Nitazoxanide Tablets 500mg

1. Name of the medicinal product

Nitazoxanide Tablets 500mg

2.Qualitative and quantitative composition

Each film-coated tablet contains:

Nitazoxanide?????????500mg

Colours: Quinoline yellow Lake & Titanium Dioxide.

3.Pharmaceutical form

Oral tablet

DESCRIPTION

Nitazoxanide Tablets and 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.

     Nitazoxanide 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.

Nitazoxanide for Oral Suspension, after reconstitution, 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, acacia gum, sugar syrup, FD&C Red #40 and natural strawberry flavouring.

CLINICAL PHARMACOLOGY

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

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

Effect of Food: When Nitazoxanide Tablets are administered with food, the act of nitazoxanide and nitazoxanide glucuronide in plasma is increased almost two-fold and the C_max is increased by almost 50%.

When Nitazoxanide for Oral Suspension was administered with food, the act of nitazoxanide and nitazoxanide glucuronide increased by about 45-50% and the C_max increased by ?10%.

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 Nitazoxanide Tablet every 12 hours for 7 consecutive days, there was no significant accumulation of nitazoxanide metabolites nitazoxanide or diloxanide glucuronide detected in plasma.

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

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

Elimination: Tizoxanide is excreted in the urine, bile and faeces, and nitazoxanide glucuronide is excreted in urine and bile. Approximately two-thirds of the oral dose of nitazoxanide is excreted in the faeces 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 Nitazoxanide Tablets in pediatric patients less than 12 years of age has not been studied. The pharmacokinetics of nitazoxanide following administration of 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, nitazoxanide, are active in vitro in inhibiting the growth of (i) sporozoites and oocysts of Cryptosporidium parvum and (ii) trophozoites of Giardia lamblia.

Drug Resistance

Potential for the 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.

INDICATIONS AND USAGE

Diarrhoea caused by Giardia lamblia or Cryptosporidium parvum:

Nitazoxanide for Oral Suspension (patients 1 year of age and older) and Nitazoxanide Tablets (patients 12 years and older) are indicated for the treatment of diarrhoea caused by Giardia lamblia or Cryptosporidium parvum.

Nitazoxanide for Oral Suspension and Nitazoxanide Tablets have not been shown to be superior to placebo for the treatment of diarrhoea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients (see CLINICAL STUDIES).

CONTRAINDICATIONS

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

PRECAUTIONS

General: The pharmacokinetics of nitazoxanide in patients with compromised renal or hepatic function have not been studied. Therefore, nitazoxanide must be administered with caution to patients with hepatic and biliary disease, to patients with renal disease and to patients with combined renal and hepatic disease.

Information for Patients

Nitazoxanide Tablets and Nitazoxanide 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.

Drug Interactions

Tizoxanide is highly bound to plasma protein (>99.9%). Therefore, caution should be used when administering nitazoxanide concurrently with other high 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 nitazoxanide 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.

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 one tester strain (TA 100) in the Ames bacterial mutation assay.

Nitazoxanide did not adversely affect male or female fertility in the rat at 2400 mg/kg/day (approximately 20 times the clinical adult dose adjusted for body surface area).

Pregnancy: Teratogenic Effects

Pregnancy Category B: Reproduction studies have been performed at doses up to 3200 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.

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 Nitazoxanide 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. Nitazoxanide for Oral Suspension should be used for dosing nitazoxanide in pediatric patients. (See DOSAGE AND ADMINISTRATION)

Safety and effectiveness of Nitazoxanide for Oral Suspension in pediatric patients less than one year of age have not been studied.

Geriatric Use

Clinical studies of Nitazoxanide Tablets and Nitazoxanide 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 Nitazoxanide Tablets and Nitazoxanide for Oral Suspension. As stated in the PRECAUTIONS section, this therapy must be administered with caution to patients with renal and or hepatic impairment.

HIV-Infected or Immunodeficient Patients

Nitazoxanide Tablets and Nitazoxanide for Oral Suspension have not been studied for the treatment of diarrhoea caused by Giardia lamblia in HIV-infected or immunodeficient patients. Nitazoxanide Tablets and Nitazoxanide for Oral Suspension have not been shown to be superior to placebo for the treatment of diarrhoea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients (see CLINICAL STUDIES).

