CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Hypersensitivity 4.1) 4.1 Hypersensitivity. ALINIA Tablets and ALINIA for Oral Suspension are contraindicated in patients with prior hypersensitivity to nitazoxanide or any other ingredient in the formulations.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse reactions in >=2% of patients were abdominal pain, headache, chromaturia, and nausea 6.1). 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 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 ALINIA was evaluated in 2177 HIV-uninfected subjects 12 months of age and older who received ALINIA Tablets or ALINIA for Oral Suspension at the recommended dose for at least three days. In pooled controlled clinical trials involving 536 HIV-uninfected subjects treated with ALINIA Tablets or ALINIA 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 ALINIA at the recommended dose for at least three days in placebo-controlled clinical trials and for 256 HIV-uninfected subjects through 11 years of age in 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 ALINIA. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. The following is list of adverse reactions spontaneously reported with ALINIA 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong-term carcinogenicity studies have not been conducted.MutagenesisNitazoxanide 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 (TA100) in the Ames bacterial mutation assay.Impairment of FertilityNitazoxanide 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Nitazoxanide is an antiprotozoal see Microbiology (12.4))]. 12.3 Pharmacokinetics. AbsorptionSingle Dosing: Following oral administration of ALINIA Tablets or Oral Suspension, the parent drug, nitazoxanide, is not detected in plasma. The pharmacokinetic parameners of the metabolites, tizoxanide and tizoxanide glucuronide are shown in Tables and below.Table 2. Mean (+/- SD) plasma pharmacokinetic parameters of tizoxanide and tizoxanide glucuronide following administration of single dose of one 500 mg ALINIA Tablet with food to subjects >=12 years of ageTizoxanideTizoxanide GlucuronideAgeC max (ug/mL) max (hr) AUC (ugohr/mL) max (ug/mL) max (hr) AUC (ugohr/mL) 12 17 years9.1 (6.1)4.0 (1-4)39.5 (24.2)7.3 (1.9)4.0 (2-8)46.5 (18.2)>18 years10.6 (2.0)3.0 (2-4)41.9 (6.0)10.5 (1.4)4.5 (4-6)63.0 (12.3)T max is given as Mean (Range) Table 3. Mean (+/-SD) plasma pharmacokinetic of tizoxanide and tizoxanide glucuronide parameter values following administration of single dose of ALINIA for Oral Suspension with food to subjects >=1year of ageTizoxanideTizoxanide GlucuronideAgeDoseC max (ug/mL) max (hr) AUC (ugohr/mL) max (ug/mL) max (hr) AUC inf (ugohr/mL) 1-3 years100 mg3.11 (2.0)3.5 (2-4)11.7 (4.46)3.64 (1.16)4.0 (3-4)19.0 (5.03)4-11 years200 mg3.00 (0.99)2.0 (1-4)13.5 (3.3)2.84 (0.97)4.0 (2-4)16.9 (5.00)>18 years500 mg5.49 (2.06)2.5 (1-5)30.2 (12.3)3.21 (1.05)4.0 (2.5-6)22.8 (6.49)T max is given as Mean (Range) Multiple dosing:Following oral administration of single ALINIA Tablet every 12 hours for consecutive days, there was no significant accumulation of nitazoxanide metabolites tizoxanide or tizoxanide glucuronide detected in plasma.Bioavailability:ALINIA for Oral Suspension is not bioequivalent to ALINIA Tablets. The relative bioavailability of the suspension compared to the tablet was 70%.When ALINIA Tablets are administered with food, the AUC of tizoxanide and tizoxanide glucuronide in plasma is increased almost two-fold and the max is increased by almost 50%. When ALINIA for Oral Suspension was administered with food, the AUC of tizoxanide and tizoxanide glucuronide increased by about 45-50% and the max increased by <=10%. ALINIA Tablets and ALINIA for Oral Suspension were administered with food in clinical trials and hence they are recomended to be administered with food [see Dosage and Administration (2.1)] DistributionIn plasma, more than 99% of tizoxanide is bound to proteins.EliminationMetabolismFollowing oral administration in humans, nitazoxanide is rapidly hydrolyzed to an active metabolite, tizoxanide (desacetyl-nitazoxanide). Tizoxanide then undergoes conjugation, primarily by glucuronidation.ExcretionTizoxanide 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.Specific PopulationsPediatric PatientsThe pharmacokinetics of tizoxanide and tizoxanide glucuronide following administration of ALINIA 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 ALINIA for Oral Suspension in pediatric patients 1-11 years of age are provided above in Table 3.Drug Interaction StudiesIn vitro studies have demonstrated that tizoxanide has no significant inhibitory effect on cytochrome P450 enzymes.

