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NITAZOXANIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Nitazoxanide, a nitrothiazole derivative, is a synthetic antiprotozoal agent.

Specific Substances

    1) N-(5-Nitro-2-thiazolyl)salicylamide acetate
    2) 2-(Acetolyloxy)-N-(5-nitro-2-thiazolyl)benzamide
    3) NTZ
    1.2.1) MOLECULAR FORMULA
    1) C12-H9-N3-O5-S

Available Forms Sources

    A) FORMS
    1) Nitazoxanide is available as 100 mg per 5 mL oral suspension, after reconstitution with sterile water (Prod Info Alinia, 2002).
    B) SOURCES
    1) Nitazoxanide is manufactured, in the United States, by Romark Pharmaceuticals (Prod Info Alinia, 2002).
    C) USES
    1) Nitazoxanide is indicated for the treatment of diarrhea, caused by Cryptosporidium parvum and Giardia lamblia, in pediatric patients 1 to 11 years of age (Prod Info Alinia, 2002).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Nitazoxanide oral suspension is used to treat diarrhea caused by Cryptosporidium parvum and Giardia lamblia in pediatric patients 1 to 11 years of age. Nitazoxanide oral tablets are used for the same indications in patients 12 years of age and older.
    B) PHARMACOLOGY: Nitazoxanide is an antiparasitic agent (nitrothiazole derivative) with antiprotozoal activity that appears to interfere with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction required for anaerobic energy metabolism.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects include abdominal pain, diarrhea, headache, nausea, vomiting.
    2) LESS FREQUENT: Although causality has not been established, other adverse effects that have been reported less frequently (less than 1%) include dizziness, somnolence, insomnia, tremor, hypesthesia, dyspepsia, anorexia, flatulence, constipation, dry mouth, thirst, discolored urine, dysuria, amenorrhea, menorrhagia, renal pain, labial edema, elevated SGPT, elevated creatinine (oral suspension), anemia, leukocytosis, rash, pruritus, eye discoloration, ear ache, epistaxis, lung disease, pharyngitis, tachycardia, syncope, hypertension, myalgia, leg cramps.
    E) WITH POISONING/EXPOSURE
    1) Specific overdose information is not available; however, single oral doses up to 4000 mg have been tolerated.
    0.2.20) REPRODUCTIVE
    A) Nitazoxanide is classified as FDA Pregnancy Category B.

Laboratory Monitoring

    A) Monitor vital signs.
    B) Nitazoxanide cannot be detected in blood. Plasma concentrations of active metabolites tizoxanide and tizoxanide glucuronide may be detected but are not clinically useful in managing overdose.
    C) Monitor fluid and electrolyte levels in patients who experience severe vomiting and/or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Significant toxicity is not expected after nitazoxanide overdose.
    C) DECONTAMINATION
    1) PREHOSPITAL: Toxicity after acute ingestion is unlikely. Gastrointestinal decontamination is generally unnecessary.
    2) HOSPITAL: Toxicity after acute ingestion is unlikely. Gastrointestinal decontamination is generally unnecessary. Consider activated charcoal only if coingestants with significant toxicity are involved. Gastric lavage may be appropriate if used soon after ingestion.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been administered concurrently.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, and remains asymptomatic, can be managed at home.
    2) OBSERVATION CRITERIA: Any patient with symptoms or deliberate overdose should be referred to a healthcare facility for observation.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected nitazoxanide overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETIC
    1) Nitazoxanide is not detected in plasma; however, the maximum plasma concentrations of the active metabolites tizoxanide and tizoxanide glucuronide are seen within 1 to 4 hours following administration of nitazoxanide oral suspension. Nitazoxanide is rapidly hydrolyzed to tizoxanide and then conjugated by glucuronidation following oral administration. Protein binding of the metabolite tizoxanide is 99%. The oral suspension and tablet forms are not bioequivalent; bioavailability of the suspension is 70% compared with the tablets. About two-thirds of the oral dose is eliminated in feces and one-third in urine. A portion of the metabolite tizoxanide is eliminated in bile. The elimination half-life of tizoxanide is in the range of 1 to 4 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause nausea and vomiting.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been determined. Single oral doses up to 4 grams have been well tolerated.
    B) THERAPEUTIC DOSE: ADULTS AND CHILDREN 12 YEARS OF AGE AND OLDER: 500 mg oral tablet every 12 hours OR 25 mL (500 mg nitazoxanide) oral suspension every 12 hours with food for 3 days. PEDIATRIC: 4 TO 11 YEARS OF AGE: 10 mL (200 mg nitazoxanide) oral suspension every 12 hours with food for 3 days. PEDIATRIC: 1 TO 3 YEARS OF AGE: 5 mL (100 mg nitazoxanide) oral suspension every 12 hours with food for 3 days.

