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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 STROMECTOL (ivermectin) in fasting healthy volunteers (representing a mean dose of 165 mcg/kg), the mean peak plasma concentrations of the major component (H2B1a) were 46.6 (±21.9) (range: 16.4-101.1) and 30.6 (±15.6) (range: 13.9-68.4) 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 2.5fold 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 to 4 weeks post-therapy. Based on this criterion, efficacy was significantly greater for STROMECTOL (ivermectin) (a single dose of 170 to 200 mcg/kg) than for albendazole (200 mg b.i.d. for 3 days). STROMECTOL (ivermectin) administered as a single dose of 200 mcg/kg for 1 day was as efficacious as thiabendazole administered at 25 mg/kg b.i.d. for 3 days. Summary of Cure Rates for Ivermectin Versus Comparative Agents in the Treatment of Strongyloidiasis Cure Rate* (%) Ivermectin** Comparative Agent Albendazole*** Comparative International Study 24/26 (92) 12/22 (55) WHO Study 126/152 (83) 67/149 (45) Thiabendazole† Comparative International Study 9/14 (64) 13/15 (87) US Studies 14/14 (100) 16/17 (94) * Number and % of evaluable patients ** 170-200 mcg/kg *** 200 mg b.i.d. for 3 days † 25 mg/kg b.i.d. for 3 days 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 STROMECTOL (ivermectin) in the treatment of onchocerciasis is based on the results of clinical studies involving 1278 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 STROMECTOL (ivermectin) 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 STROMECTOL (ivermectin) 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: 17-41 kg), similar decreases in skin microfilariae counts were observed for up to 12 months after dosing.

CLINICAL PHARMACOLOGY Mechanism Of Action Ivermectin, a member of the avermectin class, causes death of parasites, primarily through binding selectively and with high affinity to glutamate-gated chloride 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 fact that some mammals do not have glutamate-gated chloride channels, the avermectins have a low affinity for mammalian ligand-gated chloride channels, and ivermectin does not readily cross the blood-brain barrier in humans. Pharmacodynamics The pharmacodynamics of SKLICE Lotion are unknown. Pharmacokinetics The absorption of ivermectin from SKLICE Lotion was evaluated in a clinical study in subjects aged from 6 months to 3 years. This study evaluated pharmacokinetics in 20 lice infested subjects, and 13 of these subjects weighed 15 kg or less (overall weight range 8.5-23.9 kg). All enrolled subjects received a single treatment with SKLICE Lotion. The systemic ivermectin exposure was evaluated using an assay with a lower limit of quantitation of 0.05 ng/mL. The mean (± standard deviation) plasma maximum concentration (Cmax) and area under the concentration-time curve from 0 to time of last measurable concentration (AUC0-tlast) were 0.24 ± 0.23 ng/mL and 6.7 ± 11.2hr•ng/mL, respectively. These levels are much lower than those observed following oral administration of 165 mcg/kg dose of ivermectin. Clinical Studies Two identical multi-center, randomized, double-blind, vehicle-controlled studies were conducted in subjects 6 months of age and older with head lice infestation. All subjects received a single application of either SKLICE Lotion or vehicle control with instructions not to use a nit comb. For the evaluation of efficacy, the youngest subject from each household was considered to be the index subject of the household (N=289). Other enrolled infested household members received the same treatment as the youngest subject and were evaluated for all safety parameters [see ADVERSE REACTIONS]. The primary efficacy was assessed as the proportion of index subjects who were free of live lice at day 2 and through day 8 to the final evaluation 14 (+2) days following a single application. Subjects with live lice present at any time up to the final evaluation were considered treatment failures. Table 1 contains the proportion of subjects who were free of live lice in each of the two trials. Table 1: Proportion of Subjects Free of Live Lice 14 Days After Treatment Study Vehicle %(n/N) SKLICE Lotion % (n/N) Study 1 16.2% (12/74) 76.1% (54/71) Study 2 18.9% (14/74) 71.4% (50/70)