CLINICAL STUDIES SECTION.

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 double-blind, controlled trial (Study 1) 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, three-day course of treatment with ALINIA Tablets administered 500 mg twice daily was compared with placebo tablet for days. third group of patients received open-label ALINIA for Oral Suspension administered 500 mg/25 mL of suspension twice daily for days. 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 ALINIA Tablets administered 500 mg twice daily for days to placebo tablet. For both of these studies, clinical response was evaluated to days following the end of treatment. clinical response of well was defined as no symptoms, no watery stools and no more than 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 to Days Post-therapy% (Number of Successes/Total)ALINIA TabletsALINIA for Oral SuspensionPlacebo TabletsStudy 185% (46/54) 83% (45/54) 44% (12/27)Study 2100% (8/8)-30% (3/10) 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 to 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 through 11 years of age: In 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, three-day course of treatment with nitazoxanide (100 mg twice daily in pediatric patients ages 24-47 months, 200 mg twice daily in pediatric patients ages through 11 years) was compared to five-day course of treatment with metronidazole (125 mg twice daily in pediatric patients ages through years, 250 mg twice daily in pediatric patients ages through 11 years). Clinical response was evaluated to 10 days following initiation of treatment with well response defined as no symptoms, no watery stools and no more than 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 to 10 Days Following Initiation of Therapy Intent-to-Treat and Per Protocol Analyses% (Number of Successes/Total), [95% Confidence Interval]PopulationNitazoxanide (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 patients with well clinical responses had G. lamblia cysts in their stool samples to 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 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, three-day course of treatment with ALINIA Tablets administered 500 mg twice daily was compared with placebo tablet for days. third group of patients received open-label ALINIA for Oral Suspension administered 500 mg/25 mL of suspension twice daily for days. Clinical response was evaluated to days following the end of treatment. clinical response of well was defined as no symptoms, no watery stools and no more than 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 to Days Post-therapy (Number of Successes/Total)ALINIA TabletsALINIA SuspensionPlacebo TabletsIntent-to-treat analysis96% (27/28) 87% (27/31) 41% (11/27) 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 second double-blind, placebo-controlled study of 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 similar trend to the first study. Clinical response rates, evaluated to 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 C. parvum oocysts in their stool samples to 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 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, three-day course of treatment with nitazoxanide (100 mg twice daily in pediatric patients ages 12-47 months, 200 mg twice daily in pediatric patients ages through 11 years) was compared with placebo. One study was conducted in Egypt in outpatients ages 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 to days post-therapy with well response defined as no symptoms, no watery stools and no more than 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 to Days Post-therapy Intent-to-Treat Analyses% (Number of Successes/Total)PopulationNitazoxanidePlaceboOutpatient Study, age - 11 years88% (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 patients with well clinical responses had C. parvum oocysts in their stool samples to 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 three day course of nitazoxanide suspension (100 mg twice daily in pediatric patients ages 12-47 months, 200 mg twice daily in pediatric patients ages through 11 years) and were evaluated for response four days after the end of treatment.

DESCRIPTION SECTION.

