Fexinidazole

FDA Drug Information • Also known as: Fexinidazole

Brand Names: Fexinidazole
Dosage Form: POWDER
Product Type: BULK INGREDIENT

Description

11 DESCRIPTION Fexinidazole Tablets contain fexinidazole, a nitroimidazole antimicrobial drug for oral use. The chemical name of fexinidazole is 1-methyl-2-{[4-(methylthio)phenoxy]methyl}-5-nitro-1H-imidazole. Its molecular formula is C 12 H 13 N 3 O 3 S and the molecular weight is 279.3 g/mol. The structural formula is: Fexinidazole is a yellow powder. It is practically insoluble in water, sparingly soluble in acetone and acetonitrile, very slightly soluble in ethanol and slightly soluble in methanol. Fexinidazole 600 mg Tablets contain the active ingredient fexinidazole and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. Chemical Structure

What Is Fexinidazole Used For?

1 INDICATIONS AND USAGE Fexinidazole Tablets are indicated for the treatment of both the first-stage (hemolymphatic) and second-stage (meningoencephalitic) human African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense in patients 6 years of age and older and weighing at least 20 kg. Fexinidazole Tablets is a nitroimidazole antimicrobial, indicated for the treatment of both first-stage (hemolymphatic) and second-stage (meningoencephalitic) human African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense in patients 6 years of age and older and weighing at least 20 kg. ( 1 ) Limitations of Use Due to the decreased efficacy observed in patients with severe second stage HAT (cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/µL) due to T. brucei gambiense disease, Fexinidazole Tablets should only be used in these patients if there are no other available treatment options. ( 1 , 5.1 ) Limitations of Use Due to the decreased efficacy observed in patients with severe second stage HAT (cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/µL) due to T. brucei gambiense disease, Fexinidazole Tablets should only be used in these patients if there are no other available treatment options [see Warnings and Precautions (5.1) ] .

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Administer Fexinidazole Tablets once daily with food each day at about the same time of the day. Do not break or crush tablets. ( 2.1 , 2.2 ) Recommended Dosage of Fexinidazole Tablets in Patients 6 years of age and older and weighing at least 20 kg ( 2.2 ) Body Weight Type of Dose Daily Dose Number of Tablets Duration of Treatment Greater than or equal to 35 kg Loading dose 1,800 mg 3 4 days Maintenance dose 1,200 mg 2 6 days Greater than or equal to 20 kg to less than 35 kg Loading dose 1,200 mg 2 4 days Maintenance dose 600 mg 1 6 days 2.1 Important Administration Instructions Patients should be closely followed by their healthcare provider during treatment with Fexinidazole Tablets. Fexinidazole Tablets must be administered with food [see Dosage and Administration (2.2) ] . Avoid consumption of alcoholic beverages during treatment with Fexinidazole Tablets and for at least 48 hours after completing therapy [see Warnings and Precautions (5.6) ] . If a first event of vomiting occurs after receiving Fexinidazole Tablets, do not re-dose . Administer the next dose the following day using the recommended treatment schedule [see Adverse Reactions (6.1) ] . If a scheduled dose is missed (not taken on the assigned day), normal dosing should resume the following day until the full course (10 days) of treatment has been completed . The clinical consequences of multiple missed doses of Fexinidazole Tablets are not known . 2.2 Recommended Dosage Administer Fexinidazole Tablets, orally, once daily for a total of 10 days (loading dose plus maintenance dose) with food each day at about the same time of the day. Do not break or crush Fexinidazole Tablets. The recommended dosage of Fexinidazole Tablets for patients 6 years of age and older is according to body weight as described in Table 1 below. Table 1: Recommended Dosage of Fexinidazole Tablets in Patients 6 Years of Age and Older and Weighing at Least 20 kg Body weight Type of Dose Recommended Administer Fexinidazole Tablets once daily with food each day at about the same time of the day Daily Dose Number of 600 mg Fexinidazole Tablets Daily Duration of Treatment Greater than or equal to 35 kg Loading dose 1,800 mg 3 4 days Maintenance dose 1,200 mg 2 6 days Greater than or equal to 20 kg to less than 35 kg Loading dose 1,200 mg 2 4 days Maintenance dose 600 mg 1 6 days