Clinical Effects

Summary Of Exposure

    A) USES: Nitazoxanide oral suspension is used to treat diarrhea caused by Cryptosporidium parvum and Giardia lamblia in pediatric patients 1 to 11 years of age. Nitazoxanide oral tablets are used for the same indications in patients 12 years of age and older.
    B) PHARMACOLOGY: Nitazoxanide is an antiparasitic agent (nitrothiazole derivative) with antiprotozoal activity that appears to interfere with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction required for anaerobic energy metabolism.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse effects include abdominal pain, diarrhea, headache, nausea, vomiting.
    2) LESS FREQUENT: Although causality has not been established, other adverse effects that have been reported less frequently (less than 1%) include dizziness, somnolence, insomnia, tremor, hypesthesia, dyspepsia, anorexia, flatulence, constipation, dry mouth, thirst, discolored urine, dysuria, amenorrhea, menorrhagia, renal pain, labial edema, elevated SGPT, elevated creatinine (oral suspension), anemia, leukocytosis, rash, pruritus, eye discoloration, ear ache, epistaxis, lung disease, pharyngitis, tachycardia, syncope, hypertension, myalgia, leg cramps.
    E) WITH POISONING/EXPOSURE
    1) Specific overdose information is not available; however, single oral doses up to 4000 mg have been tolerated.

