Floxine-NT

Nitazoxanide:

• Indications and usage
• Dosage & administration
• Dosage forms and strengths
• Contraindications
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Microbiology
• Nonclinical toxicology
• Clinical studies
• How supplied
• Patient counseling information
• Manufacturer information
• Floxine-NT (Nitazoxanide) reviews

1 INDICATIONS AND USAGE

Diarrhea caused by Giardia lamblia or Cryptosporidium parvum:

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

Limitations of Use

Floxine-NT (Nitazoxanide) for Oral Suspension and Floxine-NT (Nitazoxanide) Tablets have not been shown to be effective for the treatment of diarrhea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients [ see Clinical Studies (14.2)]

Floxine-NT (Nitazoxanide) is an antiprotozoal indicated for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum (1).

Limitations of Use:

Floxine-NT (Nitazoxanide) has not been shown to be effective for the treatment of diarrhea caused by C. parvum in HIV-infected or immunodeficient patients (1).

2 DOSAGE & ADMINISTRATION

• Floxine-NT Tablets should not be administered to pediatric patient 11 years of age or younger ( 2.1)
• Dosage for treatment of diarrhea caused by G. lamblia or C. parvum ( 2.1):

2.1 Recommended Dosage and Important Administration Instructions

Important Administration Instructions for Pediatric Patients 11 years of Age or Younger:

Floxine-NT (Nitazoxanide) tablets should not be administered to pediatric patients 11 years of age or younger because a single tablet contains a greater amount of Floxine-NT (Nitazoxanide) than the recommended dosing in this pediatric age group.

Table 1. Recommended Dosage

2.2 Directions for Mixing Floxine-NT for Oral Suspension

Reconstitute Floxine-NT (Nitazoxanide) for Oral Suspension as follows:

• Measure 48 mL of water for preparation of the 100 mg/5 mL suspension
• Tap bottle until all powder flows freely.
• Add approximately one-half of the 48 mL of water required for reconstitution and shake vigorously to suspend powder.
• Add remainder of water and again shake vigorously

Keep container tightly closed, and shake the suspension well before each administration. The reconstituted suspension may be stored for 7 days at room temperature, after which any unused portion must be discarded.

3 DOSAGE FORMS AND STRENGTHS

• Floxine-NT Tablets: 500 mg ( 3.1)
• Floxine-NT (Nitazoxanide) for Oral Suspension: 100 mg/5 mL ( 3.2)

3.1 Floxine-NT (Nitazoxanide) Tablets (500 mg)

Round, yellow, film-coated tablets debossed with Floxine-NT (Nitazoxanide) on one side and 500 on the other side. Each tablet contains 500 mg of Floxine-NT (Nitazoxanide).

3.2 Floxine-NT for Oral Suspension (100 mg/5 mL)

Pink-colored powder formulation that, when reconstituted as directed, contains 100 mg nitazoxanide/5 mL. The reconstituted suspension has a pink color and strawberry flavor.

4 CONTRAINDICATIONS

Hypersensitivity

4.1 Hypersensitivity

Floxine-NT (Nitazoxanide) Tablets and Floxine-NT (Nitazoxanide) for Oral Suspension are contraindicated in patients with a prior hypersensitivity to Floxine-NT (Nitazoxanide) or any other ingredient in the formulations.

6 ADVERSE REACTIONS

The most common adverse reactions in ≥2% of patients were abdominal pain, headache, chromaturia, and nausea.

To report SUSPECTED ADVERSE REACTIONS, contact Romark at 813-282-8544 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of Floxine-NT (Nitazoxanide) was evaluated in 2177 HIV-uninfected subjects 12 months of age and older who received Floxine-NT (Nitazoxanide) Tablets or Floxine-NT (Nitazoxanide) for Oral Suspension at the recommended dose for at least three days. In pooled controlled clinical trials involving 536 HIV-uninfected subjects treated with Floxine-NT (Nitazoxanide) Tablets or Floxine-NT (Nitazoxanide) for Oral Suspension, the most common adverse reactions were abdominal pain, headache, chromaturia and nausea (≥2%).