Find Lowest Prices on STROMECTOL® (ivermectin) Anthelmintic Agent for Oral Administration DESCRIPTION STROMECTOL (Ivermectin) is a semisynthetic, anthelmintic agent for oral administration. Ivermectin is derived from the avermectins, a class of highly active broad-spectrum, anti-parasitic agents isolated from the fermentation products of Streptomyces avermitilis. Ivermectin is a mixture containing at least 90% 5-O demethyl-22,23-dihydroavermectin A1a and less than 10% 5-O-demethyl-25-de(1-methylpropyl)-22,23-dihydro-25-(1-methylethyl)avermectin A1a, generally referred to as 22,23-dihydroavermectin B1a and B1b, or H2B1a and H2B1b, respectively. The respective empirical formulas are C48H74O14 and C47H72O14, with molecular weights of 875.10 and 861.07, respectively. The structural formulas are: Component B1a, R = C2H5.............................Component B1b, R = CH3 Ivermectin is a white to yellowish-white, nonhygroscopic, crystalline powder with a melting point of about 155°C. It is insoluble in water but is freely soluble in methanol and soluble in 95% ethanol. STROMECTOL (ivermectin) is available in 3-mg tablets containing the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, magnesium stearate, butylated hydroxyanisole, and citric acid powder (anhydrous).

Find Lowest Prices on SKLICE (ivermectin) Lotion DESCRIPTION SKLICE (ivermectin) Lotion, for topical administration, is an off-white/tan lotion containing 0.5% ivermectin. Ivermectin, the active ingredient, is a pediculicide, derived from the fermentation of a soil dwelling actinomycete, Streptomyces avermitilis. Ivermectin is a mixture containing at least 90% 5-O-demethyl-22,23-dihydroavermectin A1a and less than 10% 5-O-demethyl-25-de(1-methylpropyl)-22,23-dihydro25- (1-methylethyl) avermectin A1a, generally referred to as 22,23-dihydroavermectin B1a and B1b, or H2B1a and H2B1b, respectively. The respective empirical formulas are C48H74O14 and C47H72O14, with molecular weights of 875.10 and 861.07, respectively. The structural formulas are: SKLICE Lotion contains the following inactive ingredients: water, olive oil, oleyl alcohol, Crodalan AWS, lanolin alcohol, cyclomethicone, shea butter, sodium citrate, sorbitan tristearate, methylparaben, propylparaben, and citric acid.

INDICATIONS STROMECTOL (ivermectin) is indicated for the treatment of the following infections: Strongyloidiasis of the intestinal tract. STROMECTOL (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. STROMECTOL (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: STROMECTOL (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 STROMECTOL (ivermectin) 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 STROMECTOL (ivermectin) 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 STROMECTOL (ivermectin) 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 STROMECTOL (ivermectin) 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 HOW SUPPLIED No. 8495 — Tablets STROMECTOL (ivermectin) 3 mg are white, round, flat, bevel-edged tablets coded MSD on one side and 32 on the other side. They are supplied as follows: NDC 0006-0032-20 unit dose packages of 20. Storage Store at temperatures below 30°C (86°F). Dist. by: MERCK & CO., INC,Whitehouse Station, NJ 08889, USA. Manufactured by: MSD BV Waarderweg 39 2031 BN Haarlem Netherlands. Issued 2009

INDICATIONS Indication SKLICE® Lotion is indicated for the topical treatment of head lice infestations in patients 6 months of age and older. Adjunctive Measures SKLICE Lotion should be used in the context of an overall lice management program: Wash (in hot water) or dry-clean all recently worn clothing, hats, used bedding and towels. Wash personal care items such as combs, brushes and hair clips in hot water. A fine-tooth comb or special nit comb may be used to remove dead lice and nits. DOSAGE AND ADMINISTRATION For topical use only. SKLICE Lotion is not for oral, ophthalmic, or intravaginal use. Apply SKLICE Lotion to dry hair in an amount sufficient (up to 1 tube) to thoroughly coat the hair and scalp. Leave SKLICE Lotion on the hair and scalp for 10 minutes, and then rinse off with water. The tube is intended for single use; discard any unused portion. Avoid contact with eyes. HOW SUPPLIED Dosage Forms And Strengths Lotion: 0.5%; each gram of lotion contains 5 mg of ivermectin. SKLICE Lotion is an off-white to tan lotion. Storage And Handling SKLICE Lotion, 0.5% is supplied in a 4 oz (117g) laminate tube (NDC 24338-183-04). Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP controlled room temperature]. Do not freeze. Distributed by: Arbor Pharmaceuticals, LLC, Atlanta, GA 30328. Manufactured by: DPT Laboratories LTD, San Antonio, TX 78215. Revised: Jan 2016

PATIENT INFORMATION STROMECTOL (ivermectin) should be taken on an empty stomach with water. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.) Strongyloidiasis: The patient should be reminded of the need for repeated stool examinations to document clearance of infection with Strongyloides stercoralis. Onchocerciasis: The patient should be reminded that treatment with STROMECTOL (ivermectin) does not kill the adult Onchocerca parasites, and therefore repeated follow-up and retreatment is usually required.

