Prescription Drug Information: Ivermectin

IVERMECTIN- ivermectin cream
Padagis US LLC

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1 INDICATIONS AND USAGE

Ivermectin cream is indicated for the treatment of inflammatory lesions of rosacea.

2 DOSAGE AND ADMINISTRATION

Apply to the affected areas of the face once daily. Use a pea-size amount for each area of the face (forehead, chin, nose, each cheek) that is affected. Spread as a thin layer, avoiding the eyes and lips.
Ivermectin cream is not for oral, ophthalmic, or intravaginal use.

3 DOSAGE FORMS AND STRENGTHS

Cream, 1%.
Each gram of Ivermectin cream contains 10 mg of ivermectin in a white to pale yellow cream base. Ivermectin cream is supplied in tubes of 45 g.

4 CONTRAINDICATIONS

None.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
During clinical trials, 2047 subjects with inflammatory lesions of rosacea received ivermectin cream once daily. A total of 1555 subjects were treated once daily for more than 12 weeks, and 519 for approximately one year.
Adverse reactions, reported in ≤ 1% of subjects treated with Ivermectin cream for at least 3 months in vehicle-controlled clinical trials, included skin burning sensation and skin irritation.

6.2 Postmarketing Experience

Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Local adverse reactions: contact dermatitis and allergic dermatitis.

7 DRUG INTERACTIONS

In vitro studies have shown that Ivermectin cream, at therapeutic concentrations, neither inhibits nor induces cytochrome P450 (CYP450) enzymes.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
The available data on the use of ivermectin, including lvermectin cream, in pregnant women are insufficient to establish a drug- associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
In animal reproduction studies, ivermectin induced adverse developmental outcomes when orally administered to pregnant rats and rabbits during the period of organogenesis at doses 1909 or 354 times the maximum recommended human dose (MRHD), respectively. These orally administered doses were maternally toxic to pregnant rats and rabbits. In a pre-and postnatal developmental study in rats, neonatal toxicity and adverse effects on behavioral development were observed when lvermectin was orally administered to pregnant females during gestation and lactation (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data
Human Data
No adequate and well-controlled trials of lvermectin cream have been conducted in pregnant women. Retrospective observational studies evaluated pregnancy outcomes in over 700 women in various stages of pregnancy who received oral Ivermectin for the treatment of soil-transmitted helminths in rural Africa. In an additional, randomized open-label trial, 397 pregnant women in their second trimester received a single dose of oral ivermectin, or ivermectin plus albendazole, for soil-transmitted helminths. When compared with a pregnant, untreated population, no differences in pregnancy outcomes were observed between the treated and untreated populations. These studies cannot definitively establish or exclude any drug-associated risk during pregnancy, because either the timing of administration during gestation was not accurately ascertained or the administration occurred only during the second trimester.

Animal Data
Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 1.5, 4, and 12mg/kg/day ivermectin were administered during the period of organogenesis to pregnant female rats.
Maternal death occurred at 12 mg/kg/day [1909 times the MRHD based on area under the curve (AUC) comparison]. Cleft palate occurred in the fetuses from the 12 mg/kg/day (1909 times the MRHD based on AUC comparison) group. No treatment related embryofetal toxicity or malformations were noted at 4 mg/kg/day (708 times the MRHD based on AUC comparison). Oral doses of 0.5, 1.5, 2.5, 3.5 and 4.5 mg/kg/day ivermectin were administered during the period of organogenesis to pregnant female rabbits. Maternal death occurred at doses ≥ 2.5 mg/kg/day (72 times the MRHD based on AUC comparison). Carpal flexure occurred in the fetuses from the 4.5 mg/kg/day (354 times the MRHD based on AUC comparison) group. Fetal weight decrease was noted at 3.5 mg/kg/day (146 times the MRHD based on AUC comparison). No treatment related embryofetal toxicity or malformations were noted at 2.5 mg/kg/day (72 times the MRHD based on AUC comparison). A pre- and postnatal development study was conducted in rats. Oral doses of 1, 2 and 4 mg/kg/day ivermectin were administered to pregnant female rats during gestational days 6-20 and lactation days 2-20. Neonatal death occurred at doses ≥ 2 mg/kg/day. Behavior development of newborn rats was adversely affected at all doses.

8.2 Lactation

Risk SummaryThe presence of ivermectin in human milk following topical administration of ivermectin has not been evaluated. There are no data available regarding the effects of ivermectin on milk production. Published literature suggests that ivermectin was detectable in human milk in 4 lactating women after a single 150 mcg/kg oral dose of ivermectin. However, there is insufficient information from this report to determine the effects of ivermectin on the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lvermectin cream and any potential adverse effects on the breastfed infant from lvermectin cream or from the underlying maternal conditions.

8.4 Pediatric Use

Safety and effectiveness of lvermectin cream in pediatric patients have not been established.

8.5 Geriatric Use

Of the 1371 subjects in the two pivotal clinical studies of lvermectin cream, 170 (12.4%) were 65 and over, while 37 (2.7%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

10 OVERDOSAGE

In accidental or significant exposure to unknown quantities of veterinary formulations of ivermectin in humans, either by ingestion, inhalation, injection, or exposure to body surfaces, the following adverse effects have been reported most frequently: rash, edema, headache, dizziness, asthenia, nausea, vomiting, and diarrhea. Other adverse effects that have been reported include: seizure, ataxia, dyspnea, abdominal pain, paresthesia, urticaria, and contact dermatitis.

In case of accidental ingestion, supportive therapy, if indicated should include parenteral fluids and electrolytes, respiratory support (oxygen and mechanical ventilation if necessary) and pressor agents if clinically significant hypotension is present. Induction of emesis and/or gastric lavage as soon as possible, followed by purgatives and other routine anti-poison measures, may be indicated if needed to prevent absorption of ingested material.

11 DESCRIPTION

lvermectin cream, 1 % is a white to pale yellow hydrophilic cream intended for topical use. Each gram of lvermectin cream contains 10 mg of ivermectin. lvermectin is a semi-synthetic derivative isolated from the fermentation of Streptomyces avermitilis that belongs to the avermectin family of macrocyclic lactones.

Ivermectin is a mixture containing not less than 95.0% and not more than 102.0% of 5-O-demethyl-22,23-dihydro-avermectin A1a plus 5-O-demethyl-25-de(1-methylpropyl)-25-(1-methylethyl)-22,23-dihydro-avermectin A1a , generally referred to as 22,23-dihydro-avermectin B1a and B1b or H2 B1a and H2 B1b , respectively; and the ratio (calculated by area percentage) of component H2 B1a /(H2 B1a + H2 B1b ) is not less than 90.0%. The respective empirical formulas of H2 B1a and H2 B1b are C48 H74 O14 and C47 H72 O14 with molecular weights of 875.10 and 861.07 respectively.

The structural formulas are:

ivermectin-chem-struct
(click image for full-size original)

Component H2 B1a : R = C2 H5 , Component H2 B1b : R = CH3 .

Ivermectin cream contains the following inactive ingredients: carbomer copolymer type B, cetyl alcohol, citric acid monohydrate, dimethicone, edetate disodium, glycerin, isopropyl palmitate, methylparaben, oleyl alcohol, phenoxyethanol, polyoxyl 20 cetostearyl ether, propylene glycol, propylparaben, purified water, sodium hydroxide, sorbitan monostearate, and stearyl alcohol.

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 ± 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.

Excretion
The 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.

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