ivermectin 10 MG/ML Injectable Solution [Noromectin]

INDICATIONS AND USAGE Ivermectin tablets, USP are indicated for the treatment of the following infections: Strongyloidiasis of the intestinal tract. Ivermectin tablets are indicated for the treatment of intestinal (i.e., nondisseminated) strongyloidiasis due to the nematode parasite Strongyloides stercoralis . This indication is based on clinical studies of both comparative and open-label designs, in which 64% to 100% of infected patients were cured following a single 200-mcg/kg dose of ivermectin. (See CLINICAL PHARMACOLOGY, Clinical Studies .) Onchocerciasis. Ivermectin tablets are indicated for the treatment of onchocerciasis due to the nematode parasite Onchocerca volvulus . This indication is based on randomized, double-blind, placebo-controlled and comparative studies conducted in 1,427 patients in onchocerciasis-endemic areas of West Africa. The comparative studies used diethylcarbamazine citrate (DEC-C). NOTE: Ivermectin tablets has no activity against adult Onchocerca volvulus 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.

DOSAGE AND ADMINISTRATION Strongyloidiasis 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 CLINICAL PHARMACOLOGY, Pharmacokinetics .) In general, additional doses are not necessary. However, follow-up stool examinations should be performed to verify eradication of infection. (See CLINICAL PHARMACOLOGY, Clinical Studies .) Table 1: Dosage Guidelines for Ivermectin Tablets for Strongyloidiasis Body Weight (kg) Single Oral Dose Number of 3-mg Tablets 15 to 24 1 tablet 25 to 35 2 tablets 36 to 50 3 tablets 51 to 65 4 tablets 66 to 79 5 tablets ≥80 200 mcg/kg Onchocerciasis 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 CLINICAL PHARMACOLOGY, Pharmacokinetics .) 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 to 25 1 tablet 26 to 44 2 tablets 45 to 64 3 tablets 65 to 84 4 tablets ≥85 150 mcg/kg

WARNINGS Historical data have shown that microfilaricidal drugs, such as diethylcarbamazine citrate (DEC-C), might cause cutaneous and/or systemic reactions of varying severity (the Mazzotti reaction) and ophthalmological reactions in patients with onchocerciasis. These reactions are probably due to allergic and inflammatory responses to the death of microfilariae. Patients treated with ivermectin tablets for onchocerciasis may experience these reactions in addition to clinical adverse reactions possibly, probably, or definitely related to the drug itself. (See ADVERSE REACTIONS, Onchocerciasis .) The treatment of severe Mazzotti reactions has not been subjected to controlled clinical trials. Oral hydration, recumbency, intravenous normal saline, and/or parenteral corticosteroids have been used to treat postural hypotension. Antihistamines and/or aspirin have been used for most mild to moderate cases. Neurotoxicity with the use of ivermectin, including alteration of consciousness of variable severity (e.g., somnolence/drowsiness, stupor, and coma), confusion, disorientation and death, has been reported in patients without onchocerciasis or in patients with onchocerciasis in the absence of Loa loa infection. These reactions have generally resolved with supportive care and the discontinuation of ivermectin.

CONTRAINDICATIONS Ivermectin Tablets are contraindicated in patients who are hypersensitive to any component of this product.

