Fexinidazole Dailymed

Fexinidazole Tablets are contraindicated in:

• Patients with known hypersensitivity to Fexinidazole Tablets and/or any nitroimidazole-class drugs (e.g., metronidazole, tinidazole).
• Patients with 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 hepatic impairment ( 4)
• Patients with Cockayne syndrome ( 4)

5warnings 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).

5.1Decreased Efficacy in Severe Human African Trypanosomiasis Caused by

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.

5.2QT 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).

5.3Neuropsychiatric 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.

5.4Neutropenia

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.

5.5Potential 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.

5.6Risk 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)] .

5.7Risk 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.

6adverse 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.

6.1Clinical 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)] .

7drug Interactions

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

7.1Pharmacodynamic 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)] .

7.2Pharmacokinetic Drug Interactions

Table 3: Effect of Fexinidazole on other Drugs

Drugs Metabolized by Cytochrome P450 (CYP) 3A4
Examples (not fully inclusive):	Lovastatin, simvastatin, nisoldipine, saquinavir, midazolam
Clinical Impact	Increased risk for adverse reactions associated with increased concentrations of the drug due to inhibition of CYP3A4 by fexinidazole [see Clinical Pharmacology (12.3)] .
Prevention or Management	Avoid concomitant use with Fexinidazole Tablets .
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 [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 these drugs.
Drugs Substrates of OCT2, OAT1, OAT3, MATE1, and MATE2-K Transporters
Examples (not fully inclusive):	Metformin, dofetilide, adefovir, cefaclor, furosemide
Clinical Impact	Increased risk for adverse reactions associated with increased concentrations of the drug due to inhibition of these transporters by fexinidazole [see Clinical Pharmacology (12.3)] .
Prevention or Management	Avoid concomitant use with Fexinidazole Tablets. If coadministration cannot be avoided, monitor for adverse reactions associated with these drugs.

Table 4: Effect of other Drugs on Fexinidazole

CYP450 Inducers
Examples (not fully inclusive):	Rifampin, phenytoin, St. John's wort, carbamazepine
Clinical Impact	Increased risk for adverse reactions associated with increased systemic exposure to the M1 and M2 metabolites of fexinidazole. M2 plasma concentrations have been associated with the increased risk of QT interval prolongation.
Prevention or Management	Avoid concomitant use with Fexinidazole Tablets [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
CYP450 Inhibitors
Examples (not fully inclusive):	Clarithromycin, itraconazole, voriconazole, erythromycin, fluconazole
Clinical Impact	Multiple CYP450 enzymes are involved in the metabolism of fexinidazole to its pharmacologically active M1 and M2 metabolites. Although no clinical drug interaction studies were performed with CYP450 inhibitors, the formation of the M1 and M2 metabolites may be decreased.
Prevention or Management	Avoid concomitant use with Fexinidazole Tablets. If coadministration cannot be avoided, monitor for lack of efficacy of fexinidazole due to potential for decreased plasma concentrations of the M1 and M2 metabolites [see Clinical Pharmacology (12.3)] .