Ivermectin

Ivermectin is indicated for the treatment of the following infections:

Ivermectin is indicated for the treatment of intestinal (i.e., nondisseminated) strongyloidiasis due to the nematode parasite

.

This indication is based on clinical studies of both comparative and open-label designs, in which 64-100% of infected patients were cured following a single 200-mcg/kg dose of ivermectin. (See

).

Ivermectin is indicated for the treatment of onchocerciasis due to the nematode parasite

.

This indication is based on randomized, double-blind, placebo-controlled and comparative studies conducted in 1427 patients in onchocerciasis-endemic areas of West Africa. The comparative studies used diethylcarbamazine citrate (DEC-C).

NOTE: Ivermectin has no activity against adult

parasites. The adult parasites reside in subcutaneous nodules which are infrequently palpable. Surgical excision of these nodules (nodulectomy) may be considered in the management of patients with onchocerciasis, since this procedure will eliminate the microfilariae- producing adult parasites.

The recommended dosage of ivermectin tablets for the treatment of strongyloidiasis is a single oral dose designed to provide approximately 200 mcg of ivermectin per kg of body weight. See Table 1 for dosage guidelines. Patients should take tablets on an empty stomach with water. (See

). In general, additional doses are not necessary. However, follow-up stool examinations should be performed to verify eradication of infection. (See ).

Table 1: Dosage Guidelines for ivermectin tablets for Strongyloidiasis

Body Weight (kg)	Single Oral Dose Number of 3-mg Tablets
15-24 25-35 36-50 51-65 66-79 ≥80	1 tablet 2 tablets 3 tablets 4 tablets 5 tablets 200 mcg/kg

The recommended dosage of ivermectin tablets for the treatment of onchocerciasis is a single oral dose designed to provide approximately 150 mcg of ivermectin per kg of body weight. See Table 2 for dosage guidelines. Patients should take tablets on an empty stomach with water. (See

). In mass distribution campaigns in international treatment programs, the most commonly used dose interval is 12 months. For the treatment of individual patients, retreatment may be considered at intervals as short as 3 months.

Table 2: Dosage Guidelines for ivermectin tablets for Onchocerciasis

Body Weight (kg)	Single Oral Dose Number of 3-mg Tablets
15-25 26-44 45-64 65-84 ≥85	1 tablet 2 tablets 3 tablets 4 tablets 150 mcg/kg

In four clinical studies involving a total of 109 patients given either one or two doses of 170 to 200 mcg/kg of ivermectin, the following adverse reactions were reported as possibly, probably, or definitely related to ivermectin:

asthenia/fatigue (0.9%), abdominal pain (0.9%)

anorexia (0.9%), constipation (0.9%), diarrhea (1.8%), nausea (1.8%), vomiting (0.9%)

dizziness (2.8%), somnolence (0.9%), vertigo (0.9%), tremor (0.9%)

pruritus (2.8%), rash (0.9%), and urticaria (0.9%).

In comparative trials, patients treated with ivermectin experienced more abdominal distention and chest discomfort than patients treated with albendazole. However, ivermectin was better tolerated than thiabendazole in comparative studies involving 37 patients treated with thiabendazole.

The Mazzotti-type and ophthalmologic reactions associated with the treatment of onchocerciasis or the disease itself would not be expected to occur in strongyloidiasis patients treated with ivermectin (See

).

Laboratory Test Findings

In clinical trials involving 109 patients given either one or two doses of 170 to

200 mcg/kg ivermectin, the following laboratory abnormalities were seen regardless of drug relationship: elevation in ALT and/or AST (2%), decrease in leukocyte count (3%). Leukopenia and anemia were seen in one patient.

Post-marketing reports of increased INR (International Normalized Ratio) have been rarely reported when ivermectin was co-administered with warfarin.

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of ivermectin.

Ivermectin was not genotoxic

in the Ames microbial mutagenicity assay of strains TA1535, TA1537, TA98, and TA100 with and without rat liver enzyme activation, the Mouse Lymphoma Cell Line L5178Y (cytotoxicity and mutagenicity) assays, or the unscheduled DNA synthesis assay in human fibroblasts.

Ivermectin had no adverse effects on the fertility in rats in studies at repeated doses of up to 3 times the maximum recommended human dose of 200 mcg/kg (on a mg/m2/day basis).

Teratogenic Effects

Ivermectin has been shown to be teratogenic in mice, rats, and rabbits when given in repeated doses of 0.2, 8.1, and 4.5 times the maximum recommended human dose, respectively (on a mg/m²/day basis). Teratogenicity was characterized in the three species tested by cleft palate; clubbed forepaws were additionally observed in rabbits. These developmental effects were found only at or near doses that were maternotoxic to the pregnant female. Therefore, ivermectin does not appear to be selectively fetotoxic to the developing fetus. There are, however, no adequate and well-controlled studies in pregnant women. Ivermectin should not be used during pregnancy since safety in pregnancy has not been established.

Ivermectin is excreted in human milk in low concentrations. Treatment of mothers who intend to breast-feed should only be undertaken when the risk of delayed treatment to the mother outweighs the possible risk to the newborn.

Safety and effectiveness in pediatric patients weighing less than 15 kg have not been established.

Clinical studies of ivermectin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, treatment of an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In immunocompromised (including HIV-infected) patients being treated for intestinal strongyloidiasis, repeated courses of therapy may be required. Adequate and well- controlled clinical studies have not been conducted in such patients to determine the optimal dosing regimen. Several treatments, i.e., at 2-week intervals, may be required, and cure may not be achievable. Control of extra-intestinal strongyloidiasis in these patients is difficult, and suppressive therapy, i.e., once per month, may be helpful.

Ivermectin USP is a semisynthetic, anthelmintic agent for oral administration. Ivermectin USP is derived from the avermectins, a class of highly active broad-spectrum, anti-parasitic agents isolated from the fermentation products of

. Ivermectin USP is a mixture containing at least 90% 5--demethyl-22,23-dihydroavermectin A_1a and less than 10% 5--demethyl-25-de(1-methylpropyl)-22,23-dihydro-25-(1-methylethyl)avermectin A_1a, generally referred to as 22,23- dihydroavermectin B_1a and B_1b, or H₂B_1a and H₂B_1b, respectively. The respective empirical formulas are C₄₈H₇₄O₁₄ and C₄₇H₇₂O₁₄, with molecular weights of 875.10 and 861.07, respectively. The structural formulas are:

Ivermectin USP is a white to yellowish-white crystalline powder with a melting point of about 155°C. It is practically insoluble in water, freely soluble in methylene chloride, soluble in ethanol.

Ivermectin tablets USP are available in 3-mg tablets containing the following inactive ingredients: microcrystalline cellulose, directly compressible starch 4001, colloidal silicon dioxide, croscarmellose sodium and magnesium stearate.