Heent

    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) EAR ACHE
    a) Ear ache was reported infrequently (less than 1% of patients) in clinical studies involving 1657 HIV-negative patients 12 years of age and older who were treated with oral nitazoxanide tablets in varying doses; however, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension (systolic BP 10 to 30 mmHg below baseline) with tachycardia developed in 3 of 6 volunteers following ingestion of a single 500 mg dose of nitazoxanide (Stockis et al, 1996); causality is unclear and the incidence is unknown.
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In clinical studies involving 1657 HIV-negative patients 12 years of age and older who were administered varying doses of oral nitazoxanide tablets, fewer than 1% of patients experienced hypertension: however, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    C) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) In clinical studies involving 1657 HIV-negative patients 12 years of age and older who were administered varying doses of oral nitazoxanide tablets, fewer than 1% of patients experienced tachycardia; however, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headaches have been reported with nitazoxanide therapy (Stockis et al, 2002; Rossignol et al, 2001; Stockis et al, 1996), and appeared to be mild and transient.
    b) In clinical studies involving 1657 HIV-negative patients 12 years of age and older who were administered varying doses of oral nitazoxanide tablets, 3.1% experienced headaches. When 613 HIV-negative pediatric patients were administered varying doses of nitazoxanide oral suspension, 1.1% experienced headaches. However, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    c) Headaches were reported, following nitazoxanide therapy, in 5 patients (n=546), who were at least 12 years of age and who were involved in a nitazoxanide clinical efficacy trial (Abaza et al, 1998).
    d) Headaches were reported in 4 of 6 patients who received 1 gram nitazoxanide orally twice daily for 7 days (Stockis et al, 2002).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness is an infrequent occurrence following therapeutic administration of nitazoxanide (Rossignol et al, 2001; Rossignol et al, 2001a; Abaza et al, 1998). In clinical studies involving 1657 HIV-negative patients 12 years of age and older who were administered nitazoxanide oral tablets in varying doses, less than 1% of patients reported syncope and dizziness. In 613 HIV-negative pediatric patients administered nitazoxanide oral suspension in varying doses, less than 1% of patients experienced dizziness. However, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    C) DROWSY
    1) WITH THERAPEUTIC USE
    a) Drowsiness and fatigue have been reported with nitazoxanide therapy (Rossignol et al, 2001; Rossignol et al, 2001a; Abaza et al, 1998) and appeared to be mild and transient in nature.
    b) Somnolence was reported in fewer than 1% of patients in clinical studies involving 1657 HIV-negative patients 12 years of age and older who were administered nitazoxanide oral tablets in varying doses; however, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    D) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia was reported in fewer than 1% of patients in clinical studies involving 1657 HIV-negative patients 12 years of age and older who were administered nitazoxanide oral tablets in varying doses; however, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    E) TREMOR
    1) WITH THERAPEUTIC USE
    a) Tremors and hypesthesia were reported in fewer than 1% of patients in clinical studies involving 1657 HIV-negative patients 12 years of age and older who were administered nitazoxanide oral tablets in varying doses; However, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain has been frequently reported with nitazoxanide therapy (Prod Info ALINIA(R) oral tablets, oral suspension, 2005; Stockis et al, 2002; Stockis et al, 2002a; Ortiz et al, 2001), but appears to be mild and transient in nature.
    b) In clinical studies involving 1657 HIV-negative patients 12 years of age and older who were administered varying doses of oral nitazoxanide tablets, 6.6% experienced abdominal pain and less than 1% reported dyspepsia. Among 613 HIV-negative pediatric patients administered varying doses of nitazoxanide oral suspension, 7.8% experienced abdominal pain. However, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    c) Abdominal pain occurred in a total of 30 patients (n=546), 12 patients who were less than 12 years of age and 18 patients who were 12 years of age or older, following therapeutic administration of nitazoxanide during a clinical efficacy trial (Abaza et al, 1998).
    B) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, and worsening diarrhea have been reported with nitazoxanide therapy (Prod Info ALINIA(R) oral tablets, oral suspension, 2005; Amadi et al, 2002; Rossignol et al, 2001a; Ortiz et al, 2001; Abaza et al, 1998), but appear to be mild and transient in nature.
    b) In clinical studies involving 1657 HIV-negative patients 12 years of age and older who were administered varying doses of oral nitazoxanide tablets, 4.2% experienced diarrhea and 3% experienced nausea; vomiting and flatulence were reported in less than 1% of patients. When 613 HIV-negative pediatric patients were administered varying doses of nitazoxanide oral suspension in clinical trials, 2.1% experienced diarrhea and 1.1% experienced vomiting; nausea and flatulence were reported in less than 1% of patients. However, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    c) Loose stools or diarrhea occurred in 13 of 32 healthy volunteers who received nitazoxanide during a clinical trial (Stockis et al, 2002).
    C) ALTERED APPETITE
    1) WITH THERAPEUTIC USE
    a) In clinical studies involving 1657 HIV-negative patients 12 years of age and older who were treated with oral nitazoxanide tablets and 613 HIV-negative pediatric patients treated with nitazoxanide oral suspension in varying doses, anorexia was observed in less than 1% of patients. However, among those treated with oral suspension, increased appetite and enlarged salivary glands were also observed in less than 1% of patients. A direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    D) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Among 1657 HIV-negative patients 12 years of age and older who were treated with oral nitazoxanide tablets in clinical studies, fewer than 1% of patients experienced constipation, dry mouth, and thirst; however, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) Elevated ALT levels and pale yellow eye discoloration occurred rarely (less than 1%) during clinical trials involving 1657 HIV-negative patients 12 years of age and older who were treated with oral nitazoxanide tablets and 613 HIV-negative pediatric patients treated with nitazoxanide oral suspension in varying doses (Prod Info ALINIA(R) oral tablets, oral suspension, 2005); it is unclear if this represents icteric sclerae. Causality for hepatic effects has not been demonstrated.