PATIENT INFORMATION SKLICE® (sklice) (ivermectin) Lotion, 0.5% Important: For use on scalp hair and scalp only. Do not use SKLICE Lotion in your eyes, mouth or vagina. Read the Patient Information that comes with SKLICE Lotion. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment. What is SKLICE Lotion? SKLICE Lotion is a prescription medicine for topical use on the hair and scalp only. SKLICE Lotion is used to treat head lice in people 6 months of age and older. It is not known if SKLICE Lotion is safe and effective for children under 6 months of age. What should I tell my healthcare provider before using SKLICE Lotion? Before using SKLICE Lotion, tell your healthcare provider if you or your child: have any skin conditions or sensitivities, have any other medical conditions, are pregnant or plan to become pregnant. It is not known if SKLICE Lotion can harm your unborn baby, and are breastfeeding or plan to breastfeed. It is not known if SKLICE Lotion passes into your breast milk. Talk to your healthcare provider if you are breastfeeding. How should I use SKLICE Lotion? Use SKLICE Lotion exactly as prescribed. Your healthcare provider will prescribe the treatment that is right for you. Do not change your treatment unless you talk to your healthcare provider. Use SKLICE Lotion when your hair is dry. It is important to use enough SKLICE Lotion to completely coat all of your hair and scalp. Leave SKLICE Lotion on your hair and scalp for a full 10 minutes. See the detailed “Patient Instructions for Use” at the end of this leaflet. You need to completely cover all the scalp and hair with lotion. Make sure that you and anyone who helps you apply SKLICE Lotion reads and understands this leaflet and the Patient Instructions for Use. Children will need an adult to apply SKLICE Lotion for them. Do not swallow SKLICE Lotion. If swallowed, call your healthcare provider or go to the nearest emergency room right away. Do not get SKLICE Lotion into your eyes. If SKLICE Lotion gets in your eye, gently flush with water. Wash your hands after applying SKLICE Lotion. When you complete your dose of SKLICE Lotion, do not use SKLICE Lotion again without talking to your healthcare provider first. What are the possible side effects of SKLICE Lotion? The most common side effects of SKLICE Lotion include: eye redness or soreness eye irritation dandruff dry skin burning sensation of the skin Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of SKLICE Lotion. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. How should I store SKLICE Lotion? Store SKLICE Lotion at room temperature between 68° to 77°F (20° to 25°C). Do not freeze SKLICE Lotion. Safely throw away any unused SKLICE Lotion. Keep SKLICE Lotion and all medicines out of reach of children. What are the ingredients in SKLICE Lotion? Active ingredient: ivermectin Inactive ingredients: water, olive oil, oleyl alcohol, Crodalan AWS, lanolin alcohol, cyclomethicone, shea butter, sodium citrate, sorbitan tristearate, methylparaben, propylparaben, and citric acid General information about SKLICE Lotion Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SKLICE Lotion for a condition for which it was not prescribed. Do not give SKLICE Lotion to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about SKLICE Lotion. If you would like more information, talk to your healthcare provider. You can also ask your healthcare provider or pharmacist for information about SKLICE Lotion that is written for health professionals. Patient Instructions for Use Before you use SKLICE Lotion, it is important that you read the Patient Information and these Patient Instructions for Use. Be sure that you read, understand, and follow these Patient Instructions for Use so that you use SKLICE Lotion the right way. Ask your healthcare provider or pharmacist if you have questions about the right way to use SKLICE Lotion. Your hair and scalp must be dry before applying SKLICE Lotion. Use the top of cap to break the tamper seal on the tube (see Figure A). Apply SKLICE Lotion directly to dry hair and scalp (see Figure B). Figure A and Figure B Completely cover your scalp and hair closest to the scalp first, and then apply outwards towards the ends of your hair (see Figure C). Rub SKLICE Lotion throughout your hair (see Figure D). Figure C and Figure D It is important to completely cover your entire head so that all lice and eggs are exposed to the lotion. Be sure that each hair is coated from the scalp to the tip. Use up to 1 entire tube (4 oz) to completely cover hair and scalp. Allow SKLICE Lotion to stay on your hair and scalp for 10 minutes after it has been applied. Use a timer or clock. Start timing after you have completely covered your hair and scalp with SKLICE Lotion (see Figure E). After 10 minutes, completely rinse SKLICE Lotion from your hair and scalp using only water (see Figure F). Figure E and Figure F You or anyone who helps you apply SKLICE Lotion should wash their hands after application. Do not use SKLICE Lotion again without talking to your healthcare provider first. How do I stop the spread of lice? To help prevent the spread of lice from one person to another, here are some steps you can take: Avoid direct head-to-head contact with anyone known to have live, crawling lice. Do not share combs, brushes, hats, scarves, bandannas, ribbons, barrettes, hair bands, towels, helmets, or other hair-related personal items with anyone else, whether they have lice or not. Avoid sleepovers and slumber parties during lice outbreaks. Lice can live in bedding, pillows, and carpets that have recently been used by someone with lice. After finishing treatment with lice medicine, check everyone in your family for lice after one week. Be sure to talk to your healthcare provider about treatments for those who have lice. Machine wash any bedding and clothing used by anyone having lice. Machine wash at high temperatures (150°F) and tumble in a hot dryer for 20 minutes. This Patient Information has been approved by the U.S. Food and Drug Administration.

