fexinidazole 600 MG Oral Tablet

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 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

WARNINGS AND PRECAUTIONS 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 ). 5.1 Decreased Efficacy in Severe Human African Trypanosomiasis Caused by Trypanosoma brucei gambiense 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. 5.2 QT Interval Prolongation 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). 5.3 Neuropsychiatric Adverse Reactions 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. 5.4 Neutropenia Neutropenia (absolute neutrophil count less than 1,000 cells/mm 3 ) 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/mm 3 . 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. 5.5 Potential for Hepatotoxicity 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. 5.6 Risk of Disulfiram-like Reaction Due to Concomitant Use with Alcohol 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) ] . 5.7 Risk of Psychotic Reactions Due to Concomitant Use with Disulfiram 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.

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 )

Mechanism of Action Fexinidazole is an antiprotozoal drug [see Microbiology (12.4) ] .