Nit Clean

Diarrhea Caused By Giardia lamblia or Cryptosporidium Parvum

Nit Clean for Oral Suspension (patients 1 year of age and older) and Nit Clean Tablets (patients 12 years and older) are indicated for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum.

Limitations Of Use

Nit Clean for Oral Suspension and Nit Clean 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]

Recommended Dosage And Important Administration Instructions

Important Administration Instructions For Pediatric Patients 11 Years Of Age Or Younger

Nit Clean 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 Dos age

Directions For Mixing Nit Clean For Oral Suspension

Reconstitute Nit Clean for Oral Suspension as follows:

• Measure 48 mL of water for preparation of the 100 mg/5 mL suspension
• Tap bottle until all powder flows freely.
• Add approximately one-half of the 48 mL of water required for reconstitution and shake vigorously to suspend powder.
• Add remainder of water and again shake vigorously

Keep container tightly closed, and shake the suspension well before each administration. The reconstituted suspension may be stored for 7 days at room temperature, after which any unused portion must be discarded.

Hypersensitivity

Nit Clean Tablets and Nit Clean for Oral Suspension are contraindicated in patients with a prior hypersensitivity to nitazoxanide or any other ingredient in the formulations.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term carcinogenicity studies have not been conducted.

Mutagenesis

Nitazoxanide was not genotoxic in the Chinese hamster ovary (CHO) cell chromosomal aberration assay or the mouse micronucleus assay. Nitazoxanide was genotoxic in one tester strain (TA100) in the Ames bacterial mutation assay.

Impairment Of Fertility

Nitazoxanide did not adversely affect male or female fertility in the rat at 2400 mg/kg/day (approximately 20 times the clinical adult dose adjusted for body surface area).

Use In Specific Populations

Pregnancy

Risk Summary

There are no data with Nit Clean 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 exposure 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 administer 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.

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 Nit Clean and any potential adverse effects on the breastfed infant from Nit Clean or from the underlying maternal condition.

Pediatric Use

The safety and efficacy of Nit Clean 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 Nit Clean for Oral Suspension 100 mg/5 mL. Furthermore, the safety and efficacy of Nit Clean 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 Nit Clean for Oral Suspension 100 mg/5 mL. [Clinical Studies]

The safety and efficacy of Nit Clean 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 Nit Clean Tablets 500 mg.

A single Nit Clean Tablet contains a greater amount of nitazoxanide than is recommended for use in pediatric patients 11 years or younger..

Safety and efficacy of Nit Clean for Oral Suspension in pediatric patients less than one year of age has not been studied.

Geriatric Use

Clinical studies of Nit Clean Tablets and Nit Clean 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 Nit Clean Tablets and Nit Clean for Oral Suspension.

Renal And Hepatic Impairment

The pharmacokinetics of nitzoxanide in patients with compromised renal or hepatic function has not been studied.

HIV-Infected Or Immunodeficient Patients

Nit Clean Tablets and Nit Clean for Oral Suspension have not been studied for the treatment of diarrhea caused by G. lamblia in HIV-infected or immunodeficient patients. Nit Clean Tablets and Nit Clean for Oral Suspension 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]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions 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 Nit Clean was evaluated in 2177 HIV-uninfected subjects 12 months of age and older who received Nit Clean Tablets or Nit Clean for Oral Suspension at the recommended dose for at least three days. In pooled controlled clinical trials involving 536 HIV-uninfected subjects treated with Nit Clean Tablets or Nit Clean 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 Nit Clean 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 Nit Clean-treated subjects based upon age.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Nit Clean. 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 Nit Clean 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

Limited information on nitazoxanide overdosage is available. Single oral doses of up to 4000 mg nitazoxanide have been administered to healthy adult volunteers without significant adverse effects. 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 Nit Clean. Because tizoxanide is highly protein bound ( > 99.9%), dialysis is unlikely to significantly reduce plasma concentrations of the drug.

Absorption

Single Dosing

Following oral administration of Nit Clean Tablets or Oral Suspension, the parent drug, nitazoxanide, is not detected in plasma. The pharmacokinetic parameners 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 Nit Clean Tablet with food to subjects ≥12 years of age

Table 3: Mean (+/-SD) plasma pharmacokinetic of tizoxanide and tizoxanide glucuronide parameter values following administration of single dose of Nit Clean for Oral Suspension with food to subjects ≥1year of age

Multiple Dosing

Following oral administration of a single Nit Clean Tablet every 12 hours for 7 consecutive days, there was no significant accumulation of nitazoxanide metabolites tizoxanide or tizoxanide glucuronide detected in plasma.

Bioavailability

Nit Clean for Oral Suspension is not bioequivalent to Nit Clean Tablets. The relative bioavailability of the suspension compared to the tablet was 70%.

When Nit Clean Tablets are administered with food, the AUCt of tizoxanide and tizoxanide glucuronide in plasma is increased almost two-fold and the Cmax is increased by almost 50%.

When Nit Clean for Oral Suspension was administered with food, the AUCt of tizoxanide and tizoxanide glucuronide increased by about 45-50% and the Cmax increased by ≥ 10%.

Nit Clean Tablets and Nit Clean for Oral Suspension were administered with food in clinical trials and hence they are recomended to be administered with food

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.