Ivermectin

INDICATIONS AND USAGE 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.

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

ADVERSE REACTIONS 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.

Pharmacokinetics Following oral administration of ivermectin, plasma concentrations are approximately proportional to the dose. In two studies, after single 12-mg doses of ivermectin 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 to 120 mg (333 to 2000 mcg/kg) ivermectin in a fasted state or 30 mg (333 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.