Nitazoxanide

Nitazoxanide is an Antiprotozoal Agent belonging to Thiazolides.

Nitazoxanide can be used in the treatment of Diarrhea, infectious

Nitazoxanide is Absorbed from the gastrointestinal tract. Time to peak plasma concentration: 1-4 hours (as tizoxanide and tizoxanide glucuronide)with Plasma protein binding: >99% (tizoxanide) and Rapidly hydrolyzed to tizoxanide (active desacetyl metabolite) which partially undergoes further conjugation, primarily by glucuronidation which gets excreted faeces (approx 67%) and urine (approx 33%). Elimination half-life: 1-1.6 hours (tizoxanide).

The common side effects associated with Nitazoxanide include Nausea, vomiting, abdominal pain, diarrhea.

Nitazoxanide is available in the form of tablets and suspension.

The molecule is available in India, USA, Germany, Japan.

Nitazoxanide is rapidly metabolized to the active metabolite tizoxanide in vivo. Activity may be due to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction which is essential to anaerobic metabolism. In vitro, nitazoxanide and tizoxanide inhibit the growth of sporozoites and oocysts of Cryptosporidium parvum and trophozoites of Giardia lamblia.

Tmax of Nitazoxanide was Within 1 to 5 hours.

Nitazoxanide is available in Tablets, Suspension.

Oral: Administer higher doses preferably at late afternoon or as bedtime doses to minimize daytime sedation.

Shake suspension well prior to administration.

Nitazoxanide can be used in the treatment of Diarrhea, infectious.

Nitazoxanide exhibits antiprotozoal activity by interfering with the pyruvate ferredoxin/flavodoxin oxidoreductase dependent electron transfer reaction, an essential reaction need for anaerobic energy metabolism of various microorganisms. Sporozoites of Cryptosporidium parvum and trophozoites of Giardia lamblia are therefore inhibited, relieving symptoms of diarrhea.

Nitazoxanide is approved for use in the following clinical indications

Diarrhea, infectious: Treatment of diarrhea caused by Cryptosporidium parvum or Giardia lamblia.

Cryptosporidiosis:

Immunocompetent patients: Oral: 500 mg every 12 hours for 3 days.

Patients with HIV (off-label use): Oral: 500 mg to 1 g twice daily for 14 days (must be used in conjunction with optimized antiretroviral therapy, electrolyte replacement, symptomatic treatment, and rehydration).

Solid organ transplant recipients (off-label use): Oral: 500 mg to 1 g twice daily for 14 days, in combination with reduction of immunosuppression, when possible. In patients with severe diarrhea or treatment failure, consider 500 mg twice daily in combination with azithromycin

Giardiasis:

Oral: 500 mg every 12 hours for 3 days. Note: Alternative agent for solid organ transplant recipients

(The dosage and duration of treatment should be as per the clinical judgement of the treating physician).

100 mg/5 mL, 500 mg

Tablets, Suspension.

Dose Adjustment in Pediatric Patient:

Balantidiasis (Balantidium coli infection) (alternative agent): Limited data available:

Children 1 to <4 years: Oral suspension: Oral: 100 mg twice daily for 3 days.

Children 4 to <12 years: Oral suspension: Oral: 200 mg twice daily for 3 days.

Children ≥12 years and Adolescents: Oral suspension, tablet: Oral: 500 mg twice daily for 3 days.

Blastocystis, symptomatic infection with persistent diarrhea: Note: Need for treatment is controversial as clinical significance of infection is unknown. Limited data available:

Children 1 to <4 years: Oral suspension: Oral: 100 mg twice daily for 3 days.

Children 4 to <12 years: Oral suspension: Oral: 200 mg twice daily for 3 days.

Children ≥12 years and Adolescents: Oral suspension, tablet: Oral: 500 mg twice daily for 3 days.

Cryptosporidiosis (Cryptosporidium parvum infection):

Note: Treatment duration is 3 days in immunocompetent patients . For immunocompromised patients, including those who are HIV-exposed/-infected, suggested treatment duration is 3 to 14 days or longer, despite uncertain efficacy; HIV-infected patients should also receive optimized combination antiretroviral therapy.