11 DESCRIPTION. ALINIA Tablets and ALINIA for Oral Suspension contain the active ingredient, nitazoxanide, synthetic antiprotozoal for oral administration. Nitazoxanide is 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 12H 9N 3O 5S and the molecular weight is 307.3. The structural formula is: ALINIA 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, D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. Aluminum Lake, and FD&C Blue No. Aluminum Lake.ALINIA for Oral Suspension, when reconstituted with 48 mL of water, produces 60 mL of homogeneous suspension with pink color that contains 100 mg nitazoxanide per 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE ADMINISTRATION. ALINIA 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): AgeDosageDuration1-3 years5 mL of ALINIA for Oral Suspension (100 mg nitazoxanide) every 12 hours with food4-11 years10 mL of ALINIA for Oral Suspension (200 mg nitazoxanide) every 12 hours with food3 days12 years and olderOne ALINIA Tablet (500 mg nitazoxanide) every 12 hours with food or 25 mL of ALINIA for Oral Suspension (500 mg nitazoxanide) every 12 hours with food ALINIA 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:ALINIA tablets should not be administered to pediatric patients 11 years of age or younger because single tablet contains greater amount of nitazoxanide than the recommended dosing in this pediatric age group.Table 1. Recommended DosageAgeDosageDuration1-3 years5 mL of ALINIA for Oral suspension(100 mg nitazoxanide) taken orally every 12 hours with food4-11 years10 mL of ALINIA for Oral Suspension(200 mg nitazoxanide) taken orally every 12 hours with food3 Days12 years and olderOne ALINIA Tablet (500 mg nitazoxanide) taken orally every 12 hours with food or 25 mL of ALINIA for Oral Suspension (500 mg nitazoxanide) taken orally every 12 hours with food 2.2 Directions for Mixing ALINIA for Oral Suspension. Reconstitute ALINIA for Oral Suspension as follows:Measure 48 mL of water for preparation of the 100 mg/5 mL suspensionTap 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 vigorouslyKeep container tightly closed, and shake the suspension well before each administration. The reconstituted suspension may be stored for days at room temperature, after which any unused portion must be discarded.. 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. ALINIA Tablets: 500 mg 3.1) ALINIA for Oral Suspension: 100 mg/5 mL 3.2) ALINIA Tablets: 500 mg 3.1) ALINIA for Oral Suspension: 100 mg/5 mL 3.2) 3.1 ALINIA Tablets (500 mg). Round, yellow, film-coated tablets debossed with ALINIA on one side and 500 on the other side. Each tablet contains 500 mg of nitazoxanide.. 3.2 ALINIA 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 pink color and strawberry flavor.

DRUG INTERACTIONS SECTION.

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). 7.1 Highly Protein Bound Drugs with Narrow Therapeutic Indices. Tizoxanide (the active metabolite of nitazoxanide) is highly bound to plasma protein (>99.9%). Therefore, monitor for adverse reactions when administering nitazoxanide concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices, as competition for binding sites may occur (e.g., warfarin).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of ALINIA Tablets and ALINIA 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 ALINIA Tablets and ALINIA for Oral Suspension.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 ALINIA Tablets (500 mg). ALINIA tablets are round, yellow, film-coated tablets debossed with ALINIA on one side and 500 on the other side. Each tablet contains 500 mg of nitazoxanide. The tablets are packaged in HDPE bottles of 12 and 30 tablets.Bottles of 12 tablets NDC 67546-111-14Bottles of 30 tablets NDC 67546-111-12Store the tablets at 25 oC (77 oF); excursions permitted to 15 oC-30 oC (59 oF-86 oF). [See USP Controlled Room Temperature] 16.2 ALINIA for Oral Suspension (100 mg/5 mL). ALINIA for oral suspension is pink-colored powder formulation that, when reconstituted as directed, contains 100 mg nitazoxanide/5 mL. The reconstituted suspension has pink color and strawberry flavor. Alinia for oral suspension is available as:Bottles of 60 mL NDC 67546-212-21Store the unsuspended powder at 25 oC (77 oF); excursions permitted to 15 oC-30 oC (59 oF-86 oF). [See USP Controlled Room Temperature] The reconstituted suspension may be stored for days at room temperature, after which any unused portion must be discarded [see Dosage and Administration (2.2)].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Diarrhea caused by Giardia lamblia or Cryptosporidium parvum: ALINIA for Oral Suspension (patients year of age and older) and ALINIA Tablets (patients 12 years and older) are indicated for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum. Limitations of UseALINIA for Oral Suspension and ALINIA 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)] ALINIA is an antiprotozoal indicated for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum (1). Limitations of Use:ALINIA has not been shown to be effective for the treatment of diarrhea caused by C. parvum in HIV-infected or immunodeficient patients (1).

LACTATION SECTION.

8.2 Lactation. Risk SummaryNo information regarding the presence of nitazoxanide 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 mothers clinical need for ALINIA and any potential adverse effects on the breastfed infant from ALINIA or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Nitazoxanide is an antiprotozoal see Microbiology (12.4))].

MICROBIOLOGY SECTION.

12.4 MICROBIOLOGY. Mechanism of ActionThe 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 G. lamblia directly reduces 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 nitazoxanide exhibits antiprotozoal activity. ResistanceA potential for development of resistance by C. parvum or G. lamblia to nitazoxanide has not been examined. Antimicrobial ActivityNitazoxanide 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 MethodsFor protozoa such as C. parvum and G. lamblia, standardized tests for use in clinical microbiology laboratories are not available.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLong-term carcinogenicity studies have not been conducted.MutagenesisNitazoxanide 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 (TA100) in the Ames bacterial mutation assay.Impairment of FertilityNitazoxanide 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).

