Fexinidazole
Generic: FEXINIDAZOLE
Basic Information
Manufacturer
Sanofi-Aventis U.S. LLC
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
74a611bc-9977-46bb-b626-0370b3031628
Indications & Usage
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) ] .
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) ] .
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 (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) ] .
( 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) ] .