2.1 Recommended Dosage and Important Administration Instructions

Important Administration Instructions for Pediatric Patients 11 years of Age or Younger:

ALINIA 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

2.2 Directions for Mixing ALINIA for Oral Suspension

Reconstitute ALINIA 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.

3.1 ALINIA Tablets (500 mg)

Round, yellow, film-coated tablets debossed with ALINIA on one side and 500 on the other side. Each tablet contains 500 mg of nitazoxanide.

3.2 ALINIA for Oral Suspension (100 mg/5 mL)

Pink-colored powder formulation that, when reconstituted as directed, contains 100 mg nitazoxanide/5 mL. The reconstituted suspension has a pink color and strawberry flavor.

4.1 Hypersensitivity

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

6.1 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 ALINIA was evaluated in 2177 HIV-uninfected subjects 12 months of age and older who received ALINIA 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 ALINIA 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 ALINIA 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 ALINIA-treated subjects based upon age.

6.2 Postmarketing Experience

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

7.1 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).

8.1 Pregnancy

Risk Summary

There are no data with ALINIA 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.

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 ALINIA and any potential adverse effects on the breastfed infant from ALINIA 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 ALINIA 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 ALINIA Tablets 500 mg.

A single ALINIA 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 ALINIA 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 ALINIA Tablets and ALINIA for Oral Suspension.

8.6 Renal and Hepatic Impairment

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

8.7 HIV-Infected or Immunodeficient Patients

ALINIA 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. ALINIA Tablets and ALINIA 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 (14)]

12.1 Mechanism of Action

Nitazoxanide is an antiprotozoal [ see Microbiology (12.4))].

12.3 Pharmacokinetics

Absorption

Single Dosing:

Following oral administration of ALINIA 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 ALINIA Tablet with food to subjects ≥12 years of age

*T max is given as a Mean (Range)

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

*T max is given as a Mean (Range)

Multiple dosing:

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

Bioavailability:

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

When ALINIA Tablets are administered with food, the AUC t of tizoxanide and tizoxanide glucuronide in plasma is increased almost two-fold and the C max is increased by almost 50%.

When ALINIA for Oral Suspension was administered with food, the AUC t of tizoxanide and tizoxanide glucuronide increased by about 45-50% and the C max increased by ≤10%.

ALINIA Tablets and ALINIA for Oral Suspension were administered with food in clinical trials and hence they are recomended 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 ALINIA Tablets in pediatric patients 12-17 years of age are provided above in Table 2. The pharmacokinetics of tizoxanide and tizoxanide glucuronide following administration of ALINIA for Oral Suspension in pediatric patients 1-11 years of age are provided above in Table 3.

Drug Interaction Studies

In vitro studies have demonstrated that tizoxanide has no significant inhibitory effect on cytochrome P450 enzymes.

13.1 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).

14.1 Diarrhea Caused by G. lamblia

Diarrhea caused by G. lamblia in adults and adolescents 12 years of age or older:

In a double-blind, controlled trial (Study 1) conducted in Peru and Egypt in adults and adolescents with diarrhea and with one or more enteric symptoms (e.g., abdominal pain, nausea, vomiting, fever, abdominal distention, loss of appetite, flatulence) caused by G. lamblia, a three-day course of treatment with ALINIA Tablets administered 500 mg twice daily was compared with a placebo tablet for 3 days. A third group of patients received open-label ALINIA for Oral Suspension administered 500 mg/25 mL of suspension twice daily for 3 days. A second double-blind, controlled trial (Study 2) conducted in Egypt in adults and adolescents with diarrhea and with or without enteric symptoms (e.g., abdominal colic, abdominal tenderness, abdominal cramps, abdominal distention, fever, bloody stool) caused by G. lamblia compared ALINIA Tablets administered 500 mg twice daily for 3 days to a placebo tablet. For both of these studies, clinical response was evaluated 4 to 7 days following the end of treatment. A clinical response of ‘well’ was defined as ‘no symptoms, no watery stools and no more than 2 soft stools with no hematochezia within the past 24 hours’ or ‘no symptoms and no unformed stools within the past 48 hours.’ The following clinical response rates were obtained:

Table 4. Adult and Adolescent Patients with Diarrhea Caused by G. lamblia

Clinical Response Rates* 4 to 7 Days Post-therapy

% (Number of Successes/Total)

* Includes all patients randomized with G. lamblia as the sole pathogen. Patients failing to complete the studies were treated as failures.