Safety data were analyzed separately for 280 HIV-uninfected subjects ≥12 years of age receiving Floxine-NT (Nitazoxanide) at the recommended dose for at least three days in 5 placebo-controlled clinical trials and for 256 HIV-uninfected subjects 1 through 11 years of age in 7 controlled clinical trials. There were no differences between the adverse reactions reported for ALINIA-treated subjects based upon age.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of Floxine-NT (Nitazoxanide). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following is a list of adverse reactions spontaneously reported with Floxine-NT (Nitazoxanide) Tablets which were not included in clinical trial listings:

Gastrointestinal disorders: diarrhea, gastroesophageal reflux disease

Nervous System disorders: dizziness

Respiratory, thoracic and mediastinal disorders: dyspnea

Skin and subcutaneous tissue disorders: rash, urticaria

7 DRUG INTERACTIONS

Competition for binding sites may occur when administered concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices. Monitor for adverse reactions.

7.1 Highly Protein Bound Drugs with Narrow Therapeutic Indices

Tizoxanide (the active metabolite of Floxine-NT (Nitazoxanide)) is highly bound to plasma protein (>99.9%). Therefore, monitor for adverse reactions when administering Floxine-NT (Nitazoxanide) concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices, as competition for binding sites may occur (e.g., warfarin).

8 USE IN SPECIFIC POPULATIONS

Pediatric Patients: Safety and efficacy of Floxine-NT for Oral Suspension in pediatric patients less than one year of age has not been studied ( 8.4).

8.1 Pregnancy

Risk Summary

There are no data with Floxine-NT (Nitazoxanide) in pregnant women to inform a drug-associated risk. No teratogenicity or fetotoxicity was observed in animal reproduction studies with administration of Floxine-NT (Nitazoxanide) to pregnant rats and rabbits during organogenesis at exposure 30 and 2 times, respectively, the exposure at the maximum recommended human dose of 500 mg twice daily based on body surface area (BSA).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Floxine-NT (Nitazoxanide) was administered orally to pregnant rats at doses of 0, 200, 800 or 3200 mg/kg/day on gestation days 6 to 15. Floxine-NT (Nitazoxanide) produced no evidence of systemic maternal toxicity when administer once daily via oral gavage to pregnant female rats at levels up to 3200 mg/kg/day during the period of organogenesis .

In rabbits, Floxine-NT (Nitazoxanide) was administered at doses of 0, 25, 50, or 100 mg/kg/day on gestation days 7 to 20. Oral treatment of pregnant rabbits with Floxine-NT (Nitazoxanide) during organogenesis resulted in minimal maternal toxicity and no external fetal anomalies.

8.2 Lactation

Risk Summary

No information regarding the presence of Floxine-NT in human milk, the effects on the breastfed infant, or the effects on milk production is available. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for Floxine-NT (Nitazoxanide) and any potential adverse effects on the breastfed infant from Floxine-NT (Nitazoxanide) or from the underlying maternal condition.

8.4 Pediatric Use

The safety and efficacy of Floxine-NT (Nitazoxanide) for Oral Suspension for the treatment of diarrhea caused by G. lamblia or C. parvum in pediatric patients 1 to 11 years of age has been established based on three (3) randomized, controlled studies with 104 pediatric subjects treated with Floxine-NT (Nitazoxanide) for Oral Suspension 100 mg/5 mL. Furthermore, the safety and efficacy of Floxine-NT (Nitazoxanide) for Oral Suspension for the treatment of diarrhea caused by G. lamblia or C. parvum in pediatric patients 12 to 17 years of age has been established based on two (2) randomized controlled studies with 44 pediatric subjects treated with Floxine-NT (Nitazoxanide) for Oral Suspension 100 mg/5 mL. [ see Clinical Studies (14.1)]

The safety and efficacy of Floxine-NT (Nitazoxanide) Tablets for the treatment of diarrhea caused by G. lamblia or C. parvum in pediatric patients 12 to 17 years of age has been established based on three (3) randomized controlled studies with 47 pediatric subjects treated with Floxine-NT (Nitazoxanide) Tablets 500 mg.