OVERDOSAGE SECTION.

10 OVERDOSAGE. Limited information on nitazoxanide overdosage is available. 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 ALINIA. Because tizoxanide is highly protein bound (>99.9%), dialysis is unlikely to significantly reduce plasma concentrations of the drug.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Alinia (nitazoxanide) Tablets 30 ct Label. NDC 67546-111-12Alinia(R)(nitazoxanide) tablets500 mgRx Only 30 TABLETS. Alinia Tablets 30 ct Label.

PATIENT MEDICATION INFORMATION SECTION.

17 PATIENT COUNSELING INFORMATION. Advise patients and parents/caregivers of pediatric patients taking ALINIA Tablets or ALINIA for Oral Suspension of the following information:Dosage and Administration:ALINIA Tablets and ALINIA for Oral Suspension should be taken with food.ALINIA 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 days, after which any unused portion must be discarded.Drug-drug Interactions: Avoid concurrent warfarin use.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and efficacy of ALINIA for Oral Suspension for the treatment of diarrhea caused by G. lamblia or C. parvum in pediatric patients to 11 years of age has been established based on three (3) randomized, controlled studies with 104 pediatric subjects treated with ALINIA for Oral Suspension 100 mg/5 mL. Furthermore, the safety and efficacy of ALINIA 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 ALINIA for Oral Suspension 100 mg/5 mL. see Clinical Studies (14.1)] The safety and efficacy of ALINIA 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 ALINIA Tablets 500 mg. single ALINIA Tablet contains greater amount of nitazoxanide than is recommended for use in pediatric patients 11 years or younger. see Dosage and Administration (2.1)]. Safety and efficacy of ALINIA for Oral Suspension in pediatric patients less than one year of age has not been studied.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionSingle Dosing: Following oral administration of ALINIA Tablets or Oral Suspension, the parent drug, nitazoxanide, is not detected in plasma. The pharmacokinetic parameners of the metabolites, tizoxanide and tizoxanide glucuronide are shown in Tables and below.Table 2. Mean (+/- SD) plasma pharmacokinetic parameters of tizoxanide and tizoxanide glucuronide following administration of single dose of one 500 mg ALINIA Tablet with food to subjects >=12 years of ageTizoxanideTizoxanide GlucuronideAgeC max (ug/mL) max (hr) AUC (ugohr/mL) max (ug/mL) max (hr) AUC (ugohr/mL) 12 17 years9.1 (6.1)4.0 (1-4)39.5 (24.2)7.3 (1.9)4.0 (2-8)46.5 (18.2)>18 years10.6 (2.0)3.0 (2-4)41.9 (6.0)10.5 (1.4)4.5 (4-6)63.0 (12.3)T max is given as Mean (Range) Table 3. Mean (+/-SD) plasma pharmacokinetic of tizoxanide and tizoxanide glucuronide parameter values following administration of single dose of ALINIA for Oral Suspension with food to subjects >=1year of ageTizoxanideTizoxanide GlucuronideAgeDoseC max (ug/mL) max (hr) AUC (ugohr/mL) max (ug/mL) max (hr) AUC inf (ugohr/mL) 1-3 years100 mg3.11 (2.0)3.5 (2-4)11.7 (4.46)3.64 (1.16)4.0 (3-4)19.0 (5.03)4-11 years200 mg3.00 (0.99)2.0 (1-4)13.5 (3.3)2.84 (0.97)4.0 (2-4)16.9 (5.00)>18 years500 mg5.49 (2.06)2.5 (1-5)30.2 (12.3)3.21 (1.05)4.0 (2.5-6)22.8 (6.49)T max is given as Mean (Range) Multiple dosing:Following oral administration of single ALINIA Tablet every 12 hours for consecutive days, there was no significant accumulation of nitazoxanide metabolites tizoxanide or tizoxanide glucuronide detected in plasma.Bioavailability:ALINIA for Oral Suspension is not bioequivalent to ALINIA Tablets. The relative bioavailability of the suspension compared to the tablet was 70%.When ALINIA Tablets are administered with food, the AUC of tizoxanide and tizoxanide glucuronide in plasma is increased almost two-fold and the max is increased by almost 50%. When ALINIA for Oral Suspension was administered with food, the AUC of tizoxanide and tizoxanide glucuronide increased by about 45-50% and the max increased by <=10%. ALINIA Tablets and ALINIA for Oral Suspension were administered with food in clinical trials and hence they are recomended to be administered with food [see Dosage and Administration (2.1)] DistributionIn plasma, more than 99% of tizoxanide is bound to proteins.EliminationMetabolismFollowing oral administration in humans, nitazoxanide is rapidly hydrolyzed to an active metabolite, tizoxanide (desacetyl-nitazoxanide). Tizoxanide then undergoes conjugation, primarily by glucuronidation.ExcretionTizoxanide 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.Specific PopulationsPediatric PatientsThe pharmacokinetics of tizoxanide and tizoxanide glucuronide following administration of ALINIA 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 ALINIA for Oral Suspension in pediatric patients 1-11 years of age are provided above in Table 3.Drug Interaction StudiesIn vitro studies have demonstrated that tizoxanide has no significant inhibitory effect on cytochrome P450 enzymes.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no data with ALINIA in pregnant women to inform drug-associated risk. No teratogenicity or fetotoxicity was observed in animal reproduction studies with administration of nitazoxanide to pregnant rats and rabbits during organogenesis at exposure 30 and 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.DataAnimal DataNitazoxanide was administered orally to pregnant rats at doses of 0, 200, 800 or 3200 mg/kg/day on gestation days to 15. 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, nitazoxanide was administered at doses of 0, 25, 50, or 100 mg/kg/day on gestation days to 20. Oral treatment of pregnant rabbits with nitazoxanide during organogenesis resulted in minimal maternal toxicity and no external fetal anomalies.

