fort Worth, Texas 76177 USA

Made in Canada.

P52476-2

Instructions for Use

SOOLANTRA (soo lan’ trah) (ivermectin) cream, 1%

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

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

1. Open the tube of SOOLANTRA 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 SOOLANTRA cream to your face, squeeze a pea-sized amount of SOOLANTRA cream from the tube onto your fingertip. See Figure C.

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

3. Apply SOOLANTRA to the affected areas of your face once a day. Use a pea-sized amount of SOOLANTRA 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 SOOLANTRA 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 SOOLANTRA cream?
Store SOOLANTRA cream at room temperature between 68°F to 77°F (20°C to 25°C).

Keep SOOLANTRA cream out of the reach of children.

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

Marketed by:
GALDERMA LABORATORIES, L.P.Fort Worth, TX 76177 USA

Made in Canada.

Issued: July 2018

P52476-2

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