A single Floxine-NT (Nitazoxanide) Tablet contains a greater amount of Floxine-NT (Nitazoxanide) than is recommended for use in pediatric patients 11 years or younger. [ see Dosage and Administration (2.1)].

Safety and efficacy of Floxine-NT (Nitazoxanide) for Oral Suspension in pediatric patients less than one year of age has not been studied.

8.5 Geriatric Use

Clinical studies of Floxine-NT Tablets and Floxine-NT (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 Floxine-NT (Nitazoxanide) Tablets and Floxine-NT (Nitazoxanide) for Oral Suspension.

8.6 Renal and Hepatic Impairment

The pharmacokinetics of nitzoxanide in patients with compromised renal or hepatic function has not been studied.

8.7 HIV-Infected or Immunodeficient Patients

Floxine-NT (Nitazoxanide) Tablets and Floxine-NT (Nitazoxanide) for Oral Suspension have not been studied for the treatment of diarrhea caused by G. lamblia in HIV-infected or immunodeficient patients. Floxine-NT (Nitazoxanide) Tablets and Floxine-NT (Nitazoxanide) for Oral Suspension have not been shown to be superior to placebo for the treatment of diarrhea caused by C. parvum in HIV-infected or immunodeficient patients [ see Clinical Studies (14)]

10 OVERDOSAGE

Limited information on Floxine-NT (Nitazoxanide) overdosage is available. Single oral doses of up to 4000 mg Floxine-NT (Nitazoxanide) have been administered to healthy adult volunteers without significant adverse effects. In the event of overdose, gastric lavage may be appropriate soon after oral administration. Patients should be observed and given symptomatic and supportive treatment. There is no specific antidote for overdose with Floxine-NT (Nitazoxanide). Because tizoxanide is highly protein bound (>99.9%), dialysis is unlikely to significantly reduce plasma concentrations of the drug.

11 DESCRIPTION

Floxine-NT (Nitazoxanide) Tablets and Floxine-NT (Nitazoxanide) for Oral Suspension contain the active ingredient, Floxine-NT (Nitazoxanide), a synthetic antiprotozoal for oral administration. Floxine-NT (Nitazoxanide) is a light yellow crystalline powder. It is poorly soluble in ethanol and practically insoluble in water. Chemically, Floxine-NT (Nitazoxanide) is 2-acetyloxy- N-(5-nitro-2-thiazolyl)benzamide. The molecular formula is C ₁₂H ₉N ₃O ₅S and the molecular weight is 307.3. The structural formula is:

Floxine-NT (Nitazoxanide) Tablets contain 500 mg of Floxine-NT (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.

Floxine-NT (Nitazoxanide) for Oral Suspension, when reconstituted with 48 mL of water, produces 60 mL of a homogeneous suspension with a pink color that contains 100 mg Floxine-NT (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, maltodextrin, modified food starch, triacetin, FD&C Red No. 40 and artificial strawberry flavoring.

structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Floxine-NT is an antiprotozoal [ see Microbiology (12.4))].

12.3 Pharmacokinetics

Absorption

Single Dosing:

Following oral administration of Floxine-NT (Nitazoxanide) Tablets or Oral Suspension, the parent drug, Floxine-NT (Nitazoxanide), is not detected in plasma. The pharmacokinetic parameners of the metabolites, tizoxanide and tizoxanide glucuronide are shown in Tables 2 and 3 below.

Table 2. Mean (+/- SD) plasma pharmacokinetic parameters of tizoxanide and tizoxanide glucuronide following administration of a single dose of one 500 mg Floxine-NT (Nitazoxanide) Tablet with food to subjects ≥12 years of age

*T _max is given as a Mean (Range)

Table 3. Mean (+/-SD) plasma pharmacokinetic of tizoxanide and tizoxanide glucuronide parameter values following administration of single dose of Floxine-NT (Nitazoxanide) for Oral Suspension with food to subjects ≥1year of age

*T _max is given as a Mean (Range)

Multiple dosing:

Following oral administration of a single Floxine-NT (Nitazoxanide) Tablet every 12 hours for 7 consecutive days, there was no significant accumulation of Floxine-NT (Nitazoxanide) metabolites tizoxanide or tizoxanide glucuronide detected in plasma.

