Nitazoxanide

1 INDICATIONS AND 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 tablets are antiprotozoal indicated for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum (1 ). Limitations of Use: Nitazoxanide tablets have not been shown to be effective for the treatment of diarrhea caused by C. parvum in HIV-infected or immunodeficient patients (1).

2 DOSAGE AND 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 500 mg nitazoxanide tablet 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 500 mg nitazoxanide tablet taken orally every 12 hours with food 3 days

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

12.3 Pharmacokinetics Absorption Single Dosing: Following oral administration of nitazoxanide tablets, the parent drug, nitazoxanide, is not detected in plasma. The pharmacokinetic parameters of the metabolites, tizoxanide and tizoxanide glucuronide are shown in Tables 2 and 3 below. Table 2. Mean (± SD) plasma pharmacokinetic parameters of tizoxanide and tizoxanide glucuronide following administration of a single dose of one 500 mg nitazoxanide tablet with food to subjects ≥12 years of age Tizoxanide Tizoxanide Glucuronide Age C max (mcg/mL) *T max (hr) AUC τ (mcg•hr/mL) C max (mcg/mL) *T max (hr) AUC τ (mcg•hr/mL) 12 to 7 years 9.1 (6.1) 4.0 (1 to 4) 39.5 (24.2) 7.3 (1.9) 4.0 (2 to 8) 46.5 (18.2) ≥18 years 10.6 (2.0) 3.0 (2 to 4) 41.9 (6.0) 10.5 (1.4) 4.5 (4 to 6) 63.0 (12.3) * T max is given as a Mean (Range) Multiple dosing: Following oral administration of a single nitazoxanide tablet every 12 hours for 7 consecutive days, there was no significant accumulation of nitazoxanide metabolites tizoxanide or tizoxanide glucuronide detected in plasma. Bioavailability: Alina for oral suspension is not bioequivalent to nitazoxanide tablets. The relative bioavailability of the suspension compared to the tablet was 70%. When nitazoxanide tablets are administered with food, the AUC τ of tizoxanide and tizoxanide glucuronide in plasma is increased almost two-fold and the C max is increased by almost 50%. Nitazoxanide tablets were administered with food in clinical trials and hence they are recommended to be administered with food [see Dosage and Administration ( 2.1 )] . Distribution In plasma, more than 99% of tizoxanide is bound to proteins. Elimination Metabolism Following oral administration in humans, nitazoxanide is rapidly hydrolyzed to an active metabolite, tizoxanide (desacetyl-nitazoxanide). Tizoxanide then undergoes conjugation, primarily by glucuronidation. Excretion Tizoxanide is excreted in the urine, bile and feces, and tizoxanide glucuronide is excreted in urine and bile. Approximately two-thirds of the oral dose of nitazoxanide is excreted in the feces and one-third in the urine. Specific Populations Pediatric Patients The pharmacokinetics of tizoxanide and tizoxanide glucuronide following administration of nitazoxanide tablets in pediatric patients 12 to 17 years of age are provided above in Table 2. Mean (±SD) plasma pharmacokinetic parameters of tizoxanide and tizoxanide glcuronide following administration of a single dose of one 500 mg nitazoxanide tablet with food to subject ≥12 years of age. Drug Interaction Studies In vitro studies demonstrated that tizoxanide has no significant inhibitory effect on cytochrome P450 enzymes.