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Alinia

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Alinia

CLINICAL PHARMACOLOGY

Absorption: Following oral administration of Alinia (nitazoxanide) Tablets or Oral Suspension, maximum plasma concentrations of the active metabolites tizoxanide and tizoxanide glucuronide are observed within 1-4 hours. The parent nitazoxanide is not detected in plasma. Pharmacokinetic parameters of tizoxanide and tizoxanide glucuronide are shown in Tables 1 and 2 below.

Table 1. Mean (±SD) plasma pharmacokinetic parameter values following administration of a single dose of one 500 mg Alinia (nitazoxanide) Tablet with food to subjects ≥ 12 years of age

Age Tizoxanide Tizoxanide glucuronide
Cmax
(μg/mL)
Tmax*
(hr)
AUCι
(μg•hr/mL)
Cmax
(μg/mL)
Tmax*
(hr)
AUCι
(μg•hr/mL)
12-17 years 9.1 (6.1) 4.0 (1-4) 39.5 (24.2) 7.3 (1.9) 4.0 (2-8) 46.5 (18.2)
≥18 years 10.6 (2.0) 3.0 (2-4) 41.9 (6.0) 10.5 (1.4) 4.5 (4-6) 63.0 (12.3)
* Tmax is given as a Mean (Range)

Table 2. Mean (± SD) plasma pharmacokinetic parameter values following administration of a single dose of Alinia (nitazoxanide) for Oral Suspension with food to subjects 1 through 11 years of age

Age Tizoxanide Tizoxanideglucuronide
Dose Cmax
(μg/mL)
Tmax*
(hr)
AUCinf
(μg•hr/mL)
Cmax
(μg/mL)
Tmax*
(hr)
AUCinf
(μg•hr/mL)
1-3 years 100 mg 3.11 (2.0) 3.5 (2-4) 11.7 (4.46) 3.64 (1.16) 4.0 (3-4) 19.0 (5.03)
4-11 years 200 mg 3.00 (0.99) 2.0 (1-4) 13.5 (3.3) 2.84 (0.97) 4.0 (2-4) 16.9 (5.00)
*Tmax is given as Mean (Range)

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

Effect of Food: When Alinia (nitazoxanide) Tablets are administered with food, the AUCι of tizoxanide and tizoxanide glucuronide in plasma is increased almost two-fold and the Cmax is increased by almost 50%.

When Alinia (nitazoxanide) for Oral Suspension was administered with food, the AUCι of tizoxanide and tizoxanide glucuronide increased by about 45-50% and the Cmax increased by ≥10%.

Alinia (nitazoxanide) Tablets and for Oral Suspension were administered with food in clinical trials and hence they are recommended to be administered with food (see DOSAGE AND ADMINISTRATION).

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

Distribution: In plasma, more than 99% of tizoxanide is bound to proteins.

Metabolism: Following oral administration in humans, nitazoxanide is rapidly hydrolyzed to an active metabolite, tizoxanide (desacetyl-nitazoxanide). Tizoxanide then undergoes conjugation, primarily by glucuronidation. In vitro metabolism studies have demonstrated that tizoxanide has no significant inhibitory effect on cytochrome P450 enzymes.

Elimination: 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.

Special Populations

Patients with Impaired Hepatic and/or Renal Function: The pharmacokinetics of nitazoxanide in patients with impaired hepatic and/or renal function has not been studied.

Geriatric Patients: The pharmacokinetics of nitazoxanide in geriatric patients has not been studied.

Pediatric Patients: The pharmacokinetics of nitazoxanide following administration of Alinia (nitazoxanide) Tablets in pediatric patients less than 12 years of age has not been studied. The pharmacokinetics of nitazoxanide following administration of Alinia (nitazoxanide) for Oral Suspension in pediatric patients less than one year of age has not been studied.

Microbiology

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.

Activity in vitro

Nitazoxanide and its metabolite, tizoxanide, are active in vitro in inhibiting the growth of (i) sporozoites and oocysts of Cryptosporidium parvum and (ii) trophozoites of Giardia lamblia.

Drug Resistance

A potential for development of resistance by Cryptosporidium parvum or Giardia lamblia to nitazoxanide has not been examined.

Susceptibility Tests

For protozoa such as Cryptosporidium parvum and Giardia lamblia, standardized tests for use in clinical microbiology laboratories are not available.

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 (nitazoxanide) Tablets administered 500 mg BID was compared with a placebo tablet and Alinia (nitazoxanide) 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 (nitazoxanide) Tablets administered 500 mg BID for 3 days to a placebo. 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 Clinical Response Rates* 4 to 7 Days Post-therapy % (Number of Successes/Total)

  Alinia Tablets Alinia for Oral Suspension Placebo Tablets
Study 1 85% (46/54) ¶ § 83% (45/54) ¶ § 44% (12/27)
Study 2 100% (8/8) - 30% (3/10)
*Includes all patients randomized with Giardia 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 of the 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 Clinical Response Rates 7 to 10 Days Following Initiation of Therapy Intent-to-Treat and Per Protocol Analyses % (Number of Successes/Total ), [95% Confidence Interval]

Population Nitazoxanide
(3 days)
Metronidazole
(5 days)
95% CI Diff§
Intent-to-treat analysis† 85% (47/55) 80% (44/55 ) [-9%, 20%]
Per protocol analysis¶ 90% (43/48) 83% (39/47 ) [-8%, 21%]
† 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 of the 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 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 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 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:

Pediatric Patients with Diarrhea Caused by Cryptosporidium parvum Clinical Response Rates 3 to 7 Days Post-therapy, Intent-to-Treat Analyses % (Number of Successes/Total)

Population Nitazoxanide* Placebo
Outpatient Study, age 1 - 11 years 88% (21/24) 38% (9/24)
Inpatient Study, Malnourished¶, age 12-35 months 56% (14/25) 23% (5/22 )
*Clinical response rates statistically significantly higher compared to placebo.
60% considered severely underweight, 19% moderately underweight, 17% mild underweight.

Some of the 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.

Another double-blind, placebo-controlled study was conducted in hospitalized, severely malnourished pediatric patients with acquired immune deficiency syndrome (AIDS) in Zambia. In this study, 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) did not produce clinical cure rates that were significantly different from the placebo control.

Last reviewed on RxList: 4/10/2008
This monograph has been modified to include the generic and brand name in many instances.

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