Bioavailability:

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

When Floxine-NT (Nitazoxanide) Tablets are administered with food, the AUC _t of tizoxanide and tizoxanide glucuronide in plasma is increased almost two-fold and the C _max is increased by almost 50%.

When Floxine-NT (Nitazoxanide) for Oral Suspension was administered with food, the AUC _t of tizoxanide and tizoxanide glucuronide increased by about 45-50% and the C _max increased by ≤10%.

Floxine-NT (Nitazoxanide) Tablets and Floxine-NT (Nitazoxanide) for Oral Suspension were administered with food in clinical trials and hence they are recomended to be administered with food

Distribution

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

Elimination

Metabolism

Following oral administration in humans, Floxine-NT (Nitazoxanide) is rapidly hydrolyzed to an active metabolite, tizoxanide (desacetyl-nitazoxanide). Tizoxanide then undergoes conjugation, primarily by glucuronidation.

Excretion

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 Floxine-NT (Nitazoxanide) is excreted in the feces and one-third in the urine.

Specific Populations

Pediatric Patients

The pharmacokinetics of tizoxanide and tizoxanide glucuronide following administration of Floxine-NT (Nitazoxanide) Tablets in pediatric patients 12-17 years of age are provided above in Table 2. The pharmacokinetics of tizoxanide and tizoxanide glucuronide following administration of Floxine-NT (Nitazoxanide) for Oral Suspension in pediatric patients 1-11 years of age are provided above in Table 3.

Drug Interaction Studies

In vitro studies have demonstrated that tizoxanide has no significant inhibitory effect on cytochrome P450 enzymes.

12.4 MICROBIOLOGY

Mechanism of Action

The antiprotozoal activity of Floxine-NT (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 G. lamblia directly reduces Floxine-NT (Nitazoxanide) by transfer of electrons in the absence of ferredoxin. The DNA-derived PFOR protein sequence of C. parvum appears to be similar to that of G. lamblia. Interference with the PFOR enzyme-dependent electron transfer reaction may not be the only pathway by which Floxine-NT (Nitazoxanide) exhibits antiprotozoal activity.

Resistance

A potential for development of resistance by C. parvum or G. lamblia to Floxine-NT (Nitazoxanide) has not been examined.

Antimicrobial Activity

Floxine-NT (Nitazoxanide) and its metabolite, tizoxanide, are active in vitro in inhibiting the growth of (i) sporozoites and oocysts of C. parvum and (ii) trophozoites of G. lamblia.

Susceptibility Test Methods

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term carcinogenicity studies have not been conducted.

Mutagenesis

Floxine-NT (Nitazoxanide) was not genotoxic in the Chinese hamster ovary (CHO) cell chromosomal aberration assay or the mouse micronucleus assay. Floxine-NT (Nitazoxanide) was genotoxic in one tester strain (TA100) in the Ames bacterial mutation assay.

Impairment of Fertility

Floxine-NT (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).

14 CLINICAL STUDIES

14.1 Diarrhea Caused by G. lamblia

Diarrhea caused by G. lamblia in adults and adolescents 12 years of age or older:

In a double-blind, controlled trial conducted in Peru and Egypt in adults and adolescents with diarrhea and with one or more enteric symptoms (e.g., abdominal pain, nausea, vomiting, fever, abdominal distention, loss of appetite, flatulence) caused by G. lamblia, a three-day course of treatment with Floxine-NT (Nitazoxanide) Tablets administered 500 mg BID was compared with a placebo tablet for 3 days. A third group of patients received open-label Floxine-NT (Nitazoxanide) for Oral Suspension administered 500 mg/25 mL of suspension BID for 3 days. A second double-blind, controlled trial (Study 2) conducted in Egypt in adults and adolescents with diarrhea and with or without enteric symptoms (e.g., abdominal colic, abdominal tenderness, abdominal cramps, abdominal distention, fever, bloody stool) caused by G. lamblia compared Floxine-NT (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. 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:

Table 4. Adult and Adolescent Patients with Diarrhea Caused by G. lamblia

Clinical Response Rates* 4 to 7 Days Post-therapy

% (Number of Successes/Total)

* Includes all patients randomized with G. 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 G. 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 G. lamblia in pediatric patients 1 through 11 years of age:

In a randomized, controlled trial conducted in Peru in 110 pediatric patients with diarrhea and with or without enteric symptoms (e.g., abdominal distention, right iliac fossa tenderness) caused by G. lamblia, a three-day course of treatment with Floxine-NT (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:

Table 5. Clinical Response Rates in Pediatric Patients 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 G. 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.