OVERDOSE Significant lethality was observed in mice and rats after single oral doses of 25 to 50 mg/kg and 40 to 50 mg/kg, respectively. No significant lethality was observed in dogs after single oral doses of up to 10 mg/kg. At these doses, the treatment-related signs that were observed in these animals include ataxia, bradypnea, tremors, ptosis, decreased activity, emesis, and mydriasis. In accidental intoxication with, 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 poisoning, 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. CONTRAINDICATIONS STROMECTOL (ivermectin) is contraindicated in patients who are hypersensitive to any component of this product.

OVERDOSE 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 poisoning, 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. CONTRAINDICATIONS None.

SIDE EFFECTS Strongyloidiasis In four clinical studies involving a total of 109 patients given either one or two doses of 170 to 200 mcg/kg of STROMECTOL (ivermectin) , the following adverse reactions were reported as possibly, probably, or definitely related to STROMECTOL (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 STROMECTOL (ivermectin) experienced more abdominal distention and chest discomfort than patients treated with albendazole. However, STROMECTOL (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 STROMECTOL (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 STROMECTOL (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 STROMECTOL (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 STROMECTOL (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 STROMECTOL (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 STROMECTOL (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. DRUG INTERACTIONS Post-marketing reports of increased INR (International Normalized Ratio) have been rarely reported when ivermectin was co-administered with warfarin.

SIDE EFFECTS 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 clinical practice. The data described below reflect exposure to a single 10 minute treatment of SKLICE Lotion in 379 patients, ages 6 months and older, in placebo-controlled trials. Of these subjects, 47 subjects were age 6 months to 4 years, 179 subjects were age 4 to 12 years, 56 subjects were age 12 to 16 years and 97 subjects were age 16 or older. Adverse reactions, reported in less than 1% of subjects treated with SKLICE Lotion, include conjunctivitis, ocular hyperemia, eye irritation, dandruff, dry skin, and skin burning sensation. DRUG INTERACTIONS No information provided.