¶ Clinical response rates statistically significantly higher when compared to placebo.

§ The 95% confidence interval of the difference in response rates for the tablet and suspension is (-14%, 17%).

Some patients with ‘well’ clinical responses had G. lamblia cysts in their stool samples 4 to 7 days following the end of treatment. The relevance of stool examination results in these patients is unknown. Patients should be managed based upon clinical response to treatment.

Diarrhea caused by G. lamblia in pediatric patients 1 through 11 years of age:

In a randomized, controlled trial conducted in Peru in 110 pediatric patients with diarrhea and with or without enteric symptoms (e.g., abdominal distention, right iliac fossa tenderness) caused by G. lamblia, a three-day course of treatment with nitazoxanide (100 mg twice daily in pediatric patients ages 24-47 months, 200 mg twice daily in pediatric patients ages 4 through 11 years) was compared to a five-day course of treatment with metronidazole (125 mg twice daily in pediatric patients ages 2 through 5 years, 250 mg twice daily in pediatric patients ages 6 through 11 years). Clinical response was evaluated 7 to 10 days following initiation of treatment with a ‘well’ response defined as ‘no symptoms, no watery stools and no more than 2 soft stools with no hematochezia within the past 24 hours’ or ‘no symptoms and no unformed stools within the past 48 hours.’ The following clinical cure rates were obtained:

Table 5. Clinical Response Rates in Pediatric Patients 7 to 10 Days Following Initiation of Therapy

Intent-to-Treat and Per Protocol Analyses

% (Number of Successes/Total), [95% Confidence Interval]

† Intent-to-treat analysis includes all patients randomized with patients not completing the study treated as failures.

¶ Per protocol analysis includes only patients who took all of their medication and completed the study. Seven patients in each treatment group missed at least one dose of medication and one in the metronidazole treatment group was lost to follow-up.

§ 95% Confidence Interval on the difference in response rates (nitazoxanide-metronidazole).

Some patients with ‘well’ clinical responses had G. lamblia cysts in their stool samples 4 to 7 days following the end of treatment. The relevance of stool examination results in these patients is unknown. Patients should be managed based upon clinical response to treatment.

14.2 Diarrhea Caused by C. parvum

Diarrhea caused by C. parvum in adults and adolescents 12 years of age or older:

In a double-blind, controlled trial conducted in Egypt in adults and adolescents with diarrhea and with or without enteric symptoms (e.g., abdominal pain/cramps, nausea, vomiting) caused by C. parvum, a three-day course of treatment with ALINIA Tablets administered 500 mg twice daily was compared with a placebo tablet for 3 days. A third group of patients received open-label ALINIA for Oral Suspension administered 500 mg/25 mL of suspension twice daily for 3 days. Clinical response was evaluated 4 to 7 days following the end of treatment. A clinical response of ‘well’ was defined as ‘no symptoms, no watery stools and no more than 2 soft stools within the past 24 hours’ or ‘no symptoms and no unformed stools within the past 48 hours.’ The following clinical response rates were obtained:

Table 6. Clinical Response Rates in Adult and Adolescent Patients 4 to 7 Days Post-therapy

% (Number of Successes/Total)

* Includes all patients randomized with C. parvum as the sole pathogen. Patients failing to complete the study were treated as failures.

¶ Clinical response rates statistically significantly higher when compared to placebo.

§ The 95% confidence interval of the difference in response rates for the tablet and suspension is (-10%, 28%).

