IVERMECTIN

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 Streptomyces avermitilis . Ivermectin USP is a mixture containing at least 90% 5- O -demethyl-22,23-dihydroavermectin A 1a and less than 10% 5- O -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 H 2 B 1a and H 2 B 1b , respectively. The respective empirical formulas are C 48 H 74 O 14 and C 47 H 72 O 14 , 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. ds

Ivermectin is indicated for the treatment of the following infections: Strongyloidiasis of the intestinal tract Ivermectin is 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 64-100% of infected patients were cured following a single 200-mcg/kg dose of ivermectin. (See CLINICAL PHARMACOLOGY, Clinical Studies ). Onchocerciasis Ivermectin is 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 1427 patients in onchocerciasis-endemic areas of West Africa. The comparative studies used diethylcarbamazine citrate (DEC-C). NOTE: Ivermectin 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.

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 15-24 25-35 36-50 51-65 66-79 ≥80 1 tablet 2 tablets 3 tablets 4 tablets 5 tablets 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 15-25 26-44 45-64 65-84 ≥85 1 tablet 2 tablets 3 tablets 4 tablets 150 mcg/kg

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

Strongyloidiasis 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: Body as a Whole: asthenia/fatigue (0.9%), abdominal pain (0.9%) Gastrointestinal: anorexia (0.9%), constipation (0.9%), diarrhea (1.8%), nausea (1.8%), vomiting (0.9%) Nervous System/Psychiatric: dizziness (2.8%), somnolence (0.9%), vertigo (0.9%), tremor (0.9%) Skin: 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 ADVERSE REACTIONS, Onchocerciasis ). 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. Onchocerciasis In clinical trials involving 963 adult patients treated with 100 to 200 mcg/kg ivermectin, worsening of the following Mazzotti reactions during the first 4 days post-treatment were reported: arthralgia/synovitis (9.3%), axillary lymph node enlargement and tenderness (11.0% and 4.4%, respectively), cervical lymph node enlargement and tenderness (5.3% and 1.2%, respectively), inguinal lymph node enlargement and tenderness (12.6% and 13.9%, respectively), other lymph node enlargement and tenderness (3.0% and 1.9%, respectively), pruritus (27.5%), skin involvement including edema, papular and pustular or frank urticarial rash (22.7%), and fever (22.6%). (See WARNINGS ). In clinical trials, ophthalmological conditions were examined in 963 adult patients before treatment, at day 3, and months 3 and 6 after treatment with 100 to 200 mcg/kg ivermectin. Changes observed were primarily deterioration from baseline 3 days post-treatment. Most changes either returned to baseline condition or improved over baseline severity at the month 3 and 6 visits. The percentages of patients with worsening of the following conditions at day 3, month 3 and 6, respectively, were: limbitis: 5.5%, 4.8%, and 3.5% and punctate opacity: 1.8%, 1.8%, and 1.4%. The corresponding percentages for patients treated with placebo were: limbitis: 6.2%, 9.9%, and 9.4% and punctate opacity: 2.0%, 6.4%, and 7.2%. (See WARNINGS ). In clinical trials involving 963 adult patients who received 100 to 200 mcg/kg ivermectin, the following clinical adverse reactions were reported as possibly, probably, or definitely related to the drug in ≥1% of the patients: facial edema (1.2%), peripheral edema (3.2%), orthostatic hypotension (1.1%), and tachycardia (3.5%). Drug- related headache and myalgia occurred in <1% of patients (0.2% and 0.4%, respectively). However, these were the most common adverse experiences reported overall during these trials regardless of causality (22.3% and 19.7%, respectively). A similar safety profile was observed in an open study in pediatric patients ages 6 to 13. The following ophthalmological side effects do occur due to the disease itself but have also been reported after treatment with ivermectin: abnormal sensation in the eyes, eyelid edema, anterior uveitis, conjunctivitis, limbitis, keratitis, and chorioretinitis or choroiditis. These have rarely been severe or associated with loss of vision and have generally resolved without corticosteroid treatment. Laboratory Test Findings In controlled clinical trials, the following laboratory adverse experiences were reported as possibly, probably, or definitely related to the drug in ≥1% of the patients: eosinophilia (3%) and hemoglobin increase (1%). Post-Marketing Experience The following adverse reactions have been reported since the drug was registered overseas: Onchocerciasis Conjunctival hemorrhage All Indications Hypotension (mainly orthostatic hypotension), worsening of bronchial asthma, toxic epidermal necrolysis, Stevens-Johnson syndrome, seizures, hepatitis, elevation of liver enzymes, and elevation of bilirubin. Neurotoxicity including alteration of consciousness of variable severity (e.g., somnolence/drowsiness, stupor, and coma), confusion, disorientation, and death (see WARNINGS ). To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy's Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. for voluntary reporting of adverse reactions.

Post-marketing reports of increased INR (International Normalized Ratio) have been rarely reported when ivermectin was co-administered with warfarin. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of ivermectin. Ivermectin was not genotoxic in vitro in the Ames microbial mutagenicity assay of Salmonella typhimurium 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). Pregnancy 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/m 2 /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. Nursing Mothers 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. Pediatric Use Safety and effectiveness in pediatric patients weighing less than 15 kg have not been established. Geriatric Use 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. Strongyloidiasis in Immunocompromised Hosts 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.