Nitazoxanide

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 Annora Pharma Private Limited at 1-866-495-1995 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 Alina 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 Alina 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

8 USE IN SPECIFIC POPULATIONS 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 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 )] . 8.5 Geriatric Use Clinical studies of nitazoxanide tablets 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. 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 have not been studied for the treatment of diarrhea caused by G. lamblia in HIV-infected or immunodeficient patients. Nitazoxanide tablets have not been shown to be superior to placebo for the treatment of diarrhea caused by C. parvum in HIV-infected or immunodeficient patients [see Clinical Studies ( 14 )] .