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) DISCOLORED URINE
    1) WITH THERAPEUTIC USE
    a) Yellow-green urine discoloration occurred in several patients following therapeutic administration of nitazoxanide (Stockis et al, 2002; Stockis et al, 2002a; Rossignol et al, 2001a). Discolored urine was also reported infrequently (less than 1% of patients) in clinical studies involving 1657 HIV-negative patients 12 years of age and older who were treated with oral nitazoxanide tablets and 613 HIV-negative pediatric patients treated with nitazoxanide oral suspension in varying doses. A direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    B) DYSURIA
    1) WITH THERAPEUTIC USE
    a) Dysuria was reported infrequently (less than 1% of patients) in clinical studies involving 1657 HIV-negative patients 12 years of age and older who were treated with oral nitazoxanide tablets in varying doses; however, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    C) DISORDER OF MENSTRUATION
    1) WITH THERAPEUTIC USE
    a) Amenorrhea and menorrhagia were reported infrequently (less than 1% of patients) in clinical studies involving 1657 HIV-negative patients 12 years of age and older who were treated with oral nitazoxanide tablets in varying doses; however, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    D) RENAL PAIN
    1) WITH THERAPEUTIC USE
    a) Kidney pain was reported infrequently (less than 1% of patients) in clinical studies involving 1657 HIV-negative patients 12 years of age and older who were treated with oral nitazoxanide tablets in varying doses; however, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    E) GENITAL EDEMA
    1) WITH THERAPEUTIC USE
    a) Edema of the labia was reported infrequently (less than 1% of patients) in clinical studies involving 1657 HIV-negative patients 12 years of age and older who were treated with oral nitazoxanide tablets in varying doses; however, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    F) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) Elevated creatinine levels occurred rarely (less than 1%) during clinical trials involving 613 HIV-negative pediatric patients treated with nitazoxanide oral suspension in varying doses; however, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia occurred infrequently (less than 1% of patients) in clinical studies involving 1657 HIV-negative patients 12 years of age and older who were treated with oral nitazoxanide tablets in varying doses; however, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    B) LEUKOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Leukocytosis occurred infrequently (less than 1% of patients) in clinical studies involving 1657 HIV-negative patients 12 years of age and older who were treated with oral nitazoxanide tablets in varying doses; however, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In clinical studies involving 1657 HIV-negative patients 12 years of age and older who were administered varying doses of oral nitazoxanide tablets, fewer than 1% of patients reported a rash; however, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    B) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Sweating was observed in fewer than 1% of patients in clinical studies involving 613 HIV-negative patients 11 years of age and younger who were administered varying doses of nitazoxanide oral suspension; however, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    C) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) In clinical studies involving 1657 HIV-negative patients 12 years of age and older who were treated with oral nitazoxanide tablets and 613 HIV-negative pediatric patients treated with nitazoxanide oral suspension in varying doses, pruritus was observed in less than 1% of patients; however, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) PATHOLOGICAL FRACTURE
    1) WITH THERAPEUTIC USE
    a) Spontaneous bone fractures were reported in less than 1% of patients in clinical trials among 1657 HIV-negative patients 12 years of age and older who were administered nitazoxanide oral tablets in varying doses. A direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) In clinical studies involving 1657 HIV-negative patients 12 years of age and older who were treated with oral nitazoxanide tablets in varying doses, allergic reaction was observed in less than 1% of patients. However, a direct causal relationship to the drug has not been established (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).

Reproductive

    3.20.1) SUMMARY
    A) Nitazoxanide is classified as FDA Pregnancy Category B.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) There were no apparent teratogenic effects following administration of nitazoxanide at doses up to 3200 mg/kg/day in rats (approximately 48 times the human clinical dose adjusted for body surface area) and 100 mg/kg/day in rabbits (approximately 3 times the human clinical dose adjusted for body surface area) (Prod Info Alinia, 2002).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Nitazoxanide is classified as FDA Pregnancy Category B (Prod Info Alinia, 2002).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether nitazoxanide is excreted in human breast milk (Prod Info Alinia, 2002).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS55981-09-4 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs.
    B) Nitazoxanide cannot be detected in blood. Plasma concentrations of active metabolites tizoxanide and tizoxanide glucuronide may be detected but are not clinically useful in managing overdose.
    C) Monitor fluid and electrolyte levels in patients who experience severe vomiting and/or diarrhea.
    4.1.2) SERUM/BLOOD
    A) Nitazoxanide cannot be detected in blood. Plasma concentrations of active metabolites tizoxanide and tizoxanide glucuronide may be detected but are not clinically useful in managing overdose (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    B) Monitor fluid and electrolyte levels in patients who experience severe vomiting and/or diarrhea.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe vomiting, profuse diarrhea, severe abdominal pain, dehydration, and electrolyte abnormalities.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, and remains asymptomatic, can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patient with symptoms or deliberate overdose should be referred to a healthcare facility for observation.

