Nitazoxanide

1 INDICATIONS & USAGE Diarrhea caused by Giardia lamblia or Cryptosporidium parvum: Nitazoxanide tablets (patients 12 years and older) are indicated for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum . Limitations of Use Nitazoxanide tablets have not been shown to be effective for the treatment of diarrhea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients [see Clinical Studies (14.2)]. Nitazoxanide tablet is an antiprotozoal indicated for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum (1). Limitations of Use: Nitazoxanide tablet has not been shown to be effective for the treatment of diarrhea caused by C. parvum in HIV-infected or immunodeficient patients (1).

2 DOSAGE & ADMINISTRATION Nitazoxanide tablets should not be administered to pediatric patient 11 years of age or younger (2.1). Dosage for treatment of diarrhea caused by G. lamblia or C. parvum (2.1): Age Dosage Duration 12 years and older One nitazoxanide tablet (500 mg nitazoxanide) every 12 hours with food 3 days 2.1 Recommended Dosage and Important Administration Instructions Important Administration Instructions for Pediatric Patients 11 years of Age or Younger: Nitazoxanide tablets should not be administered to pediatric patients 11 years of age or younger because a single tablet contains a greater amount of nitazoxanide than the recommended dosing in this pediatric age group. Table 1. Recommended Dosage Age Dosage Duration 12 years and older One nitazoxanide tablet (500 mg nitazoxanide) taken orally every 12 hours with food. 3 days

3 DOSAGE FORMS & STRENGTHS Nitazoxanide Tablets: 500 mg (3.1) 3.1 Nitazoxanide Tablets (500 mg) Round, yellow, film-coated tablets debossed with ‘ZNN’ on one side, plain on the other side, and free from physical defects. Each tablet contains 500 mg of nitazoxanide.

4 CONTRAINDICATIONS Hypersensitivity (4.1) 4.1 Hypersensitivity Nitazoxanide tablets and ALINIA for Oral Suspension are contraindicated in patients with a prior hypersensitivity to nitazoxanide or any other ingredient in the formulations.

6 ADVERSE REACTIONS The most common adverse reactions in ≥2% of patients were abdominal pain, headache, chromaturia, and nausea (6.1). To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 practice. The safety of nitazoxanide was evaluated in 2177 HIV-uninfected subjects 12 months of age and older who received nitazoxanide tablets or ALINIA for Oral Suspension at the recommended dose for at least three days. In pooled controlled clinical trials involving 536 HIV-uninfected subjects treated with nitazoxanide tablets or ALINIA for Oral Suspension, the most common adverse reactions were abdominal pain, headache, chromaturia and nausea (≥2%). Safety data were analyzed separately for 280 HIV-uninfected subjects ≥12 years of age receiving nitazoxanide at the recommended dose for at least three days in 5 placebo-controlled clinical trials and for 256 HIV-uninfected subjects 1 through 11 years of age in 7 controlled clinical trials. There were no differences between the adverse reactions reported for nitazoxanide-treated subjects based upon age. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of nitazoxanide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following is a list of adverse reactions spontaneously reported with nitazoxanide tablets which were not included in clinical trial listings: Gastrointestinal disorders : diarrhea, gastroesophageal reflux disease Nervous System disorders: dizziness Respiratory, thoracic and mediastinal disorders : dyspnea Skin and subcutaneous tissue disorders: rash, urticaria

7 DRUG INTERACTIONS Competition for binding sites may occur when administered concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices. Monitor for adverse reactions (7). 7.1 Highly Protein Bound Drugs with Narrow Therapeutic Indices Tizoxanide (the active metabolite of nitazoxanide) is highly bound to plasma protein (>99.9%). Therefore, monitor for adverse reactions when administering nitazoxanide concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices, as competition for binding sites may occur (e.g., warfarin).