In a second double-blind, placebo-controlled study of nitazoxanide tablets conducted in Egypt in adults and adolescents with diarrhea and with or without enteric symptoms (e.g., abdominal colic, abdominal cramps, epigastric pain) caused by C. parvum as the sole pathogen, clinical and parasitological response rates showed a similar trend to the first study. Clinical response rates, evaluated 2 to 6 days following the end of treatment, were 71% (15/21) in the nitazoxanide group and 42.9% (9/21) in the placebo group.

Some patients with ‘well’ clinical responses had C. parvum oocysts in their stool samples 4 to 7 days following the end of treatment. The relevance of stool examination results in these patients is unknown. Patients should be managed based upon clinical response to treatment.

Diarrhea caused by C. parvum in pediatric patients 1 through 11 years of age :

In two double-blind, controlled trials in pediatric patients with diarrhea and with or without enteric symptoms (e.g., abdominal distention, colic, left iliac fossa tenderness) caused by C. parvum, a three-day course of treatment with nitazoxanide (100 mg twice daily in pediatric patients ages 12-47 months, 200 mg twice daily in pediatric patients ages 4 through 11 years) was compared with a placebo. One study was conducted in Egypt in outpatients ages 1 through 11 years with diarrhea caused by C. parvum. Another study was conducted in Zambia in malnourished pediatric patients admitted to the hospital with diarrhea caused by C. parvum. Clinical response was evaluated 3 to 7 days post-therapy with a ‘well’ response defined as ‘no symptoms, no watery stools and no more than 2 soft stools within the past 24 hours’ or ‘no symptoms and no unformed stools within the past 48 hours.’ The following clinical response rates were obtained:

Table 7. Clinical Response Rates in Pediatric Patients 3 to 7 Days Post-therapy Intent-to-Treat Analyses

% (Number of Successes/Total)

* Clinical response rates statistically significantly higher compared to placebo.

¶ 60% considered severely underweight, 19% moderately underweight, 17% mild underweight.

Some patients with ‘well’ clinical responses had C. parvum oocysts in their stool samples 3 to 7 days following the end of treatment. The relevance of stool examination results in these patients is unknown. Patients should be managed based upon clinical response to treatment.

Diarrhea caused by C. parvum in Acquired Immune Deficiency Syndrome (AIDS) patients :

A double-blind, placebo-controlled trial did not produce clinical cure rates that were significantly different from the placebo control when conducted in hospitalized, severely malnourished pediatric patients with acquired immune deficiency syndrome (AIDS) in Zambia. In this study, the pediatric patients received a three day course of nitazoxanide suspension (100 mg twice daily in pediatric patients ages 12-47 months, 200 mg twice daily in pediatric patients ages 4 through 11 years) and were evaluated for response four days after the end of treatment.

16.1 ALINIA Tablets (500 mg)

ALINIA tablets are round, yellow, film-coated tablets debossed with ALINIA on one side and 500 on the other side. Each tablet contains 500 mg of nitazoxanide. The tablets are packaged in HDPE bottles of 12 and 30 tablets.

Bottles of 12 tablets NDC 67546-111-14

Bottles of 30 tablets NDC 67546-111-12

Store the tablets at 25 oC (77 oF); excursions permitted to 15 oC-30 oC (59 oF-86 oF). [See USP Controlled Room Temperature]

16.2 ALINIA for Oral Suspension (100 mg/5 mL)

ALINIA for oral suspension is a pink-colored powder formulation that, when reconstituted as directed, contains 100 mg nitazoxanide/5 mL. The reconstituted suspension has a pink color and strawberry flavor. Alinia for oral suspension is available as:

Bottles of 60 mL NDC 67546-212-21

Store the unsuspended powder at 25 oC (77 oF); excursions permitted to 15 oC-30 oC (59 oF-86 oF). [See USP Controlled Room Temperature]

The reconstituted suspension may be stored for 7 days at room temperature, after which any unused portion must be discarded [see Dosage and Administration (2.2)]