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Nitazoxanide, Indications, Dosage, Side Effects, Interactions, Pregnancy

Nitazoxanide is a synthetic benzamide with antiprotozoal activity. Nitazoxanide exerts its antiprotozoal activity by interfering with the pyruvate ferredoxin/flavodoxin oxidoreductase dependent electron transfer reaction, which is essential to anaerobic energy metabolism. PFOR enzyme reduces nitazoxanide, thereby impairing the energy metabolism. However, interference with the PFOR enzyme-dependent electron transfer reaction may not be the only pathway by which nitazoxanide exhibits antiprotozoal activity. Nitazoxanide is active against Giardia lamblia and Cryptosporidium parvum.

Nitazoxanide is an antimicrobial with activity against several parasitic worms and protozoa that is used predominantly in the United States in the treatment of giardiasis and cryptosporidiosis. Nitazoxanide therapy has not been reported to cause serum aminotransferase elevations during therapy or clinically apparent liver injury.

Nitazoxanide is a broad-spectrum antiparasitic, antiparasitic and broad-spectrum antiviral drug synthetic nitrothiazolyl-salicylamide derivative and an anti-protozoal agent. It is approved for treatment of infectious diarrhea caused by Cryptosporidium parvum and Giardia lamblia in patients 1 year of age and older. Following oral administration it is rapidly hydrolyzed to its active metabolite, tizoxanide, which is 99% protein bound. Peak concentrations are observed 1–4 hours after administration. It is excreted in the urine, bile, and feces. Untoward effects include abdominal pain, vomiting, and diarrhea.

Mechanism of Action of Nitazoxanide

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. Nitazoxanide is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that nitazoxanide inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), all folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Nitazoxanide is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, nitazoxanide is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells.

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Indications of Nitazoxanide

Dwarf Tapeworm Infection (Hymenolepis nana)
Ascariasis
Amebiasis
Diarrhea with vomiting
Giardiasis
Ascariasis
Cestode infections
Clostridium difficile infection recurrence
Cryptosporidiosis infection
Diarrhea caused by Cryptosporidium parvum
Diarrhea caused by Giardia lamblia
Giardiasis
Trichuriasis
For the treatment of diarrhea in adults and children caused by the protozoa Giardia lamblia, and for the treatment of diarrhea in children caused by the protozoan, Cryptosporidium parvum.
Nitazoxanide has not been shown to be superior to placebo medication for the management of diarrhea caused by Cryptosporidium parvum in patients with HIV/immunodeficiency

Contra-Indications of Nitazoxanide

Nitazoxanide is contraindicated only in individuals who have experienced a hypersensitivity reaction to nitazoxanide or the inactive ingredients of a nitazoxanide formulation

Dosage of Nitazoxanide

Strengths: 500 mg ,100 mg/5 mL

Amebiasis

500 mg twice daily with food for 3 days.
1000 mg twice daily with food for 14 days or until diarrhea resolves.

Cryptosporidiosis

500 mg twice daily with food for 3 days.
1000 mg twice daily with food for 14 days or until diarrhea resolves.

Giardiasis

500 mg twice daily with food for 3 days.
1000 mg twice daily with food for 14 days or until diarrhea resolves.

Cryptosporidiosis

12 to 47 months: 100 mg (5 mL) by mouth with food every 12 hours for 3 days.
4 to 11 years: 200 mg (10 mL) with food every 12 hours for 3 days.
Greater than or equal to 12 years: 500 mg twice daily with food for 3 days.

Pediatric Giardiasis

12 to 47 months: 100 mg (5 mL) by mouth with food every 12 hours for 3 days.
4 to 11 years: 200 mg (10 mL) with food every 12 hours for 3 days.
Greater than or equal to 12 years: 500 mg twice daily with food for 3 days.

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Ascariasis

2 to 3 years: 100 mg/5 mL
4 to 11 years: 200 mg/10 mL

Hymenolepis nana

to 3 years: 100 mg/5 mL
4 to 11 years: 200 mg/10 mL

Pediatric Amebiasis

500 mg twice daily with food for 3 days.

Side Effects of Nitazoxanide

The most common side effects

Abdominal or stomach cramps
dizziness or lightheadedness
heartburn
Stomach pain, especially if it comes along with fever and diarrhea or constipation
Yellowing of the skin or eyes
Loss of appetite
Constipation
Chest pain or discomfort
lightheadedness, dizziness, or fainting
unusual tiredness or weakness
fast, pounding, or irregular heartbeat or pulse
increased watering of mouth
lightheadedness
constipation;
vision changes;
breast swelling (in men or women); or
decreased sex drive, impotence, or difficulty having an orgasm.
blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
restless muscle movements in your eyes, tongue, jaw, or neck;

Common

Drowsiness and lightheadedness the day after taking the medicine.
Confusion.
Numbed emotions.
Visual disturbances such as blurred vision or double vision.
Shaky movements and unsteady walk (ataxia).
Muscle weakness.
Dizziness.
A headache.
Skin rashes.
Disturbances of the gut such as diarrhea, c onstipation, nausea, vomiting or abdominal pain.
Changes in sex drive.
Low blood pressure (hypotension).
Blood disorders.
Unexpected aggression, restlessness or irritability.
Nightmares or hallucinations

Rare

agitation
anxiety
behavioral changes, including aggressiveness, angry outbursts,
confusion
increased trouble sleeping
muscle spasms
shortness of breath
difficult or labored breathing
difficulty with swallowing
dizziness, faintness, or lightheadedness
frequent urination
hallucinations
bloating or swelling of the face, arms, hands, lower legs, or feet
blurred vision
hives or welts, itching, or skin rash
the increased volume of pale, dilute urine

Drug Interactions of Nitazoxanide

Nitazoxanide may interact with following drugs, supplements, & may change the efficacy of drugs

barbiturates (e.g., phenobarbital, butalbital)
benzodiazepines (e.g., diazepam, lorazepam)
phenothiazines (e.g., perphenazine, fluphenazine)
quinidine
ritonavir
tricyclic antidepressants (e.g., amitriptyline, nortriptyline)

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Pregnancy & Lactation of Nitazoxanide

FDA Pregnancy Category B

Pregnancy

There are no data with nitazoxanide in human pregnancy to inform a drug-associated risk. Animal reproductive studies performed in rats and rabbits at doses up to 2 and 30 times the recommended daily human dose demonstrated no evidence of teratogenicity or fetotoxicity due to nitazoxanide.

Breastfeeding

There is no information about the presence of nitazoxanide in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for nitazoxanide and any potential adverse effects on the breastfed infant from nitazoxanide or the mother’s underlying condition.