Children 1 to <4 years: Oral suspension: Oral: 100 mg every 12 hours.

Children 4 to <12 years: Oral suspension: Oral: 200 mg every 12 hours.

Children ≥12 years and Adolescents: Oral suspension, tablet: Oral: 500 mg every 12 hours.

Fascioliasis (Fasciola hepatica; sheep liver fluke infection): Limited data available:

Children 1 to <4 years: Oral suspension: Oral: 100 mg every 12 hours for 7 days.

Children 4 to <12 years: Oral suspension: Oral: 200 mg every 12 hours for 7 days.

Children ≥12 years and Adolescents: Oral suspension, tablet: Oral: 500 mg every 12 hours for 7 days.

Giardiasis (Giardia duodenalis/intestinalis/lamblia infection); independent of HIV status :

Children 1 to <4 years: Oral suspension: Oral: 100 mg every 12 hours for 3 days.

Children 4 to <12 years: Oral suspension: Oral: 200 mg every 12 hours for 3 days.

Children ≥12 years and Adolescents: Oral suspension, tablet: Oral: 500 mg every 12 hours for 3 days.

Hymenolepiasis (Hymenolepis nana; dwarf tapeworm infection): Limited data available :

Children 1 to <4 years: Oral suspension: Oral: 100 mg twice daily for 3 days.

Children 4 to <12 years: Oral suspension: Oral: 200 mg twice daily for 3 days.

Children ≥12 years and Adolescents: Oral suspension, tablet: Oral: 500 mg twice daily for 3 days.

Some formulations may contain sucrose.

The dietary restriction should be individualized as per patient requirements.

Hypersensitivity to Nitazoxanide, 4-aminoquinoline compounds, or any component of the formulation; the presence of retinal or visual field changes of any etiology (when used for indications other than acute malaria).

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Disease-related concerns:

• HIV: Nitazoxanide had not been studied for treatment of diarrhea caused by G. lamblia in patients with HIV infection. Nitazoxanide has not been shown to be superior to placebo for treatment of diarrhea caused by C. parvum in patients with HIV.

Special populations:

• Immunocompromised patients: Nitazoxanide had not been studied for treatment of diarrhea caused by G. lamblia in patients with immunodeficiency. Nitazoxanide has not been shown to be superior to placebo for treatment of diarrhea caused by C. parvum in patients with immunodeficiency.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse; some data suggest that benzoate displaces bilirubin from protein-binding site; avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.

May enhance the sedative effect of alcohol.

Tizoxanide, the active metabolite of nitazoxanide, is present in breast milk.

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.

Food increases AUC. Management: Take with food.

The adverse reactions related to Nitazoxanide can be categorized as

• Common

Nausea, vomiting, abdominal pain, diarrhea

• Less Common

Headache, dizziness.

• Rare

Skin rash, urticaria.

The clinically relevant drug interactions of Nitazoxanide is briefly summarized here

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.

The common side of Nitazoxanide include the following:

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.

• 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.

Pharmacodynamics

Nitazoxanide is an antiprotozoal agent which impairs the anaerobic metabolism of susceptible organisms via the interference of the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction. In vitro, it inhibits the growth of sporozoites and oocysts of Cryptosporidium parvum and the trophozoites of Giardia lamblia.

Pharmacokinetics

Absorption: Absorbed from the gastrointestinal tract. Time to peak plasma concentration: 1-4 hours (as tizoxanide and tizoxanide glucuronide).

Distribution: Plasma protein binding: >99% (tizoxanide).

Metabolism: Rapidly hydrolysed to tizoxanide (active desacetyl metabolite) which partially undergoes further conjugation, primarily by glucuronidation.

Excretion: Via faeces (approx 67%) and urine (approx 33%). Elimination half-life: 1-1.6 hours (tizoxanide).

1. https://www.uptodate.com/contents/Nitazoxanide-drug-information?search=Nitazoxanide&source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F23890541
2. https://www.mims.com/india/drug/info/Nitazoxanide?type=full
3. https://www.ncbi.nlm.nih.gov/books/NBK537225/
4. https://go.drugbank.com/drugs/DB00321
5. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/071297s030lbl.pdf