8 USE IN SPECIFIC POPULATIONS Pediatric Patients: Safety and efficacy of ALINIA ® for Oral Suspension in pediatric patients less than one year of age has not been studied (8.4). 8.1 Pregnancy Risk Summary There are no data with nitazoxanide in pregnant women to inform a drug-associated risk. No teratogenicity or fetotoxicity was observed in animal reproduction studies with administration of nitazoxanide to pregnant rats and rabbits during organogenesis at exposures 30 and 2 times, respectively, the exposure at the maximum recommended human dose of 500 mg twice daily based on body surface area (BSA). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Nitazoxanide was administered orally to pregnant rats at doses of 0, 200, 800 or 3200 mg/kg/day on gestation days 6 to 15. Nitazoxanide produced no evidence of systemic maternal toxicity when administered once daily via oral gavage to pregnant female rats at levels up to 3200 mg/kg/day during the period of organogenesis. In rabbits, nitazoxanide was administered at doses of 0, 25, 50, or 100 mg/kg/day on gestation days 7 to 20. Oral treatment of pregnant rabbits with nitazoxanide during organogenesis resulted in minimal maternal toxicity and no external fetal anomalies. 8.2 Lactation Risk Summary No information regarding the presence of nitazoxanide in human milk, the effects on the breastfed infant, or the effects on milk production is available. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for nitazoxanide and any potential adverse effects on the breastfed infant from nitazoxanide or from the underlying maternal condition. 8.4 Pediatric Use The safety and efficacy of ALINIA for Oral Suspension for the treatment of diarrhea caused by G. lamblia or C. parvum in pediatric patients 1 to 11 years of age has been established based on three (3) randomized, controlled studies with 104 pediatric subjects treated with ALINIA for Oral Suspension 100 mg/5 mL. Furthermore, the safety and efficacy of ALINIA for Oral Suspension for the treatment of diarrhea caused by G. lamblia or C. parvum in pediatric patients 12 to 17 years of age has been established based on two (2) randomized controlled studies with 44 pediatric subjects treated with ALINIA for Oral Suspension 100 mg/5 mL [see Clinical Studies (14.1)] . The safety and efficacy of nitazoxanide tablets for the treatment of diarrhea caused by G. lamblia or C. parvum in pediatric patients 12 to 17 years of age has been established based on three (3) randomized controlled studies with 47 pediatric subjects treated with nitazoxanide tablets 500 mg. A single nitazoxanide tablet contains a greater amount of nitazoxanide than is recommended for use in pediatric patients 11 years or younger. [see Dosage and Administration (2.1)]. Safety and efficacy of ALINIA for Oral Suspension in pediatric patients less than one year of age has not been studied. 8.5 Geriatric Use Clinical studies of nitazoxanide tablets and ALINIA for Oral Suspension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing nitazoxanide tablets and ALINIA for Oral Suspension. 8.6 Renal and Hepatic Impairment The pharmacokinetics of nitazoxanide in patients with compromised renal or hepatic function has not been studied. 8.7 HIV-Infected or Immunodeficient Patients Nitazoxanide tablets and ALINIA for Oral Suspension have not been studied for the treatment of diarrhea caused by G. lamblia in HIV-infected or immunodeficient patients. Nitazoxanide tablets and ALINIA for Oral Suspension have not been shown to be su …

12.1 Mechanism of Action Nitazoxanide is an antiprotozoal [ see Microbiology (12.4) ].

11 DESCRIPTION Nitazoxanide tablets contain the active ingredient, nitazoxanide, a synthetic antiprotozoal for oral administration. Nitazoxanide is a light yellow crystalline powder. It is poorly soluble in ethanol and practically insoluble in water. Chemically, nitazoxanide is 2-acetyloxy- N -(5-nitro-2-thiazolyl)benzamide. The molecular formula is C 12 H 9 N 3 O 5 S and the molecular weight is 307.3. The structural formula is: Nitazoxanide tablets contain 500 mg of nitazoxanide and the following inactive ingredients: corn starch, sodium starch glycolate type A, sucrose, hydroxypropyl methylcellulose, talc, magnesium stearate, polyvinyl alcohol, titanium dioxide, D&C yellow #10 aluminum lake, lecithin (soy), xanthan gum, FD&C yellow #6 aluminum lake, FD&C blue #2 aluminum lake. structure

10 OVERDOSAGE Limited information on nitazoxanide overdosage is available. In the event of overdose, gastric lavage may be appropriate soon after oral administration. Patients should be observed and given symptomatic and supportive treatment. There is no specific antidote for overdose with nitazoxanide. Because tizoxanide is highly protein bound (>99.9%), dialysis is unlikely to significantly reduce plasma concentrations of the drug.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Nitazoxanide Tablets (500 mg) Nitazoxanide Tablets are round, yellow, film-coated tablets debossed with ‘ZNN’ on one side, plain on the other side, and free from physical defects. Each tablet contains 500 mg of nitazoxanide. The tablets are packaged in HDPE bottles as: Bottles of 6 tablets NDC 70954-934-10 Bottles of 12 tablets NDC 70954-934-20 Bottles of 30 tablets NDC 70954-934-30 Store the tablets at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].