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage and Important Administration Instructions. Important Administration Instructions for Pediatric Patients 11 years of Age or Younger:ALINIA tablets should not be administered to pediatric patients 11 years of age or younger because single tablet contains greater amount of nitazoxanide than the recommended dosing in this pediatric age group.Table 1. Recommended DosageAgeDosageDuration1-3 years5 mL of ALINIA for Oral suspension(100 mg nitazoxanide) taken orally every 12 hours with food4-11 years10 mL of ALINIA for Oral Suspension(200 mg nitazoxanide) taken orally every 12 hours with food3 Days12 years and olderOne ALINIA Tablet (500 mg nitazoxanide) taken orally every 12 hours with food or 25 mL of ALINIA for Oral Suspension (500 mg nitazoxanide) taken orally every 12 hours with food.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pediatric Patients: Safety and efficacy of ALINIA for Oral Suspension in pediatric patients less than one year of age has not been studied 8.4). 8.1 Pregnancy. Risk SummaryThere are no data with ALINIA in pregnant women to inform drug-associated risk. No teratogenicity or fetotoxicity was observed in animal reproduction studies with administration of nitazoxanide to pregnant rats and rabbits during organogenesis at exposure 30 and 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.DataAnimal DataNitazoxanide was administered orally to pregnant rats at doses of 0, 200, 800 or 3200 mg/kg/day on gestation days to 15. 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, nitazoxanide was administered at doses of 0, 25, 50, or 100 mg/kg/day on gestation days to 20. Oral treatment of pregnant rabbits with nitazoxanide during organogenesis resulted in minimal maternal toxicity and no external fetal anomalies.. 8.2 Lactation. Risk SummaryNo information regarding the presence of nitazoxanide 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 mothers clinical need for ALINIA and any potential adverse effects on the breastfed infant from ALINIA or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and efficacy of ALINIA for Oral Suspension for the treatment of diarrhea caused by G. lamblia or C. parvum in pediatric patients to 11 years of age has been established based on three (3) randomized, controlled studies with 104 pediatric subjects treated with ALINIA for Oral Suspension 100 mg/5 mL. Furthermore, the safety and efficacy of ALINIA 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 ALINIA for Oral Suspension 100 mg/5 mL. see Clinical Studies (14.1)] The safety and efficacy of ALINIA 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 ALINIA Tablets 500 mg. single ALINIA Tablet contains greater amount of nitazoxanide than is recommended for use in pediatric patients 11 years or younger. see Dosage and Administration (2.1)]. Safety and efficacy of ALINIA for Oral Suspension in pediatric patients less than one year of age has not been studied.. 8.5 Geriatric Use. Clinical studies of ALINIA Tablets and ALINIA 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 ALINIA Tablets and ALINIA 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. ALINIA Tablets and ALINIA for Oral Suspension have not been studied for the treatment of diarrhea caused by G. lamblia in HIV-infected or immunodeficient patients. ALINIA Tablets and ALINIA 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)].