14.2 Diarrhea Caused by C. parvum

Diarrhea caused by C. parvum in adults and adolescents 12 years of age or older:

In a double-blind, controlled trial conducted in Egypt in adults and adolescents with diarrhea and with or without enteric symptoms (e.g., abdominal pain/cramps, nausea, vomiting) caused by C. parvum, a three-day course of treatment with Floxine-NT (Nitazoxanide) Tablets administered 500 mg BID was compared with a placebo tablet for 3 days. A third group of patients received open-label Floxine-NT (Nitazoxanide) for Oral Suspension administered 500 mg/25 mL of suspension BID for 3 days. 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 within the past 24 hours’ or ‘no symptoms and no unformed stools within the past 48 hours.’ The following clinical response rates were obtained:

Table 6. Clinical Response Rates in Adult and Adolescent Patients 4 to 7 Days Post-therapy

% (Number of Successes/Total)

* Includes all patients randomized with C. 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 Floxine-NT (Nitazoxanide) tablets conducted in Egypt in adults and adolescents with diarrhea and with or without enteric symptoms (e.g., abdominal colic, abdominal cramps, epigastric pain) caused by C. 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 Floxine-NT (Nitazoxanide) group and 42.9% (9/21) in the placebo group.

Some patients with ‘well’ clinical responses had C. 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.

Diarrhea caused by C. parvum in pediatric patients 1 through 11 years of age :

In two double-blind, controlled trials in pediatric patients with diarrhea and with or without enteric symptoms (e.g., abdominal distention, colic, left iliac fossa tenderness) caused by C. parvum, a three-day course of treatment with Floxine-NT (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 within the past 24 hours’ or ‘no symptoms and no unformed stools within the past 48 hours.’ The following clinical response rates were obtained:

Table 7. Clinical Response Rates in Pediatric Patients 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 C. parvum 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.

Diarrhea caused by C. parvum in Acquired Immune Deficiency Syndrome (AIDS) patients :

A double-blind, placebo-controlled trial 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 Floxine-NT (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.

16 HOW SUPPLIED

16.1 Floxine-NT Tablets (500 mg)

Floxine-NT (Nitazoxanide) tablets are round, yellow, film-coated tablets debossed with Floxine-NT (Nitazoxanide) on one side and 500 on the other side. Each tablet contains 500 mg of Floxine-NT (Nitazoxanide). The tablets are packaged in HDPE bottles of 12 and 30 tablets.

Bottles of 12 tablets NDC 67546-111-14

Bottles of 30 tablets NDC 67546-111-12

Store the tablets at 25 ^oC (77 ^oF); excursions permitted to 15 ^oC-30 ^oC (59 ^oF-86 ^oF).

16.2 Floxine-NT for Oral Suspension (100 mg/5 mL)

Floxine-NT (Nitazoxanide) for oral suspension is a pink-colored powder formulation that, when reconstituted as directed, contains 100 mg nitazoxanide/5 mL. The reconstituted suspension has a pink color and strawberry flavor. Floxine-NT (Nitazoxanide) for oral suspension is available as:

Bottles of 60 mL NDC 27437-106-01

Store the unsuspended powder at 25 ^oC (77 ^oF); excursions permitted to 15 ^oC-30 ^oC (59 ^oF-86 ^oF).

The reconstituted suspension may be stored for 7 days at room temperature, after which any unused portion must be discarded

17 PATIENT COUNSELING INFORMATION

Advise patients and parents/caregivers of pediatric patients taking Floxine-NT (Nitazoxanide) Tablets or Floxine-NT (Nitazoxanide) for Oral Suspension of the following information:

Dosage and Administration:

Floxine-NT (Nitazoxanide) Tablets and Floxine-NT (Nitazoxanide) for Oral Suspension should be taken with food.