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious and otherwise important adverse reactions are discussed in greater detail in other sections of labeling: Decreased Efficacy in Severe Human African Trypanosomiasis Caused by Trypanosoma brucei gambiense [see Warnings and Precautions (5.1) ] QT Interval Prolongation [see Warnings and Precautions (5.2) ] Neuropsychiatric Adverse Reactions [see Warnings and Precautions (5.3) ] Neutropenia [see Warnings and Precautions (5.4) ] Potential for Hepatotoxicity [see Warnings and Precautions (5.5) ] Most common adverse reactions (incidence >10%) are headache, vomiting, insomnia, nausea, asthenia, tremor, decreased appetite, dizziness, hypocalcemia, dyspepsia, back pain, upper abdominal pain, and hyperkalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 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 reaction 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. Fexinidazole Tablets were evaluated for the treatment of HAT due to T. brucei gambiense in three clinical trials, of which one was comparative and two were noncomparative. Trial 1 compared the safety of Fexinidazole Tablets to nifurtimox-eflornithine combination therapy (NECT) in second stage, meningoencephalitic HAT (N=394). Trial 2 enrolled patients with stage 1 hemolymphatic and early stage 2 HAT (N=230), and Trial 3 assessed the safety of fexinidazole in pediatric patients aged 6 years or older with any stage HAT (N=125). The three trials were primarily conducted in the Democratic Republic of Congo (DRC) and a total of 749 patients received at least one dose of study medication. The patients ranged from 6 to 73 years of age, and 11 were more than 65 years old. Trials 1 and 3 enrolled more males than females (61% and 54% were males, respectively), while the gender distribution was equally balanced in Trial 2. The mean BMI ranged from 16.1 to 19.3 kg/m 2 across trials which was consistent with the nutritional status of the study population. Patients with AST/ALT >2 times the upper limit of normal or total bilirubin >1.5 the upper limit of normal were excluded from the trials. Trial 1 included 264 patients in the fexinidazole treatment arm and 130 patients in the NECT treatment arm. The patients were followed for up to 24 months from the completion of treatment. Common Adverse Reactions The most common adverse reactions occurring in >10% of HAT patients (15 years of age and older) receiving Fexinidazole Tablets in Trial 1 were headache, vomiting, insomnia, nausea, asthenia, tremor, decreased appetite, dizziness, hypocalcemia, dyspepsia, back pain, upper abdominal pain, and hyperkalemia. Selected adverse reactions occurring in ≥2% of HAT patients 15 years of age and older receiving Fexinidazole Tablets in Trial 1 are provided in Table 2. Table 2: Selected Adverse Reactions Occurring in ≥2% of HAT Patients 15 Years of Age and Older Receiving Fexinidazole Tablets in Trial 1 Adverse Reaction Fexinidazole Tablets N=264 N (%) NECT N=130 N (%) Blood and lymphatic system disorders Neutropenia Defined as an absolute neutrophil count of less than 1,000 cells/mm 3 occurring at any time following the first dose of study drug to the end of the study. 15 (5.7%) 4 (3.1%) Cardiac disorders Palpitations 13 (4.9%) 5 (3.8%) Eye disorders Photophobia 6 (2.3%) 0 Gastrointestinal disorders Vomiting 75 (28.4%) 37 (28.4%) Nausea 68 (25.8%) 20 (15.4%) Dyspepsia 34 (12.9%) 10 (7.7%) Abdominal pain upper 27 (10.2%) 6 (4.6%) Salivary hypersecretion 16 (6.1%) 3 (2.3%) Constipation 13 (4.9%) 2 (1.5%) Abdominal distension 8 (3.0%) 0 Gastritis 8 (3.0%) 2 (1.5%) General disorders and administration site conditions Asthenia 60 (22.7%) 19 (14.6%) Feeling hot 25 (9.5%) 3 (2.3%) Chest pain 23...

Drug Interactions

7 DRUG INTERACTIONS Avoid use of herbal medicines and supplements. ( 7.1 ) See full prescribing information for complete list of clinically significant drug interactions. ( 7.2 ) 7.1 Pharmacodynamic Interactions Herbal Medicines and Supplements There is a potential for pharmacodynamic interactions and/or toxicities between fexinidazole and herbal medicines and supplements. Avoid concomitant use of herbal medicines and supplements during treatment with Fexinidazole Tablets. Drugs that May Prolong the QT Interval and/or Induce Bradycardia Coadministration of Fexinidazole Tablets with drugs known to block potassium channels (e.g., antiarrhythmics, neuroleptics, fluoroquinolones, imidazole and triazole antifungals, pentamidine) prolong the QT interval (e.g., antimalarials, phenothiazines, tricyclic antidepressants, terfenadine and astemizole, IV erythromycin, and quinolone antibacterial drugs) and/or induce bradycardia (such as β-blockers) should be avoided [see Warnings and Precautions (5.2) ] . 7.2 Pharmacokinetic Drug Interactions Table 3: Effect of Fexinidazole on other Drugs Drugs Metabolized by Cytochrome P450 (CYP) 3A4/5 Examples (not fully inclusive): Lovastatin, simvastatin, nisoldipine, saquinavir, midazolam, certain hormonal contraceptives (e.g., birth control pills, skin patches, implant) Clinical Impact Fexinidazole is considered a moderate CYP3A4/5 inducer [see Clinical Pharmacology (12.3) ] . Co-administration of Fexinidazole Tablets and CYP3A4/5 substrates may reduce the systemic exposures of CYP3A4/5 substrate drug(s), which may lead to reduced efficacy [see Clinical Pharmacology (12.3) ] . Prevention or Management Avoid concomitant use with Fexinidazole Tablets . If coadministration cannot be avoided, monitor for lack of efficacy of sensitive substrate drugs. If concomitant use of oral contraceptives cannot be avoided, an alternative contraceptive that is not affected by enzyme inducers (e.g., intrauterine system) or additional nonhormonal contraception (e.g., condoms) is recommended during treatment with Fexinidazole Tablets and for at least 5 days after the last dose. Drugs Metabolized by CYP1A2 or CYP2C19 Examples (not fully inclusive): CYP1A2: duloxetine, tacrine, tizanidine, theophylline CYP2C19: lansoprazole, mephenytoin, diazepam Clinical Impact Increased risk for adverse reactions associated with increased concentrations of the drug due to inhibition of either CYP1A2 or CYP2C19 by fexinidazole [see Clinical Pharmacology (12.3) ] . Prevention or Management Monitor for adverse reactions associated with these drugs when used concomitantly with Fexinidazole Tablets. Drugs Metabolized by CYP2B6 Examples (not fully inclusive): Bupropion, efavirenz Clinical Impact Increased risk for the lack of efficacy associated with decreased plasma concentrations of the drug due to induction of CYP2B6 by fexinidazole and Metabolite M1 [see Clinical Pharmacology (12.3) ] . Prevention or Management Avoid concomitant use with Fexinidazole...

Contraindications

4 CONTRAINDICATIONS Fexinidazole Tablets are contraindicated in: Patients with known hypersensitivity to Fexinidazole Tablets and/or any nitroimidazole-class drugs (e.g., metronidazole, tinidazole). Patients with severe hepatic impairment [see Warnings and Precautions (5.5) , Adverse Reactions (6.1) , and Use in Specific Populations (8.7) ] . Patients with Cockayne syndrome. Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of metronidazole, another nitroimidazole drug, structurally related to fexinidazole, in patients with Cockayne syndrome [see Adverse Reactions (6.2) ] . Known hypersensitivity to fexinidazole, and/or nitroimidazole drugs ( 4 ) Patients with severe hepatic impairment ( 4 ) Patients with Cockayne syndrome ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary There are risks to the mother and fetus associated with untreated HAT due to T. brucei gambiense during pregnancy (see Clinical Considerations ) . Available data from clinical trials with fexinidazole use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects or miscarriage. There were no effects on prenatal development in embryo-fetal studies where pregnant rats were administered oral fexinidazole during organogenesis at a dose similar to the clinical dose based on AUC comparisons. Effects of fexinidazole on embryo-fetal development were observed in the rat and in the rabbit at doses harmful to the dams only. Exposure of fexinidazole and its metabolites at those maternal toxic doses in rats and rabbits were 2 times and less than 0.02 times the clinical exposure, respectively. In the prenatal and postnatal development study, administration of oral fexinidazole to pregnant rats during organogenesis and through lactation resulted in lower body weights in first generation offspring from dams treated at approximately 1.03 times the clinical exposure based on AUC comparisons. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. 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. Clinical Considerations Disease-associated maternal and/or embryo/fetal Risk There are adverse effects on maternal and fetal outcomes associated with untreated HAT due to T. brucei gambiense in pregnancy. Disease progression may occur during pregnancy. Pregnant women should be treated for HAT due to T. brucei gambiense during pregnancy to prevent vertical transmission. For timing of treatment during pregnancy, consider the benefits of Fexinidazole Tablets to...

Overdosage

10 OVERDOSAGE Randomized, controlled clinical studies were conducted in normal adult male subjects who were administered single or multiple oral doses of fexinidazole of up to 3,600 mg daily for 14 days (not an approved dose). The subjects experienced adverse reactions of increased transaminases, vomiting and panic attack [see Adverse Reactions (6.1) ] . Reported symptoms of overdosage in a pediatric HAT patient following ingestion of a higher than recommended dosing regimen in Trial 3 included vomiting over the first 5 days of treatment and increased potassium and decreased calcium levels from Day 11 to Week 9. There is no specific antidote for Fexinidazole Tablets. Treatment should be supportive with appropriate monitoring.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Fexinidazole 600 mg tablets are pale-yellow, round, biconvex tablets debossed with "4512" on one side. Fexinidazole 600 mg tablets are supplied as: NDC 0024-4512-24, child-resistant blister pack of 24 tablets (10-day dose pack) for adults and pediatric patients weighing 35 kg or more. NDC 0024-4512-14, child-resistant blister pack of 14 tablets (10-day dose pack) for pediatric patients older than 6 years weighing 20 kg to less than 35 kg. Store below 30°C (86°F). Store in the original package in order to protect from light and moisture.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.