IVERMECTIN: 3,018 Adverse Event Reports & Safety Profile

SOOLANTRA (ivermectin) cream, 1% is a white to pale yellow hydrophilic cream intended for topical use. Each gram of SOOLANTRA cream contains 10 mg of ivermectin. Ivermectin is a semi-synthetic derivative isolated from the fermentation of Streptomyces avermitilis that belongs to the avermectin family of macrocyclic lactones. Ivermectin is a mixture containing not less than 95.0% and not more than 102.0% of 5-O-demethyl-22,23-dihydroavermectin A 1a plus 5-O-demethyl-25-de(1-methylpropyl)-25-(1-methylethyl)-22,23-dihydroavermectin 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; and the ratio (calculated by area percentage) of component H 2 B 1a /(H 2 B 1a + H 2 B 1b ) is not less than 90.0%. The respective empirical formulas of H 2 B 1a and H 2 B 1b 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: Component H 2 B 1a : R = C 2 H 5 , Component H 2 B 1b : R = CH 3 . SOOLANTRA cream contains the following inactive ingredients: carbomer copolymer type B, cetyl alcohol, citric acid monohydrate, dimethicone, edetate disodium, glycerin, isopropyl palmitate, methylparaben, oleyl alcohol, phenoxyethanol, polyoxyl 20 cetostearyl ether, propylene glycol, propylparaben, purified water, sodium hydroxide, sorbitan monostearate, and stearyl alcohol. ivermectin-chem-struct

Directions Important: Read warnings before use .Children 6 months of age to under 12 years of age : an adult should supervise use Adults and children 6 months of age and over: Inspect All houschold members should be checked by anothe!person for lice and/or nits (eggs) Use a magnifying glassin bright light to help you see thelice and/or nits(eggs) Use a tool, such as a comb or two unsharpened pencilsto lift and part the hair Look for tiny nits near the scalp, beginning at the backof theneck and behind the ears Examine small sections ofthe hair (1-2 inches wide) ata time .Unlike dandruff, nits stick to the hair, Dandruff shouldmove when lightly touched If either lice or nits (eggs) are found, treat with product Treat Your hair and scalp must be DRY before applyingproduct Apply the product directly onto dry hair and scalp Completely cover your scalp and hair closest to thescalp first.and then apply outwards towards the endsofyour hair Use only as much asneeded to fully cover hair andscalp up to one full bottle, and discard the remainingRub product throughout your hair Itis important to completely cover your entire head sothat all lice and eggs are exposed to the lotion, Be surethat each hair is coated from the scalp to the tip Wait and Rinse Allow product to stay on your hair and scalp for 10minutes after it has been applied, Use a timer or clockStart timing after you have completely covered yourhair and scalp with product.

After

10 minutes, rinse product completely from youhair and scalp using only water. After rinsing, dry and style hair as usual.

Wait

24 hoursbefore applying shampoo. After treatment Wash your hands after applying product. -Nit combing is not necessary whentreating with product for it to work, but ifdesired, a fne-tooth comb or special nitcomb may be used to remove dead liceand nits.This is a single use product, Discard bottle after use.Do not use again on the same personand same lice infestation without talkingto a healthcare provider frst.If infestation continues, see a doctor forother treatments. Machine wash any bedding and clothingused by anyone having lice, Machinewash at high temperatures (150°F) andtumble in a hot dryer for 20 minutes.After fnishing treatment with licemedicine, check everyone in your famillyfor lice after one week. Considertreatment for those who have lice.

Directions Important: Read warnings on carton before use. children 6 months of age to under 12 years of age: an adult should supervise use. adults and children 6 months of age and over: Inspect all household members should be checked by another person for lice and/or nits (eggs) use a magnifying glass in bright light to help you see the lice and/or nits (eggs) use a tool, such as a comb or two unsharpened pencils, to lift and part the hair look for tiny nits near the scalp, beginning at the back of the neck and behind the ears examine small sections of the hair (1-2 inches wide) at a time unlike dandruff, nits stick to the hair. Dandruff should move when lightly touched. If either lice or nits (eggs) are found, treat with product. Treat your hair and scalp must be DRY before applying product use the top of cap to break the tamper seal on the tube apply product directly to dry hair and scalp completely cover your scalp and hair closest to the scalp first, and then apply outwards towards the ends of your hair use only amount needed to completely cover hair and scalp, up to 1 entire tube, and discard the remaining rub product throughout your hair 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. Wait and rinse allow product 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 product.

After

10 minutes, rinse product completely from your hair and scalp using only water after rinsing, dry and style as usual.

Wait

24 hours before applying shampoo. After treatment wash your hands after applying product nit combing is not necessary when treating with product for it to work, but if desired, a fine-tooth comb or special nit comb may be used to remove dead lice and nits this is a single use product. Discard tube after use. Do not use again on the same person and same lice infestation without talking to a healthcare provider first if infestation continues, see a doctor for other treatments 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. After finishing treatment with lice medicine, check everyone in your family for lice after one week. Consider treatment for those who have lice.

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

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 tablets, the following adverse reactions were reported as possibly, probably, or definitely related to ivermectin tablets: 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 tablets experienced more abdominal distention and chest discomfort than patients treated with albendazole. However, ivermectin tablet 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 tablets. (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 tablets, 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 tablets, 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 tablets. 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 tablets, 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 tablets: 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 Advagen Pharma Ltd, at +1-866-488-0312 or FDA at 1-800 FDA-1088 or www.fda.gov/medwatch.

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.

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. Information for Patients Ivermectin tablets 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 ivermectin tablets do not kill the adult Onchocerca parasites, and therefore repeated follow-up and retreatment is usually required.

Drug Interactions

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/m 2 /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 tablets 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.

DRUG INTERACTIONS 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.

Active ingredient Ivermectin 0.5%

Inactive ingredients butylated hydroxyanisole, castor oil, cetyl alcohol, citric acid anhydrous, crodalan AWS, cyclomethicone, glycerin, imidurea, lanolin alcohols, methylparaben, oleyl alcohol, olive oil, propylene glycol, propylparaben, purified water, shea butter, sodium citrate anhydrous, sorbitan tristearate, and stearyl alcohol.