Monitoring

    A) Monitor vital signs.
    B) Nitazoxanide cannot be detected in blood. Plasma concentrations of active metabolites tizoxanide and tizoxanide glucuronide may be detected but are not clinically useful in managing overdose.
    C) Monitor fluid and electrolyte levels in patients who experience severe vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Toxicity after acute ingestion is unlikely. Gastrointestinal decontamination is generally unnecessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Significant toxicity is unlikely after overdose. Gastrointestinal decontamination is not routinely necessary unless another toxic coingestant is involved.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) In case of nitazoxanide overdose, treatment should be symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MONITORING OF PATIENT
    1) Monitor vital signs.
    2) Monitor serum electrolytes in patients who experience severe vomiting and/or diarrhea.
    3) Nitazoxanide cannot be detected in blood. Plasma concentrations of active metabolites tizoxanide and tizoxanide glucuronide may be detected but are not widely available or clinically useful in managing overdose.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been determined. Single oral doses up to 4 grams have been well tolerated.
    B) THERAPEUTIC DOSE: ADULTS AND CHILDREN 12 YEARS OF AGE AND OLDER: 500 mg oral tablet every 12 hours OR 25 mL (500 mg nitazoxanide) oral suspension every 12 hours with food for 3 days. PEDIATRIC: 4 TO 11 YEARS OF AGE: 10 mL (200 mg nitazoxanide) oral suspension every 12 hours with food for 3 days. PEDIATRIC: 1 TO 3 YEARS OF AGE: 5 mL (100 mg nitazoxanide) oral suspension every 12 hours with food for 3 days.

Therapeutic Dose

    7.2.1) ADULT
    A) DIARRHEA CAUSED BY GIARDIA LAMBLIA OR CRYPTOSPORIDIUM PARVUM
    1) Recommended dose: 1 (500 mg) tablet OR 25 mL (500 mg) oral suspension, every 12 hours with food for 3 days (Prod Info Alinia(R) oral tablets, oral suspension, 2013).
    7.2.2) PEDIATRIC
    A) DIARRHEA CAUSED BY GIARDIA LAMBLIA OR CRYPTOSPORIDIUM PARVUM
    1) LESS THAN 12 MONTHS OF AGE: The safety and efficacy of nitazoxanide in pediatric patients less than 12 months of age have not been established (Prod Info Alinia(R) oral tablets, oral suspension, 2013).
    2) 1 TO 3 YEARS OF AGE: Recommended dose: 5 mL (100 mg) oral suspension every 12 hours with food for 3 days. Tablets should NOT be administered to pediatric patients 11 years of age or younger (Prod Info Alinia(R) oral tablets, oral suspension, 2013).
    3) 4 TO 11 YEARS OF AGE: Recommended dose: 10 mL (200 mg) oral suspension every 12 hours with food for 3 days. Tablets should NOT be administered to pediatric patients 11 years of age or younger (Prod Info Alinia(R) oral tablets, oral suspension, 2013).
    4) 12 YEARS OF AGE AND OLDER: Recommended dose is 1 (500) mg tablet OR 25 mL (500 mg) oral suspension, every 12 hours with food for 3 days (Prod Info Alinia(R) oral tablets, oral suspension, 2013).

Maximum Tolerated Exposure

    A) Single oral doses of up to 4 grams have been administered to healthy volunteers without the occurrence of significant adverse effects (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).

Workplace Standards

    A) ACGIH TLV Values for CAS55981-09-4 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS55981-09-4 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS55981-09-4 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS55981-09-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 1350 mg/kg (RTECS, 2003)
    B) LD50- (ORAL)RAT:
    1) > 10 g/kg (RTECS, 2003)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Nitazoxanide is an antiparasitic agent (nitrothiazole derivative) (Stockis et al, 1996; Dubreuil et al, 1996).
    B) Antiprotozoal activity of nitazoxanide appears related to interference with the pyruvate:ferredoxin oxidoreductase (PFOR) enzyme-dependent electron transfer reaction; this reaction is required for anaerobic energy metabolism. In vitro studies have demonstrated that nitazoxanide is directly reduced by the PFOR enzyme from Giardia lamblia via transfer of electrons in the absence of ferredoxin (Prod Info ALINIA(R) oral tablets, oral suspension, 2005).
    C) Nitazoxanide and tizoxanide (active metabolite) are active in vitro against sporozoites and oocysts of Cryptosporidium parvum and trophozoites of Giardia lamblia (Prod Info ALINIA(R) oral tablets, oral suspension, 2005). The drug has shown some activity against anaerobic bacterial isolates, but has no activity against most other gram-positive or gram-negative pathogens (Dubreuil et al, 1996).
    D) Metronidazole-resistant Helicobacter pylori has been susceptible to nitazoxanide in vitro (Dubreuil et al, 1996).

Physicochemical

Physical Characteristics

    A) Nitazoxanide is a light yellow crystalline powder that is poorly soluble in ethanol and practically insoluble in water (Prod Info Alinia, 2002).

Molecular Weight

    A) 307.3 (Sweetman, 2002)

References

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