Floxine-NT (Nitazoxanide) for Oral Suspension: The container should be kept tightly closed, and the suspension should be shaken well before each administration. The suspension may be stored at room temperature for 7 days, after which any unused portion must be discarded.

Drug-drug Interactions:

Avoid concurrent warfarin use.

MANUFACTURER INFORMATION

Romark, L.C.

3000 Bayport Drive, Suite 200, Tampa, FL 33607

Telephone: 813-282-8544, Fax: 813-282-1162

E-mail: customer.serviceFloxine-NT (Nitazoxanide)romark.com

Web site: www.romark.com

Floxine-NT (Nitazoxanide) for Oral Suspension is distributed by Lupin Pharmaceuticals, Inc. under license from Romark.

Lupin Pharma

Baltimore, Maryland 21202 United States

US Patents No. 5,578,621; 6,020,353; 5,968,961; 5,387,598; 6,117,894; 5,965,590.

Floxine-NT (Nitazoxanide) is a registered trademark of Romark.

PI-111/106-04 R.07/16

Romark Logo Lupin Logo

Ofloxacin:

• Pharmacological action
• Pharmacokinetics
• Why is Floxine-NT prescribed?
• Dosage and administration
• Floxine-NT (Ofloxacin) side effects, adverse reactions
• Floxine-NT contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Floxine-NT drug interactions
• Floxine-NT in case of emergency / overdose
• Floxine-NT (Ofloxacin) reviews

Pharmacological action

Floxine-NT is an antimicrobial agents of broad-spectrum action type from fluoroquinolone group. Bactericidal action of Floxine-NT (Ofloxacin) is due to blockage of the enzyme DNA gyrase in bacterial cells. This medication is highly active against most of gram-negative bacteria: Escherichia coli, Salmonella spp., Shigella spp., Proteus spp., Morganella morganii, Klebsiella spp. (including Klebsiella pneumoniae), Enterobacter spp., Serratia spp., Citrobacter spp., Yersinia spp., Providencia spp., Haemophilus influenzae, Neisseria gonorrhoeae, Neisseria meningitidis, Mycoplasma spp., Legionella pneumophila, Acinetobacter spp., and Chlamydia spp.

Floxine-NT (Ofloxacin) is active against some gram-positive bacteria (including Staphylococcus spp., Streptococcus spp., especially beta-hemolytic streptococci).

Enterococcus faecalis, Streptococcus pneumoniae, Pseudomonas spp. are moderately susceptible to Floxine-NT (Ofloxacin).

Anaerobic bacteria (except Bacteroides ureolyticus) are insensitive to Floxine-NT (Ofloxacin).

This drug is resistant to beta-lactamases.

Pharmacokinetics

After oral administration Floxine-NT (Ofloxacin) is rapidly and completely absorbed from the gastrointestinal tract. Ingestion has a little effect on the extent of absorption but may slow its speed. C_max plasma levels reached in 2 hours.

The protein binding is 25%. Floxine-NT (Ofloxacin) is widely distributed in tissues and body fluids (organs of urinary system, reproductive organs, prostate, lung, ENT organs, gall bladder, bone, skin).This medicine is excreted in the urine in unchanged form (about 80% in 24 h). A small portion of the active substance (4%) is excreted in the feces. T_1/2 is 6 h.

Why is Floxine-NT prescribed?

Infectious-inflammatory diseases caused by microorganisms sensitive to Floxine-NT (Ofloxacin), including: diseases of the lower respiratory tract, ear, nose, throat, skin, soft tissues, bones, joints, infectious and inflammatory diseases of the abdominal organs (except bacterial enteritis) and pelvic infection, kidney and urinary tract, prostatitis, gonorrhea.

Dosage and administration

Dosing regimen of Floxine-NT is individual. Daily dose of 200-800 mg, the multiplicity of application 2 times / day. For patients with impaired renal function (creatinine clearance 20-50 ml / min), the first dose is 200 mg, then 100 mg every 24 hours. When CC is less than 20 ml / min, the first dose is 200 mg, then 100 mg every 48 hours.