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 STROMECTOL (ivermectin) 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. PRECAUTIONS General After treatment with microfilaricidal drugs, patients with hyperreactive onchodermatitis (sowda) may be more likely than others to experience severe adverse reactions, especially edema and aggravation of onchodermatitis. Rarely, patients with onchocerciasis who are also heavily infected with Loa loa may develop a serious or even fatal encephalopathy either spontaneously or following treatment with an effective microfilaricide. In these patients, the following adverse experiences have also been reported: pain (including neck and back pain), red eye, conjunctival hemorrhage, dyspnea, urinary and/or fecal incontinence, difficulty in standing/walking, mental status changes, confusion, lethargy, stupor, seizures, or coma. This syndrome has been seen very rarely following the use of ivermectin. In individuals who warrant treatment with ivermectin for any reason and have had significant exposure to Loa loa-endemic areas of West or Central Africa, pretreatment assessment for loiasis and careful post-treatment follow-up should be implemented. 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 Pregnancy Category C 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. Nursing Mothers STROMECTOL (ivermectin) is excreted in human milk in low concentrations. Treatment of mothers who intend to breastfeed 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 STROMECTOL (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.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Ingestion In Pediatric Patients In order to prevent ingestion, SKLICE Lotion should only be administered to pediatric patients under the direct supervision of an adult. Patient Counseling Information “See FDA-approved patient labeling (PATIENT INFORMATION)”. Inform the patient and caregiver of the following instructions: Apply SKLICE Lotion to dry scalp and dry scalp hair. Avoid contact with eyes. Do not swallow SKLICE Lotion. Keep out of reach of children. Use on children should be under the direct supervision of an adult. For single use only; do not retreat. Discard tube after use. Wash hands after applying SKLICE Lotion. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of SKLICE Lotion or ivermectin. Ivermectin was not genotoxic in vitro in the Ames test, the mouse lymphoma assay, or the unscheduled DNA synthesis assay in human fibroblasts. Ivermectin had no adverse effects on fertility in rats at repeated oral doses of up to 3.6 mg/kg/day. Use In Specific Populations Pregnancy Pregnancy Category C There are no adequate and well-controlled studies with SKLICE Lotion in pregnant women. SKLICE Lotion should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No comparisons of animal exposure with human exposure are provided due to the low systemic exposure noted in the clinical pharmacokinetic study [see CLINICAL PHARMACOLOGY]. Human Data There are published reports of oral ivermectin use during human pregnancy. In an open label study, 397 women in their second trimester of pregnancy were treated with ivermectin tablets and albendazole at the labeled dose rate for soil-transmitted helminths and compared with a pregnant, non-treated population. No differences in pregnancy outcomes were observed between treated and untreated populations. Animal Data Systemic embryofetal development studies were conducted in mice, rats and rabbits. Oral doses of 0.1, 0.2, 0.4, 0.8, and 1.6 mg/kg/day ivermectin were administered during the period of organogenesis (gestational days 6-15) to pregnant female mice. Maternal death occurred at 0.4 mg/kg/day and above. Cleft palate occurred in the fetuses from the 0.4, 0.8, and 1.6 mg/kg/day groups. Exencephaly was seen in the fetuses from the 0.8 mg/kg group. Oral doses of 2.5, 5, and 10 mg/kg/day ivermectin were administered during the period of organogenesis (gestational days 6-17) to pregnant female rats. Maternal death and pre-implantation loss occurred at 10 mg/kg/day. Cleft palate and wavy ribs were seen in fetuses from the 10 mg/kg/day group. Oral doses of 1.5, 3, and 6 mg/kg/day ivermectin were administered during the period of organogenesis (gestational days 6-18) to pregnant female rabbits. Maternal toxicity and abortion occurred at 6 mg/kg/day. Cleft palate and clubbed forepaws occurred in the fetuses from the 3 and 6 mg/kg groups. These teratogenic effects were found only at or near doses that were maternally toxic to the pregnant female. Therefore, ivermectin does not appear to be selectively fetotoxic to the developing fetus. Nursing Mothers Following oral administration, ivermectin is excreted in human milk in low concentrations. This has not been evaluated following topical administration. Caution should be exercised when SKLICE Lotion is administered to a nursing woman. Pediatric Use The safety and effectiveness of SKLICE Lotion have been established for pediatric patients 6 months of age and older [see CLINICAL PHARMACOLOGY and Clinical Studies]. The safety of SKLICE Lotion has not been established in pediatric patients below the age of 6 months. SKLICE Lotion is not recommended in pediatric patients under 6 months of age because of the potential increased systemic absorption due to a high ratio of skin surface area to body mass and the potential for an immature skin barrier and risk of ivermectin toxicity. Geriatric Use Clinical studies of SKLICE Lotion 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.