Fexinidazole

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) ] .

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

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 (8.7%) 5 (3.8%) Gait disturbance 12 (4.5%) 2 (1.5%) Metabolism and nutrition disorders Decreased appetite 56 (21.2%) 24 (18.5%) Hypocalcemia 36 (13.6%) 3 (2.3%) Hypoalbuminemia 23 (8.7%) 4 (3.1%) Musculoskeletal and connective tissue disorders Back pain 30 (11.4%) 12 (9.2%) Neck pain 23 (8.7%) 7 (5.4%) Muscle Spasms 7 (2.7%) 1 (0.8%) Nervous system disorders Headache 92 (34.8%) 32 (24.6%) Tremor 58 (22.0%) 15 (11.5%) Dizziness 50 (18.9%) 18 (13.8%) Extrapyramidal disorder 9 (3.4%) 2 (1.5%) Paresthesia 6 (2.3%) 0 Psychiatric disorders Insomnia 74 (28.0%) 15 (11.5%) Agitation 10 (3.8%) 1 (0.8%) Anxiety 10 (3.8%) 0 Abnormal behavior 7 (2.7%) 1 (0.8%) Respiratory, thoracic and mediastinal disorders Cough 16 (6.0%) 6 (4.6%) Dyspnea 6 (2.3%) 1 (0.8%) Skin and subcutaneous tissue disorders Pruritus 10 (3.8%) 4 (3.1%) Hyperhidrosis 7 (2.7%) 2 (1.5%) Vascular disorders Hot flush 13 (4.9%) 4 (3.1%) Hypertension 12 (4.5%) 1 (0.8%) Other Adverse Reactions with Fexinidazole Tablets Occurring in Trial 1 The following adverse reactions were reported in less than 2% of patients aged 15 years and older with HAT, treated with Fexinidazole Tablets in Trial 1: Psychiatric Disorders: hallucinations, psychotic disorder, depression, personality change, suicidal ideation Laboratory Investigations: elevations of liver transaminases [see Warnings and Precautions (5.5)] and Overdosage (10) ] The safety profile of Fexinidazole Tablets in Trials 2 and 3, including in pediatric subjects aged 6–15 years old, was similar to that of Trial 1 [see Use in Specific Populations (8.4) ] . Specific Adverse Reactions Vomiting In the clinical trials, the incidence of vomiting within 30 minutes of administration of Fexinidazole Tablets was higher in pediatric patients (20%) than in adult patients (6.1%). There was a trend of increased incidence of vomiting during the loading phase. Generally, vomiting did not lead to treatment discontinuation. 6.2 Postmarketing Experience The following adverse reaction has been identified and reported during post-approval use of other nitroimidazole agents. Because the reports of this reaction are voluntary and the population is of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure. Metronidazole, Another Nitroimidazole Product, Structurally Related to Fexinidazole: Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, another nitroimidazole agent structurally related to fexinidazole, have been reported in patients with Cockayne syndrome (latency from drug start to signs of liver failure as short as 2 days) [see Contraindications (4) ] .

12.3 Pharmacokinetics The pharmacokinetics (PK) of fexinidazole and its two pharmacologically active M1 (sulfoxide) and M2 (sulfone) metabolites following administration of the recommended adult dosage regimen of Fexinidazole Tablets in 12 healthy adult male subjects under fed conditions are presented in Table 5. Table 5: Pharmacokinetics of Fexinidazole and its Active M1 and M2 Metabolites following Administration of Fexinidazole Tablets 1,800 mg Once Daily for 4 Days, Then 1,200 mg Once Daily for 6 Days to Healthy Adult Subjects Under Fed Conditions (N=12) Fexinidazole M1 M2 C max = maximum plasma concentration; T max = time to maximum concentration; CSF = cerebrospinal fluid; CYP = cytochrome P450 enzymes; AUC 0–24 hours = area under the plasma concentration-time curve from time zero to 24 hours, AUC 0–t = area under the plasma concentration-time curve from time zero to the last timepoint with measurable analyte concentrations; DBS = dried blood spot NA: Not available or not applicable Mean (±SD) C max mcg/mL Day 1 1.6 (±0.4) 8.1 (±2.2) 7.5 (±3.3) Day 4 0.8 (±0.3) 8.0 (±2.3) 19.6 (±5.4) Day 10 0.5 (±0.2) 5.9 (±2.1) 12.5 (±3.5) Mean (±SD) AUC (0–24 hours) mcg∙h/mL Day 1 14.3 (±2.6) 102.3 (±28.5) 110.1 (±41.1) Day 4 11.6 (±2.2) 127.9 (±49.2) 391.5 (±126.7) Day 10 7.0 (±2.5) 84.2 (±36.3) 252.4 (±73.6) Absorption Median T max (Range) on Day 4 , hours 4 (0–9) 4 (0–6) 6 (0–24) Effect of Food The effect of food following administration of a single 1,200 mg dose with a meal containing approximately 963 Kcal with 62% of total calories from fat, 17% from protein, and 21% from carbohydrate (n=12). The AUC of fexinidazole, M1, and M2 were approximately 4 to 5-fold higher following administration with food compared to the fasted state. Distribution Apparent Volume of Distribution on Day 4, L 3222 (±1199) NA NA Plasma Protein Binding 98% 41% 57% Mean (Range) CSF concentrations at 24 hours after the last fexinidazole dose on Day 10, mcg/mL From study in patient with HAT. NA 1.39 (0–4.5) 6.45 (0.3–14.9) Mean (Range) CSF to DBS Ratios NA 0.53 (0.1–2.2) 0.36 (0.1–0.8) Elimination Mean (±SD) Day 10 Half-life, hours 15 (±6) 16 (±6) 23 (±4) Mean (±SD) Apparent Clearance on Day 4, L/hour 161 (±37) NA NA Metabolism Fexinidazole Fexinidazole is metabolized to M1 by several CYP450 enzymes, including CYP3A4 and flavin monooxygenases. Active Metabolites Several CYP450 enzymes including, CYP3A4 and flavin monooxygenases, are involved in the metabolism of M1 to M2. M2 is not further metabolized. The AUC 0–24 of M1 and M2 are 11 and 34-fold higher, respectively, than that of fexinidazole. Excretion Urine Less than 3.2% of a given dose of Fexinidazole Tablets, primarily as M1 and M2 metabolites Specific Populations Elderly patients No specific pharmacokinetic studies have been performed in patients older than 65 years of age. In a population PK analysis of patients with HAT over a range of ages from 6 to 71 years, age was not a significant covariate affecting the PK of fexinidazole and the M1 and M2 metabolites and no differences in the PK of any of these three moieties were observed. Pediatric patients The ranges of plasma AUC values of fexinidazole, M1, and M2 in pediatric and adult HAT patients with body weights greater than or equal to 20 kg were overlapping following administration of Fexinidazole Tablets at the recommended pediatric and adult dosage regimens, indicating similar systemic exposures across body weights of 20 kg and greater. Hepatic impairment Following a single 1200 mg dose of Fexinidazole Tablets to subjects with mild hepatic impairment (Child-Pugh A; n=7), fexinidazole, M1 and M2 AUC estimates were 1.40-fold higher, 1.13-fold higher, and 1.20-fold higher, respectively, and their half-life estimates were 1.38-fold higher, 1.18-fold higher, and 0.93-fold lower, respectively. Sum of AUCs of active metabolites M1 and M2 was increased by 5%, in comparison to subjects without hepatic impairment (n=7). In the same study, in subjects with moderate hepatic impairment (Child-Pugh Class B, n=7), fexinidazole, M1 and M2 AUC estimates were 1.36-fold higher, 1.46-fold higher, and 0.65-fold lower, respectively, and their half-life estimates were 1.77-fold higher, 1.25-fold higher, and 1.34-fold higher, respectively. Sum of AUCs of active metabolites M1 and M2 was decreased by 18%, compared to subjects without hepatic impairment (n=7). The unbound fraction of fexinidazole was not affected by mild or moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh class C) on fexinidazole pharmacokinetics is unknown. [ see Contraindications (4) and Use in Specific Populations (8.7) ]. Renal Impairment A population PK analysis, based on baseline renal function, was carried out with data from 317 HAT patients enrolled in clinical trials that included 212 patients with normal renal function (eGFR greater than or equal to 90 mL/min/1.73 m 2 ), 89 patients with mild renal impairment (eGFR 60 to less than 90 mL/min/1.73 m 2 ), and 14 patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m 2 ). The predicted AUC 0–24 estimates for fexinidazole and its M1 and M2 metabolites were similar in patients with mild or moderate renal impairment compared to those patients without renal impairment. The PK of fexinidazole in patients with severe renal impairment has not been studied [see Use in Specific Populations (8.6) ] . Race/ethnicity Insufficient data were available from the clinical trials to assess the effect of race or ethnicity on fexinidazole PK. Drug Interaction Studies In vitro studies Cytochrome P450 (CYP450) and UDP-glucuronosyl transferase (UGT) Enzymes: Fexinidazole has the potential to inhibit CYP1A2, CYP2B6, CYP2C19, CYP2D6, and CYP3A4/5; M1 has the potential to inhibit CYP2C19; M2 does not inhibit any CYPs. Fexinidazole has the potential to induce CYP1A2 and CYP2B6. Metabolite M1 has the potential to induce CYP1A2, CYP2B6, CYP3A5, UGT1A4, UGT2B4 and UGT2B7. Metabolite M2 has the potential to induce UGT2B4 [see Drug Interactions (7.2) ] . Transporter Systems: Fexinidazole inhibits OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1 and MATE2-K transporters. M1 inhibits OAT3, MATE1, and MATE2-K. M2 inhibits OCT2, OAT1, OAT3, MATE1, and MATE2-K. Coadministration with Fexinidazole Tablets may increase the plasma concentrations of drugs that are substrates of these aforementioned transporters [see Drug Interactions (7.2) ] . Fexinidazole, M1, or M2 do not inhibit P-gp or BCRP. Clinical studies A clinical drug-drug interaction study evaluated the effect of fexinidazole following administration of 1,800 mg Fexinidazole Tablets for four days, followed by 1,200 mg on Day 5, with single dose administration of 100 mg caffeine (probe substrate of CYP1A2) and 20 mg omeprazole (probe substrate of CYP2C19) on Day 4 in healthy subjects. The mean caffeine AUC was 2-fold higher, with no significant increase in C max compared to when caffeine was administered alone. The mean C max and AUC of omeprazole were approximately 2-fold higher compared to when omeprazole was administered alone [see Drug Interactions (7.2) ] . A clinical drug-drug interaction study evaluated the effect of fexinidazole following administration of 1,800 mg Fexinidazole Tablets for four days, followed by 1,200 mg on Day 5 (not an approved dosing regimen), with single dose administration of 2 mg midazolam (probe substrate of CYP3A4/5) on Day 4 in healthy subjects. The mean midazolam AUC was decreased by 57%, mean C max by 39% and mean half-life by 33% compared to when midazolam was administered alone [see Drug Interactions (7.2) ]. Model-informed approaches Findings from a static mechanistic model-based analysis predicted that fexinidazole may decrease the systemic PK exposure of CYP2B6 substrates [see Drug Interactions (7.2) ] . This model-based analysis predicted no significant drug interaction of fexinidazole with drugs that are substrates of CYP2C8, CYP2C9, or CYP2D6.