Nitazoxanide

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# Overview
Nitazoxanide is an anti-infective agent that is FDA approved for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum.   Common adverse reactions include abdominal pain, diarrhea, nausea, vomiting,headache.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

# Indications
Diarrhea caused by Giardia lamblia or Cryptosporidium parvum:
- Alinia for Oral Suspension (patients 1 year of age and older) and Alinia Tablets (patients 12 years and older) are indicated for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum.
- Alinia for Oral Suspension and Alinia Tablets have not been shown to be superior to placebo for the treatment of diarrhea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients

# Dosage
DIRECTIONS FOR MIXING ALINIA FOR ORAL SUSPENSION
- Prepare a suspension at time of dispensing as follows: The amount of water required for preparation of the suspension is 48 mL. Tap bottle until all powder flows freely. Add approximately one-half of the total amount of water required for reconstitution and shake vigorously to suspend powder. Add remainder of water and again shake vigorously.
- The container should be kept tightly closed, and the suspension should be shaken well before each administration. The suspension may be stored for 7 days, after which any unused portion must be discarded.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Nitazoxanide in adult patients.

### NonGuideline-Supported Use
- There is limited information regarding Off-Label NonGuideline-Supported Use of Nitazoxanide in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)

# Indications
Diarrhea caused by Giardia lamblia or Cryptosporidium parvum:
- Alinia for Oral Suspension (patients 1 year of age and older) and Alinia Tablets (patients 12 years and older) are indicated for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum.
- Alinia for Oral Suspension and Alinia Tablets have not been shown to be superior to placebo for the treatment of diarrhea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients

# Dosage
DIRECTIONS FOR MIXING ALINIA FOR ORAL SUSPENSION
- Prepare a suspension at time of dispensing as follows: The amount of water required for preparation of the suspension is 48 mL. Tap bottle until all powder flows freely. Add approximately one-half of the total amount of water required for reconstitution and shake vigorously to suspend powder. Add remainder of water and again shake vigorously.
- The container should be kept tightly closed, and the suspension should be shaken well before each administration. The suspension may be stored for 7 days, after which any unused portion must be discarded.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Nitazoxanide in pediatric patients.

### NonGuideline-Supported Use
- There is limited information regarding Off-Label NonGuideline-Supported Use of Nitazoxanide in pediatric patients.

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

# Warnings
- There is limited information regarding Warning of Nitazoxanide in pediatric patients.

# Adverse Reactions

## Clinical Trials Experience
- Alinia Tablets: In controlled and uncontrolled clinical studies of 1,657 HIV-uninfected patients age 12 years and older who received various dosage regimens of Alinia Tablets, the most common adverse events reported regardless of causality assessment were: abdominal pain (6.6%), diarrhea (4.2%), headache (3.1%) and nausea (3.0%). In placebo-controlled clinical trials using the recommended dose, the rates of occurrence of these events did not differ significantly from those of the placebo. In placebo-controlled trials of HIV-uninfected patients age 12 years and older who received Alinia Tablets for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum, less than 1% of patients discontinued therapy because of an adverse event.
- Adverse events occurring in less than 1% of the patients age 12 years and older participating in clinical trials of Alinia Tablets are listed below:
- Body as a Whole: asthenia, fever, pain, allergic reaction, pelvic pain, back pain, chills, chills and fever, flu syndrome.
- Nervous System: dizziness, somnolence, insomnia, tremor, hypesthesia.
- Digestive System: vomiting, dyspepsia, anorexia, flatulence, constipation, dry mouth, thirst.
- Urogenital System: discolored urine, dysuria, amenorrhea, metrorrhagia, kidney pain, edema labia.
- Metabolic & Nutrition: increased SGPT.
- Hemic & Lymphatic Systems: anemia, leukocytosis.
- Skin: rash, pruritus.
- Special Senses: eye discoloration, ear ache.
- Respiratory System: epistaxis, lung disease, pharyngitis.
- Cardiovascular System: tachycardia, syncope, hypertension.
- Muscular System: myalgia, leg cramps, spontaneous bone fracture.
Alinia for Oral Suspension:
- In controlled and uncontrolled clinical studies of 613 HIV-uninfected pediatric patients who received Alinia for Oral Suspension, the most frequent adverse events reported regardless of causality assessment were: abdominal pain (7.8%), diarrhea (2.1%), vomiting (1.1%) and headache (1.1%). These were typically mild and transient in nature. In placebo-controlled clinical trials, the rates of occurrence of these events did not differ significantly from those of the placebo. None of the 613 pediatric patients discontinued therapy because of adverse events.
- Adverse events occurring in less than 1% of the pediatric patients participating in clinical trials of Alinia for Oral Suspension are listed below:
- Digestive System: nausea, anorexia, flatulence, appetite increase, enlarged salivary glands.
- Body as a Whole: fever, infection, malaise.
- Metabolic & Nutrition: increased creatinine, increased SGPT.
- Skin: pruritus, sweat.
- Special Senses: eye discoloration (pale yellow).
- Respiratory System: rhinitis.
- Nervous System: dizziness.
- Urogenital System: discolored urine.
- The adverse events seen in adult patients treated with Alinia for Oral Suspension were similar to those observed in adult patients treated with Alinia Tablets.

## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Nitazoxanide in the drug label.

# Drug Interactions
- Tizoxanide is highly bound to plasma protein (>99.9%). Therefore, caution should be used 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). In vitro metabolism studies have demonstrated that tizoxanide has no significant inhibitory effect on cytochrome P450 enzymes. Although no drug-drug interaction studies have been conducted in vivo, it is expected that no significant interaction would occur when nitazoxanide is co-administered with drugs that either are metabolized by or inhibit cytochrome P450 enzymes.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B: Reproduction studies have been performed at doses up to 3,200 mg/kg/day in rats (approximately 26 times the clinical adult dose adjusted for body surface area) and 100 mg/kg/day in rabbits (approximately 2 times the clinical adult dose adjusted for surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to nitazoxanide. There are, however, no adequate and well-controlled studies in pregnant women.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nitazoxanide in women who are pregnant.

### Labor and Delivery
- There is no FDA guidance on use of Nitazoxanide during labor and delivery.

### Nursing Mothers
- It is not known whether nitazoxanide is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nitazoxanide is administered to a nursing woman.

### Pediatric Use
- A single Alinia Tablet contains a greater amount of nitazoxanide than is recommended for pediatric dosing and should therefore not be used in pediatric patients 11 years or younger. Alinia for Oral Suspension should be used for dosing nitazoxanide in pediatric patients.
- Safety and effectiveness of Alinia for Oral Suspension in pediatric patients less than 1 year of age have not been studied.

### Geriatic 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. As stated in the precautions section, this therapy must be administered with caution to patients with renal and or hepatic impairment.

### Gender
- There is no FDA guidance on the use of Nitazoxanide with respect to specific gender populations.

### Race
- There is no FDA guidance on the use of Nitazoxanide with respect to specific racial populations.

### Renal Impairment
- There is no FDA guidance on the use of Nitazoxanide in patients with renal impairment.

### Hepatic Impairment
- There is no FDA guidance on the use of Nitazoxanide in patients with hepatic impairment.

### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Nitazoxanide in women of reproductive potentials and males.

### Immunocompromised Patients
- There is no FDA guidance one the use of Nitazoxanide in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral

### Monitoring
- There is limited information regarding Monitoring of Nitazoxanide in the drug label.

# IV Compatibility
- There is limited information regarding IV Compatibility of Nitazoxanide in the drug label.

# Overdosage
- Information on nitazoxanide overdosage is not available. In acute studies in rodents and dogs, the oral LD50 was higher than 10,000 mg/kg. Single oral doses of up to 4,000 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 carefully observed and given symptomatic and supportive treatment.

# Pharmacology

## Mechanism of Action
- The antiprotozoal activity of nitazoxanide is believed to be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction which is essential to anaerobic energy metabolism. Studies have shown that the PFOR enzyme from Giardia lamblia directly reduces nitazoxanide by transfer of electrons in the absence of ferredoxin. The DNA-derived PFOR protein sequence of Cryptosporidium parvum appears to be similar to that of Giardia lamblia. Interference with the PFOR enzyme-dependent electron transfer reaction may not be the only pathway by which nitazoxanide exhibits antiprotozoal activity.

## Structure
- Alinia Tablets and Alinia for Oral Suspension contain the active ingredient, nitazoxanide, a synthetic antiprotozoal agent 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 C12H9N3O5S and the molecular weight is 307.3. The structural formula is:
- Alinia Tablets contain 500 mg of nitazoxanide and the following inactive ingredients: maize starch, pregelatinized corn starch, hydroxypropyl methylcellulose, sucrose, sodium starch glycollate, talc, magnesium stearate, soy lecithin, polyvinyl alcohol, xanthan gum, titanium dioxide, FD&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, and FD&C Blue No. 2 Aluminum Lake.
- Alinia for Oral Suspension, when reconstituted with 48 mL of water, produces 60 mL of a homogeneous suspension with a pink color that contains 100 mg nitazoxanide per 5 mL and the following inactive ingredients: sodium benzoate, sucrose, xanthan gum, microcrystalline cellulose and carboxymethylcellulose sodium, anhydrous citric acid, sodium citrate dihydrate, maltodextrin, modified food starch, triacetin, FD&C Red #40 and artificial strawberry flavoring.

## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Nitazoxanide in the drug label.

## Pharmacokinetics
- There is limited information regarding Pharmacokinetics of Nitazoxanide in the drug label.

## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term carcinogenicity studies have not been conducted.
- Nitazoxanide was not genotoxic in the Chinese hamster ovary (CHO) cell chromosomal aberration assay or the mouse micronucleus assay. Nitazoxanide was genotoxic in 1 tester strain (TA 100) in the Ames bacterial mutation assay.
- Nitazoxanide did not adversely affect male or female fertility in the rat at 2,400 mg/kg/day (approximately 20 times the clinical adult dose adjusted for body surface area).

# Clinical Studies
Diarrhea caused by Giardia lamblia in adults and adolescents 12 years of age or older:
- In a double-blind, controlled study (Study 1) conducted in Peru and Egypt in adults and adolescents with diarrhea caused by Giardia lamblia, a three-day course of treatment with Alinia Tablets administered 500 mg BID was compared with a placebo tablet for 3 days. A third group of patients received open-label Alinia for Oral Suspension administered 500mg/25mL of suspension BID for 3 days. A second double-blind, controlled study (Study 2) conducted in Egypt in adults and adolescents with diarrhea caused by Giardia lamblia compared Alinia Tablets administered 500 mg BID 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:
Adult and Adolescent Patients with Diarrhea Caused by Giardia lamblia
- Some patients with 'well' clinical responses had Giardia 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 Giardia lamblia in pediatric patients 1 through 11 years of age:
- In a randomized, controlled study conducted in Peru in 110 pediatric patients with diarrhea caused by Giardia lamblia, a three-day course of treatment with nitazoxanide (100 mg BID in pediatric patients ages 24-47 months, 200 mg BID in pediatric patients ages 4 through 11 years) was compared to a five-day course of treatment with metronidazole (125 mg BID in pediatric patients ages 2 through 5 years, 250 mg BID 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:
Pediatric Patients with Diarrhea Caused by Giardia lamblia
- Some patients with 'well' clinical responses had Giardia 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 Cryptosporidium parvum in adults and adolescents 12 years of age or older:
- In a double-blind, controlled study conducted in Egypt in adults and adolescents with diarrhea caused by Cryptosporidium parvum, a three-day course of treatment with Alinia Tablets administered 500 mg BID was compared with a placebo tablet for 3 days. A third group of patients received open-label Alinia for Oral Suspension administered 500mg/25mL of suspension BID 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:
Adult and Adolescent Patients with Diarrhea Caused by Cryptosporidium parvum
- In a second double-blind, placebo-controlled study of nitazoxanide tablets conducted in Egypt in adults and adolescents with diarrhea caused by Cryptosporidium 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 Cryptosporidium 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 Cryptosporidium parvum in pediatric patients 1 through 11 years of age:
- In two double-blind, controlled studies in pediatric patients with diarrhea caused by Cryptosporidium parvum, a three-day course of treatment with nitazoxanide (100 mg BID in pediatric patients ages 12-47 months, 200 mg BID 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 Cryptosporidium parvum. Another study was conducted in Zambia in malnourished pediatric patients admitted to the hospital with diarrhea caused by Cryptosporidium 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:
Pediatric Patients with Diarrhea Caused by Cryptosporidium parvum
- Some patients with 'well' clinical responses had Cryptosporidium 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 Cryptosporidium parvum in AIDS patients:
- A double-blind, placebo-controlled study 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 BID in pediatric patients ages 12-47 months, 200 mg BID in pediatric patients ages 4 through 11 years) and were evaluated for response four days after the end of treatment.

# How Supplied
- 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 30 tablets.
Bottles of 30            NDC 67546-111-12
- 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

## Storage
- Storage and Stability: Store the tablets, unsuspended powder, and the reconstituted oral suspension at 25C (77F); excursions permitted to 15-30C (59-86F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
Information for Patients
- Alinia Tablets and Alinia for Oral Suspension should be taken with food.
- Diabetic patients and caregivers should be aware that the oral suspension contains 1.48 grams of sucrose per 5 mL.

# Precautions with Alcohol
- Alcohol-Nitazoxanide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- ALINIA 

# Look-Alike Drug Names
- A  B

# Drug Shortage Status

# Price