Floxine-NT (Ofloxacin) side effects, adverse reactions

Digestive system: nausea, vomiting, diarrhea, abdominal pain and cramps, appetite loss, dry mouth, flatulence, gastrointestinal dysfunction, constipation; rarely - liver damage, liver necrosis, jaundice, hepatitis, intestinal perforation, pseudomembranous colitis, bleeding from the gastrointestinal tract, disorders of the oral mucosa, heartburn, elevated liver enzymes, including GGT and LDH, increased serum bilirubin.

CNS and peripheral nervous system: insomnia, dizziness, fatigue, drowsiness, nervousness; rarely - convulsions, anxiety, cognitive changes, depression, abnormal dreams, euphoria, hallucinations, paresthesia, syncope, tremor, confusion, nystagmus, suicidal thoughts or attempts, disorientation, psychotic reactions, paranoia, phobia, agitation, aggressiveness, emotional instability, peripheral neuropathy, ataxia, incoordination, exacerbation of extrapyramidal disorders, speech disorder.

Allergic reactions: skin rash, itching, rarely - angioedema, urticaria, vasculitis, allergic pneumonitis, anaphylactic shock, erythema multiforme, Stevens-Johnson syndrome, erythema nodosum, exfoliative dermatitis, toxic epidermal necrolysis, conjunctivitis.

Sexual system: an itch on the external genitalia in women, vaginitis, vaginal discharge; rare - burning, irritation, pain and rash in the genital area of women, dysmenorrhea, menorrhagia, metrorrhagia, vaginal candidiasis.

Cardiovascular system: rarely - heart failure, edema, hypertension, hypotension, palpitation, vasodilatation, cerebral thrombosis, pulmonary edema, and tachycardia.

Urinary system: rarely - dysuria, urinary frequency, urinary retention, anuria, polyuria formation of kidney stones, kidney failure, nephritis, hematuria, albuminuria, candiduria.

Musculoskeletal system: rarely - arthralgia, myalgia, tendonitis, muscle weakness, exacerbation of myasthenia gravis.

Metabolism: rarely - thirst, weight loss, hyper- or hypoglycemia (especially in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents), acidosis, increase in serum triglycerides, cholesterol, potassium.

Respiratory system: rarely - cough, runny nose, respiratory failure, dyspnea, bronchospasm, stridor.

Sensory organs: rarely - hearing loss, tinnit, diplopia, nystagmus, impaired clarity of vision, disturbances of taste, smell, photophobia.

Dermatological reactions: rarely - photosensitivity, hyperpigmentation, vesicle-bullous eruption.

Hematopoietic system: rarely - anemia, hemorrhage, pancytopenia, agranulocytosis, leukopenia, reversible suppression of bone marrow hematopoiesis, thrombocytopenia, thrombocytopenic purpura, petechiae, ecchymosis, increased prothrombin time.

Other: chest pain, sore throat, fever, body aches, rarely - fatigue, chills, malaise, epistaxis, increased sweating.

Floxine-NT contraindications

Pregnancy, lactation, childhood and adolescence to 18 years, increased sensitivity to Floxine-NT (Ofloxacin) or other quinolone derivatives.

Using during pregnancy and breastfeeding

Floxine-NT is contraindicated during pregnancy and lactation.

Category effects on the fetus by FDA - C.

Special instructions

Use with caution in patients with impaired renal function and liver.

During the period of treatment required to conduct monitoring of blood glucose. Long-term therapy is necessary to periodically monitor the kidney function, liver and peripheral blood picture.

When using Floxine-NT (Ofloxacin) it should be ensure adequate hydration of the body, the patient should be subjected to ultraviolet irradiation.

In experimental studies the mutagenic potential was not been identified. Long-term studies to determine the carcinogenicity of Floxine-NT (Ofloxacin) were not conducted.

Safety and efficacy in children and adolescents under the age of 18 is not defined.

Use with caution in patients whose activities are connected with the necessity of high concentration of attention and quickness of psychomotor reactions.

Floxine-NT drug interactions

Simultaneous administration of Floxine-NT (Ofloxacin) with: