These Highlights Do Not Include All The Information Needed To Use Fexinidazole Tablets Safely And Effectively. See Full Prescribing Information For Fexinidazole Tablets.

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)].

Store below 30°C (86°F). Store in the original package in order to protect from light and moisture.

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.

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 C₁₂H₁₃N₃O₃S 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.

Neutropenia (absolute neutrophil count less than 1,000 cells/mm³) has been reported in patients receiving Fexinidazole Tablets [see Adverse Reactions (6.1)]. In Trial 1, the adverse reaction occurred in patients with a baseline absolute neutrophil count of less than 5,000 cells/mm³. Avoid concomitant use of drugs which may cause neutropenia and monitor leukocyte count periodically. Carefully monitor patients with neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur.

The safety and effectiveness of Fexinidazole Tablets for the treatment of both the first-stage (hemolymphatic) and second-stage (meningoencephalitic) HAT due to Trypanosoma brucei gambiense have been established in pediatric patients aged 6 years and older and weighing at least 20 kg. Use of Fexinidazole Tablets for this indication is supported by evidence from an adequate and well-controlled trial in adults with additional efficacy, pharmacokinetic and safety data in pediatric patients aged 6 years and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

Pediatric patients may be more sensitive to vomiting. The safety profile for Fexinidazole Tablets in pediatric patients was generally similar to that of adult patients with the exception of more frequent vomiting within 2 hours of administration of Fexinidazole Tablets. Vomiting did not result in permanent treatment discontinuation [see Adverse Reactions (6.1)].

The safety and efficacy of Fexinidazole Tablets have not been established in pediatric patients younger than 6 years old and/or less than 20 kg in body weight.

Of the 619 subjects in the three clinical trials treated with Fexinidazole Tablets for HAT, there were 11 subjects who were 65 years of age or older, and no subjects greater than 75 years of age. There were an insufficient number of elderly subjects to detect differences in safety and/or effectiveness between elderly and younger adult patients.

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)].

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)]

• Avoid use of herbal medicines and supplements. (7.1)
• See full prescribing information for complete list of clinically significant drug interactions. (7.2)

No dosage adjustment is needed for patients with mild to moderate renal impairment with estimated glomerular filtration rates (eGFR) from 30 mL/min/1.73 m² to less than or equal to 89 mL/min/1.73 m² [see Clinical Pharmacology (12.3)]. The pharmacokinetics of fexinidazole in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²) is unknown. Avoid the use of Fexinidazole Tablets in patients with severe renal impairment.

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.

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.

No dosage adjustment of Fexinidazole Tablets is recommended for patients with mild hepatic impairment (Child-Pugh Class A). Moderate hepatic impairment (Child-Pugh Class B) increases fexinidazole and its active metabolite M1 exposures, which may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)]. Use of Fexinidazole Tablets is contraindicated in patients with severe hepatic impairment [see Contraindications (4) and Warnings and Precautions (5.5)].

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 is an antiprotozoal drug [see Microbiology (12.4)].

• Decreased Efficacy in Severe Human African Trypanosomiasis caused by Trypanosoma brucei gambiense. (1, 5.1)
• QT Interval Prolongation: Prolongation of the QT interval due to Fexinidazole Tablets occurs in a concentration-dependent manner. Avoid use in patients with known prolongation, proarrhythmic conditions, and concomitant use with drugs that prolong the QT interval, those that block cardiac potassium channels, and/or those that induce bradycardia, or are inducers of hepatic CYP450. (5.2, 7.1, 7.2, 12.2)
• Neuropsychiatric Adverse Reactions: Adverse reactions such as agitation, anxiety, abnormal behavior, depression, suicidal ideation, nightmares, hallucination, and personality change have been observed during therapy. Inform patients and their caregivers of the risk. Consider alternative therapy or increased monitoring of the patient, including hospitalization in patients with psychiatric disorders, or if these adverse reactions occur. (5.3)
• Neutropenia: Avoid concomitant use of drugs which may cause neutropenia and monitor leukocyte count periodically. Monitor patients with neutropenia for symptoms or signs of infection. (5.4, 6.1)
• Potential for Hepatotoxicity: Evaluate liver-related laboratory tests at the start and during treatment. (4, 5.5)
• Risk of Disulfiram-like Reactions Due to Concomitant Use with Alcohol: Nitroimidazole-class drugs may cause a disulfiram-like reaction in patients who concurrently consume alcohol. Advise patients to avoid consumption of alcohol during treatment with and for at least 48 hours after completing therapy. (2.1, 5.6)
• Risk of Psychotic Reactions Due to Concomitant Use with Disulfiram: Psychotic reactions have been reported in patients concurrently taking disulfiram and nitroimidazole-class drugs. Avoid use in patients who have taken disulfiram within the last two weeks. (5.7).

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)

Tablets: 600 mg of fexinidazole per tablet as pale-yellow, round, biconvex tablets debossed with "4512" on one side.

Fexinidazole Tablets have been shown to prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2)]. Treatment with Fexinidazole Tablets caused an average increase of 19 msec in the QTcF interval. In clinical trials in HAT patients, three (<1%) patients in the fexinidazole group had a QTcF value of >500 ms versus none in the nifurtimox-eflornithine combination therapy (NECT) group.

Avoid use of Fexinidazole Tablets in patients who have:

• QTcF interval greater than 470 msec
• A history of torsade de pointes, congenital long QT syndrome, cardiac arrhythmias, uncompensated heart failure, or family history of sudden death
• Uncorrected hypokalemia

Avoid concomitant administration of Fexinidazole Tablets with other drugs that are known to prolong the QT interval, those that block cardiac potassium channels, and/or those that induce bradycardia [see Drug Interactions (7.1)].

Avoid concomitant administration of Fexinidazole Tablets with drugs that are inducers of hepatic CYP450 as these drugs may significantly increase plasma concentrations of fexinidazole's active metabolites: fexinidazole sulfoxide (M1) and fexinidazole sulfone (M2). M2 plasma concentrations have been associated with increased QT prolongation risks [see Drug Interactions (7.2)].

If patients are, or need to be, treated with drugs known to prolong QTcF interval or to induce bradycardia either do not initiate therapy with Fexinidazole Tablets until such drugs are eliminated from the body (allow a washout period of 5 half-lives for such other drugs), or do not start such drugs until fexinidazole is eliminated from the body (allow a washout period of 7 days for Fexinidazole Tablets).

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)].

• Avoid use in patients with severe renal impairment. (8.6)

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/m² 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.

Elevations in liver transaminases occurred in less than two percent of patients receiving Fexinidazole Tablets for the treatment of HAT [see Adverse reactions (6.1) and Overdosage (10)]. Evaluate liver-related laboratory tests at the start [see Contraindications (4)] and during treatment with Fexinidazole Tablets. Monitor patients who develop abnormal liver-related laboratory tests during treatment with Fexinidazole Tablets.

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.

Adult patients treated with Fexinidazole Tablets reported a higher percentage of Central Nervous System (CNS) and psychiatric-related adverse reactions than those treated with nifurtimox eflornithine combination therapy (NECT) in a clinical trial [see Adverse Reactions (6.1)]. Increased incidence in insomnia, headache, and tremor was noted in the patients treated with Fexinidazole Tablets compared to NECT. In the same trial, adverse reactions representing mood changes and psychiatric disorders (such as agitation, anxiety, abnormal behavior, depression, nightmares, hallucination, and personality change) were more common in the patients treated with Fexinidazole Tablets compared to the NECT arm. Suicidal ideation has also been observed with Fexinidazole Tablets [see Adverse Reactions (6.1)]. Healthcare providers should inform patients and their caregivers of the risk for neuropsychiatric adverse reactions during treatment with Fexinidazole Tablets. In patients with current or a history of psychiatric disorders, or should such adverse reactions occur, healthcare providers should consider alternative therapy or increased monitoring of the patient, including hospitalization.

• 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.

Opening Instructions:

Press and hold down

button while pulling out

medication card.

NDC 0024-4512-24

Rx only

Fexinidazole

Tablets

600 mg per tablet

10-Day Dose Pack

for adults and children

weighing 35 kg or more

DISPENSE ONLY IN ORIGINAL PACKAGE

24 tablets

SANOFI

Psychotic reactions have been reported in patients who were concurrently taking disulfiram and nitroimidazole drugs. Avoid use of Fexinidazole Tablets in patients who have taken disulfiram within the last two weeks.

Nitroimidazole-class drugs may cause a disulfiram-like reaction characterized by flushing, rash, weakness, abdominal cramps, nausea, vomiting and headache in patients who concurrently consume alcohol. Advise patients to avoid consumption of alcohol during treatment with Fexinidazole Tablets and for at least 48 hours after completing therapy [see Dosage and Administration (2.1)].

Decreased efficacy was observed in patients treated with Fexinidazole Tablets as compared to nifurtimox-eflornithine combination therapy (NECT)-treated patients in a randomized, comparative open-label study in the subgroup of patients with severe second stage disease, as defined by cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/µL at baseline [see Clinical Studies (14)]. The 18-month success rate in this subgroup of patients with severe second stage disease was 86.9% with Fexinidazole Tablets compared to 98.7% with NECT with a difference of -11.8%, 95% confidence interval (CI) (-18.3%, -2.1%). All-cause mortality was higher in patients with severe disease treated with Fexinidazole Tablets than in patients treated with NECT through 24 months (7/160 [4.4%] vs 0/78 [0%], treatment difference 4.4%, 95% CI [-0.9%, 8.9%]).

Patients with severe second stage HAT (CSF-WBC >100 cells/µL) due to T. brucei gambiense disease should only be treated with Fexinidazole Tablets if there are no other available treatment options.

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)].

Store below 30°C (86°F). Store in the original package in order to protect from light and moisture.

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.

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 C₁₂H₁₃N₃O₃S 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.

Neutropenia (absolute neutrophil count less than 1,000 cells/mm³) has been reported in patients receiving Fexinidazole Tablets [see Adverse Reactions (6.1)]. In Trial 1, the adverse reaction occurred in patients with a baseline absolute neutrophil count of less than 5,000 cells/mm³. Avoid concomitant use of drugs which may cause neutropenia and monitor leukocyte count periodically. Carefully monitor patients with neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur.

The safety and effectiveness of Fexinidazole Tablets for the treatment of both the first-stage (hemolymphatic) and second-stage (meningoencephalitic) HAT due to Trypanosoma brucei gambiense have been established in pediatric patients aged 6 years and older and weighing at least 20 kg. Use of Fexinidazole Tablets for this indication is supported by evidence from an adequate and well-controlled trial in adults with additional efficacy, pharmacokinetic and safety data in pediatric patients aged 6 years and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

Pediatric patients may be more sensitive to vomiting. The safety profile for Fexinidazole Tablets in pediatric patients was generally similar to that of adult patients with the exception of more frequent vomiting within 2 hours of administration of Fexinidazole Tablets. Vomiting did not result in permanent treatment discontinuation [see Adverse Reactions (6.1)].

The safety and efficacy of Fexinidazole Tablets have not been established in pediatric patients younger than 6 years old and/or less than 20 kg in body weight.

Of the 619 subjects in the three clinical trials treated with Fexinidazole Tablets for HAT, there were 11 subjects who were 65 years of age or older, and no subjects greater than 75 years of age. There were an insufficient number of elderly subjects to detect differences in safety and/or effectiveness between elderly and younger adult patients.

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)].

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)]

• Avoid use of herbal medicines and supplements. (7.1)
• See full prescribing information for complete list of clinically significant drug interactions. (7.2)

No dosage adjustment is needed for patients with mild to moderate renal impairment with estimated glomerular filtration rates (eGFR) from 30 mL/min/1.73 m² to less than or equal to 89 mL/min/1.73 m² [see Clinical Pharmacology (12.3)]. The pharmacokinetics of fexinidazole in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²) is unknown. Avoid the use of Fexinidazole Tablets in patients with severe renal impairment.

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.

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.

No dosage adjustment of Fexinidazole Tablets is recommended for patients with mild hepatic impairment (Child-Pugh Class A). Moderate hepatic impairment (Child-Pugh Class B) increases fexinidazole and its active metabolite M1 exposures, which may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)]. Use of Fexinidazole Tablets is contraindicated in patients with severe hepatic impairment [see Contraindications (4) and Warnings and Precautions (5.5)].

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 is an antiprotozoal drug [see Microbiology (12.4)].

• Decreased Efficacy in Severe Human African Trypanosomiasis caused by Trypanosoma brucei gambiense. (1, 5.1)
• QT Interval Prolongation: Prolongation of the QT interval due to Fexinidazole Tablets occurs in a concentration-dependent manner. Avoid use in patients with known prolongation, proarrhythmic conditions, and concomitant use with drugs that prolong the QT interval, those that block cardiac potassium channels, and/or those that induce bradycardia, or are inducers of hepatic CYP450. (5.2, 7.1, 7.2, 12.2)
• Neuropsychiatric Adverse Reactions: Adverse reactions such as agitation, anxiety, abnormal behavior, depression, suicidal ideation, nightmares, hallucination, and personality change have been observed during therapy. Inform patients and their caregivers of the risk. Consider alternative therapy or increased monitoring of the patient, including hospitalization in patients with psychiatric disorders, or if these adverse reactions occur. (5.3)
• Neutropenia: Avoid concomitant use of drugs which may cause neutropenia and monitor leukocyte count periodically. Monitor patients with neutropenia for symptoms or signs of infection. (5.4, 6.1)
• Potential for Hepatotoxicity: Evaluate liver-related laboratory tests at the start and during treatment. (4, 5.5)
• Risk of Disulfiram-like Reactions Due to Concomitant Use with Alcohol: Nitroimidazole-class drugs may cause a disulfiram-like reaction in patients who concurrently consume alcohol. Advise patients to avoid consumption of alcohol during treatment with and for at least 48 hours after completing therapy. (2.1, 5.6)
• Risk of Psychotic Reactions Due to Concomitant Use with Disulfiram: Psychotic reactions have been reported in patients concurrently taking disulfiram and nitroimidazole-class drugs. Avoid use in patients who have taken disulfiram within the last two weeks. (5.7).

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)

Tablets: 600 mg of fexinidazole per tablet as pale-yellow, round, biconvex tablets debossed with "4512" on one side.

Fexinidazole Tablets have been shown to prolong the QT interval in a concentration-dependent manner [see Clinical Pharmacology (12.2)]. Treatment with Fexinidazole Tablets caused an average increase of 19 msec in the QTcF interval. In clinical trials in HAT patients, three (<1%) patients in the fexinidazole group had a QTcF value of >500 ms versus none in the nifurtimox-eflornithine combination therapy (NECT) group.

Avoid use of Fexinidazole Tablets in patients who have:

• QTcF interval greater than 470 msec
• A history of torsade de pointes, congenital long QT syndrome, cardiac arrhythmias, uncompensated heart failure, or family history of sudden death
• Uncorrected hypokalemia

Avoid concomitant administration of Fexinidazole Tablets with other drugs that are known to prolong the QT interval, those that block cardiac potassium channels, and/or those that induce bradycardia [see Drug Interactions (7.1)].

Avoid concomitant administration of Fexinidazole Tablets with drugs that are inducers of hepatic CYP450 as these drugs may significantly increase plasma concentrations of fexinidazole's active metabolites: fexinidazole sulfoxide (M1) and fexinidazole sulfone (M2). M2 plasma concentrations have been associated with increased QT prolongation risks [see Drug Interactions (7.2)].

If patients are, or need to be, treated with drugs known to prolong QTcF interval or to induce bradycardia either do not initiate therapy with Fexinidazole Tablets until such drugs are eliminated from the body (allow a washout period of 5 half-lives for such other drugs), or do not start such drugs until fexinidazole is eliminated from the body (allow a washout period of 7 days for Fexinidazole Tablets).

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)].

• Avoid use in patients with severe renal impairment. (8.6)

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/m² 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.

Elevations in liver transaminases occurred in less than two percent of patients receiving Fexinidazole Tablets for the treatment of HAT [see Adverse reactions (6.1) and Overdosage (10)]. Evaluate liver-related laboratory tests at the start [see Contraindications (4)] and during treatment with Fexinidazole Tablets. Monitor patients who develop abnormal liver-related laboratory tests during treatment with Fexinidazole Tablets.

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.

Adult patients treated with Fexinidazole Tablets reported a higher percentage of Central Nervous System (CNS) and psychiatric-related adverse reactions than those treated with nifurtimox eflornithine combination therapy (NECT) in a clinical trial [see Adverse Reactions (6.1)]. Increased incidence in insomnia, headache, and tremor was noted in the patients treated with Fexinidazole Tablets compared to NECT. In the same trial, adverse reactions representing mood changes and psychiatric disorders (such as agitation, anxiety, abnormal behavior, depression, nightmares, hallucination, and personality change) were more common in the patients treated with Fexinidazole Tablets compared to the NECT arm. Suicidal ideation has also been observed with Fexinidazole Tablets [see Adverse Reactions (6.1)]. Healthcare providers should inform patients and their caregivers of the risk for neuropsychiatric adverse reactions during treatment with Fexinidazole Tablets. In patients with current or a history of psychiatric disorders, or should such adverse reactions occur, healthcare providers should consider alternative therapy or increased monitoring of the patient, including hospitalization.

• 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.

Opening Instructions:

Press and hold down

button while pulling out

medication card.

NDC 0024-4512-24

Rx only

Fexinidazole

Tablets

600 mg per tablet

10-Day Dose Pack

for adults and children

weighing 35 kg or more

DISPENSE ONLY IN ORIGINAL PACKAGE

24 tablets

SANOFI

Psychotic reactions have been reported in patients who were concurrently taking disulfiram and nitroimidazole drugs. Avoid use of Fexinidazole Tablets in patients who have taken disulfiram within the last two weeks.

Nitroimidazole-class drugs may cause a disulfiram-like reaction characterized by flushing, rash, weakness, abdominal cramps, nausea, vomiting and headache in patients who concurrently consume alcohol. Advise patients to avoid consumption of alcohol during treatment with Fexinidazole Tablets and for at least 48 hours after completing therapy [see Dosage and Administration (2.1)].

Decreased efficacy was observed in patients treated with Fexinidazole Tablets as compared to nifurtimox-eflornithine combination therapy (NECT)-treated patients in a randomized, comparative open-label study in the subgroup of patients with severe second stage disease, as defined by cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/µL at baseline [see Clinical Studies (14)]. The 18-month success rate in this subgroup of patients with severe second stage disease was 86.9% with Fexinidazole Tablets compared to 98.7% with NECT with a difference of -11.8%, 95% confidence interval (CI) (-18.3%, -2.1%). All-cause mortality was higher in patients with severe disease treated with Fexinidazole Tablets than in patients treated with NECT through 24 months (7/160 [4.4%] vs 0/78 [0%], treatment difference 4.4%, 95% CI [-0.9%, 8.9%]).

Patients with severe second stage HAT (CSF-WBC >100 cells/µL) due to T. brucei gambiense disease should only be treated with Fexinidazole Tablets if there are no other available treatment options.