CLINICAL PHARMACOLOGY Pharmacokinetics Following oral administration of ivermectin, plasma concentrations are approximately proportional to the dose. In two studies, after single 12-mg doses of ivermectin tablets in fasting healthy volunteers (representing a mean dose of 165 mcg/kg), the mean peak plasma concentrations of the major component (H 2 B 1a ) were 46.6 (±21.9) (range: 16.4 to 101.1) and 30.6 (±15.6) (range: 13.9 to 68.4) ng/mL, respectively, at approximately 4 hours after dosing. ivermectin is metabolized in the liver, and ivermectin and/or its metabolites are excreted almost exclusively in the feces over an estimated 12 days, with less than 1% of the administered dose excreted in the urine. The plasma half-life of ivermectin in man is approximately 18 hours following oral administration. The safety and pharmacokinetic properties of ivermectin were further assessed in a multiple-dose clinical pharmacokinetic study involving healthy volunteers. Subjects received oral doses of 30 mg to 120 mg (333 mcg/kg to 2,000 mcg/kg) ivermectin in a fasted state or 30 mg (333 mcg/kg to 600 mcg/kg) ivermectin following a standard high-fat (48.6 g of fat) meal. Administration of 30 mg ivermectin following a high-fat meal resulted in an approximate 2.5-fold increase in bioavailability relative to administration of 30 mg ivermectin in the fasted state. In vitro studies using human liver microsomes and recombinant CYP450 enzymes have shown that ivermectin is primarily metabolized by CYP3A4. Depending on the in vitro method used, CYP2D6 and CYP2E1 were also shown to be involved in the metabolism of ivermectin but to a significantly lower extent compared to CYP3A4. The findings of in vitro studies using human liver microsomes suggest that clinically relevant concentrations of ivermectin do not significantly inhibit the metabolizing activities of CYP3A4, CYP2D6, CYP2C9, CYP1A2, and CYP2E1. Microbiology Ivermectin is a member of the avermectin class of broad-spectrum antiparasitic agents which have a unique mode of action. Compounds of the class bind selectively and with high affinity to glutamate-gated chloride ion channels which occur in invertebrate nerve and muscle cells. This leads to an increase in the permeability of the cell membrane to chloride ions with hyperpolarization of the nerve or muscle cell, resulting in paralysis and death of the parasite. Compounds of this class may also interact with other ligand-gated chloride channels, such as those gated by the neurotransmitter gamma-aminobutyric acid (GABA). The selective activity of compounds of this class is attributable to the facts that some mammals do not have glutamate-gated chloride channels and that the avermectins have a low affinity for mammalian ligand-gated chloride channels. In addition, ivermectin does not readily cross the blood-brain barrier in humans. Ivermectin is active against various life-cycle stages of many but not all nematodes. It is active against the tissue microfilariae of Onchocerca volvulus but not against the adult form. Its activity against Strongyloides stercoralis is limited to the intestinal stages. Clinical Studies Strongyloidiasis Two controlled clinical studies using albendazole as the comparative agent were carried out in international sites where albendazole is approved for the treatment of strongyloidiasis of the gastrointestinal tract, and three controlled studies were carried out in the U.S. and internationally using thiabendazole as the comparative agent. Efficacy, as measured by cure rate, was defined as the absence of larvae in at least two follow-up stool examinations 3 weeks to 4 weeks post-therapy. Based on this criterion, efficacy was significantly greater for ivermectin tablet (a single dose of 170 mcg/kg to 200 mcg/kg) than for albendazole (200 mg twice a day for 3 days). Ivermectin tablet administered as a single dose of 200 mcg/kg for 1 day was as efficacious as thiabendazole administered at 25 mg/kg twice a day for 3 days. Summary of Cure Rates for Ivermectin Versus Comparative Agents in the Treatment of Strongyloidiasis * Number and % of evaluable patients ** 170 mcg/kg to 200 mcg/kg *** 200 mg twice a day for 3 days † 25 mg/kg twice a day for 3 days Cure Rate* (%) Ivermectin ** Comparative Agent Albendazole *** Comparative International Study WHO Study 24/26 (92) 126/152 (83) 12/22 (55) 67/149 (45) Thiabendazole † Comparative International Study US Studies 9/14 (64) 14/14 (100) 13/15 (87) 16/17 (94) In one study conducted in France, a non-endemic area where there was no possibility of reinfection, several patients were observed to have recrudescence of Strongyloides larvae in their stool as long as 106 days following ivermectin therapy. Therefore, at least three stool examinations should be conducted over the three months following treatment to ensure eradication. If recrudescence of larvae is observed, retreatment with ivermectin is indicated. Concentration techniques (such as using a Baermann apparatus) should be employed when performing these stool examinations, as the number of Strongyloides larvae per gram of feces may be very low. Onchocerciasis The evaluation of ivermectin tablets in the treatment of onchocerciasis is based on the results of clinical studies involving 1,278 patients. In a double-blind, placebo-controlled study involving adult patients with moderate to severe onchocercal infection, patients who received a single dose of 150 mcg/kg ivermectin tablet experienced an 83.2% and 99.5% decrease in skin microfilariae count (geometric mean) 3 days and 3 months after the dose, respectively. A marked reduction of >90% was maintained for up to 12 months after the single dose. As with other microfilaricidal drugs, there was an increase in the microfilariae count in the anterior chamber of the eye at day 3 after treatment in some patients. However, at 3 and 6 months after the dose, a significantly greater percentage of patients treated with ivermectin tablets had decreases in microfilariae count in the anterior chamber than patients treated with placebo. In a separate open study involving pediatric patients ages 6 to 13 (n=103; weight range: 17 kg to 41 kg), similar decreases in skin microfilariae counts were observed for up to 12 months after dosing.