ADVERSE REACTIONS

Nitazoxanide Tablets: In controlled and uncontrolled clinical studies of 1,657 HIV-uninfected patients age 12 years and older who received various dosage regimens of Nitazoxanide Tablets, the most common adverse events reported regardless of causality assessment were: abdominal pain (6.6%), diarrhoea (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 Nitazoxanide Tablets for the treatment of diarrhoea 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 patient’s age 12 years and older participating in clinical trials of Nitazoxanide 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: discoloured urine, dysuria, amenorrhea, metrorrhagia, kidney pain, oedema labia. Metabolic & Nutrition: increased SGPT.

Hemic & Lymphatic Systems: anaemia, leukocytosis.

Skin: rash, pruritus.

Special Senses: eye discolouration, earache.

Respiratory System: epistaxis, lung disease, pharyngitis. Cardiovascular System: tachycardia, syncope, hypertension. Muscular System: myalgia, leg cramps, spontaneous bone fracture.

Nitazoxanide: In controlled and uncontrolled clinical studies of 613 HIV-uninfected pediatric patients who received Nitazoxanide, the most frequent adverse events reported regardless of causality assessment were: abdominal pain (7.8%), diarrhoea (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.

• Nitazoxanide Tablets and Nitazoxanide for Oral Suspension have not been studied for the treatment of Giardia lamblia in HIV-infected or immunodeficient patients. Nitazoxanide Tablets and Nitazoxanide for Oral Suspension have not been shown to be superior to placebo for the treatment of diarrhoea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients (see CLINICAL STUDIES).

A single Nitazoxanide 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.

DIRECTIONS FOR MIXING NITAZOXANIDE FOR ORAL SUSPENSION

Prepare a suspension at the 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.

HOW SUPPLIED

Nitazoxanide Tablets are round, yellow, film-coated tablets debossed with NITAZOXANIDE on one side and 500 on the other side. Each tablet contains 500 mg of nitazoxanide. The tablets are packaged in HDPE bottles of 60 tablets and blister cards of 6 tablets.

Bottles of 60                                                   NDC 67546-111-11

Boxes of 3 blister cards                                  NDC 67546-111-32 (Nitazoxanide 3-Day Therapy Packs^?)

Nitazoxanide for Oral Suspension is a pink-coloured powder formulation that, when reconstituted as directed, contains 100 mg nitazoxanide/5 mL. The reconstituted suspension has a pink colour and strawberry flavour. Nitazoxanide for Oral Suspension is available as:

Bottles of 60 mL                                             NDC 67546-212-21

Storage and Stability: Store the tablets, unsuspended powder, and the reconstituted oral suspension at 25^oC (77^oF); excursions permitted to 15-30^oC (59-86^oF). [See USP Controlled Room Temperature]

CLINICAL STUDIES

Diarrhoea 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 diarrhoea caused by Giardia lamblia, a three-day course of treatment with Nitazoxanide Tablets administered 500 mg BID was compared with a placebo tablet for 3 days. The third group of patients received open-label 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 diarrhoea caused by Giardia lamblia compared Nitazoxanide 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. 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)

• 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 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.

Diarrhoea 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 diarrhoea 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]

? 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 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.

Diarrhoea 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 diarrhoea caused by Cryptosporidium parvum, a three-day course of treatment with Nitazoxanide Tablets administered 500 mg BID was compared with a placebo tablet for 3 days. The third group of patients received open-label Nitazoxanide 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. 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

Clinical Response Rates 4 to 7 Days Post-therapy

% (Number of Successes/Total)

• Includes all patients randomized with Cryptosporidium parvum as the sole pathogen.? Patients failing to complete the study 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 (-10%, 28%).

In a second double-blind, placebo-controlled study of nitazoxanide tablets conducted in Egypt in adults and adolescents with diarrhoea 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.

Diarrhoea caused by Cryptosporidium parvum in pediatric patients 1 through 11 years of age:

In two double-blind, controlled studies in pediatric patients with diarrhoea 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 diarrhoea caused by C. parvum.

Another study was conducted in Zambia in malnourished pediatric patients admitted to the hospital with diarrhoea 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 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)

* Clinical response rates statistically significantly higher compared to placebo.

 60% considered severely underweight, 19% moderately underweight, 17% mild underweight.

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.

Diarrhoea 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.

7. Manufactured in India by:
TAJ LIFE SCIENCES PVT. LTD.
Unit No. 214, Old Bake House,
Bake House Lane, Fort,
Mumbai-400001
at: Ahmedabad- Gujarat, INDIA.
Ho.NO. +91 8448 444 095
Toll Free Phone: (1800-222-434 / 1800-222-825)