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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)].
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|
|Blood and lymphatic system disorders|
Defined as an absolute neutrophil count of less than 1,000 cells/mm3 occurring at any time following the first dose of study drug to the end of the study.
|15 (5.7%)||4 (3.1%)|
| Palpitations||13 (4.9%)||5 (3.8%)|
| Photophobia||6 (2.3%)||0|
| 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|
| 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%)|
| 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
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.
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)].
There are risks to the mother and fetus associated with untreated HAT due to T. brucei gambiense during pregnancy (see Clinical Considerations). Available data from clinical trials with fexinidazole use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects or miscarriage.
There were no effects on prenatal development in embryo-fetal studies where pregnant rats were administered oral fexinidazole during organogenesis at a dose similar to the clinical dose based on AUC comparisons. Effects of fexinidazole on embryo-fetal development were observed in the rat and in the rabbit at doses harmful to the dams only. Exposure of fexinidazole and its metabolites at those maternal toxic doses in rats and rabbits were 2 times and less than 0.02 times the clinical exposure, respectively. In the prenatal and postnatal development study, administration of oral fexinidazole to pregnant rats during organogenesis and through lactation resulted in lower body weights in first generation offspring from dams treated at approximately 1.03 times the clinical exposure based on AUC comparisons.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Disease-associated maternal and/or embryo/fetal Risk
There are adverse effects on maternal and fetal outcomes associated with untreated HAT due to T. brucei gambiense in pregnancy. Disease progression may occur during pregnancy. Pregnant women should be treated for HAT due to T. brucei gambiense during pregnancy to prevent vertical transmission. For timing of treatment during pregnancy, consider the benefits of Fexinidazole Tablets to the mother and the potential risks to the fetus.
In the embryo-fetal toxicity studies, pregnant rats were exposed from gestation day (GD) 6 through GD 17. There was no effect on prenatal development in the rat up to the daily dose of 200 mg/kg, similar to the clinical dose based on AUC comparisons.
Maternal toxicity was evidenced by the significantly reduced body weight gain observed at 800 mg/kg. Delayed ossification (sternebrae, metacarpals and caudal vertebrae) and reduced fetal and placental weights were observed in the presence of maternal toxicity.
In the rabbit embryo-fetal development study, pregnant rabbits were exposed from GD 6 to GD 20. Fexinidazole resulted in abortions in the presence of maternal toxicity (reduced food consumption and reduced body weight gain) at doses of 20 mg/kg/day and above, less than 0.02 times the clinical exposures, based on pharmacokinetics comparisons.
In the prenatal and postnatal development study, female rats were exposed from GD 6 to lactation day 21. Lower body weights were reported in F1 pups from dams treated (approximately 1.03 times the clinical exposure based on AUC comparisons) throughout lactation. Sexual maturity showed a minimal delay for both males and females. Postweaning development for behavior and reproductive performance did not indicate any late adverse effect on the progeny.
There are no data on the presence of fexinidazole in human milk or the effect on milk production. There are no reports of adverse effects to the breastfed child associated with fexinidazole exposure through breastmilk based on a limited number of reported cases. Fexinidazole is present in rat milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Fexinidazole Tablets and any potential adverse effects on the breastfed child from fexinidazole or from the underlying maternal condition.
In lactating rats given a single oral dose of 800 mg/kg 14C-fexinidazole, fexinidazole and/or related metabolites were detected in the milk.
Concentration-dependent QTcF prolongation was observed with administration of Fexinidazole Tablets. Based on the exposure-response relationship, the mean (upper 90% confidence interval) increase in QTcF is predicted to be 19.0 msec (23.3 msec) at the recommended dosing regimen. The observed increase in QTcF appears to be associated with the M2 (sulfone) metabolite of fexinidazole [see Warning and Precautions (5.2)].
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.
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.
No specific PK studies were conducted in patients with hepatic impairment. Furthermore, insufficient data were available to assess the effect of hepatic impairment on fexinidazole PK from the clinical trials [see Use in Specific Populations (8.7)].
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 m2), 89 patients with mild renal impairment (eGFR 60 to less than 90 mL/min/1.73 m2), and 14 patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2). The predicted AUC0–24 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)].
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) 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, M1, or M2 do not induce CYP3A4; fexinidazole and M1 have the potential to induce CYP1A2 and CYP2B6 [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.
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 Cmax compared to when caffeine was administered alone. The mean Cmax and AUC of omeprazole were approximately 2-fold higher compared to when omeprazole was administered alone [see Drug Interactions (7.2)].
Findings from a static mechanistic model-based analysis predicted that fexinidazole may significantly increase the systemic PK exposure (AUC) of sensitive CYP3A4 substrates and 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.
Mechanism of Action
Studies with Trypanosoma brucei and other protozoans suggest that, like for other nitro-containing drugs, the nitroreductase (NTR) enzyme plays an important role in the bioactivation of fexinidazole resulting in generation of reactive amines and damage to DNA and proteins. The activity of fexinidazole and its metabolites (M1 and M2) is trypanocidal and appears to be concentration and time dependent. However, the precise mechanism by which fexinidazole and the two metabolites exhibit activity against T. brucei is not known.
Fexinidazole and its two metabolites, M1 and M2, are active against the trypanosomes of Trypanosoma brucei gambiense.
In vitro studies suggest a potential for development of resistance in T. brucei against fexinidazole.
The mechanism of resistance appears to be similar to other nitro-containing drugs, such as nifurtimox, and include down-regulation of Type 1 NTR. However, the clinical relevance of these findings is not known.
Nonclinical studies suggest cross-resistance between fexinidazole and other nitro-containing drugs such as nifurtimox. This appears to be due to down regulation of Type I NTR. Although the clinical relevance of these findings is not known, the potential for the development of resistance to fexinidazole in patients previously treated with nifurtimox-eflornithine combination therapy (NECT) cannot be discounted.
No carcinogenicity study was performed with fexinidazole.
Carcinogenicity has been observed in mice and rats treated chronically with nitroimidazole-class drugs which are structurally similar to fexinidazole. It is unclear if the findings of tumors in lifetime rodent studies indicate a risk to patients taking a 10-day treatment of Fexinidazole Tablets for HAT.
Fexinidazole and the M2 metabolite were mutagenic in the Ames test. Fexinidazole was negative in the in vitro micronucleus test in cultured human peripheral blood lymphocytes, the rat liver unscheduled DNA synthesis (UDS) assay, and the in vivo mouse micronucleus assay.
Impairment of Fertility
In the fertility and early embryonic development study, male rats were treated for 28 days prior to start of cohabitation with treated females and throughout the cohabitation period until sacrifice. Female rats were treated for 14 days prior to start of cohabitation with treated males throughout the cohabitation period until copulation occurred and up to GD 7. Fexinidazole showed no effect on fertility parameters and no evidence of impairment of reproductive performance up to the dose of 600 mg/kg/day (estimated to be approximately 1.03 times the clinical exposure based on AUC comparisons).
The efficacy and safety of Fexinidazole Tablets were evaluated in a randomized, comparative open-label trial (Trial 1, NCT01685827) conducted in adult patients with late second-stage HAT due to T. brucei gambiense. Patients had evidence of parasites in blood, lymph and/or cerebrospinal fluid (CSF) at trial enrollment. If testing for parasites in CSF was negative, a CSF WBC >20 cells/μL was required to confirm late second-stage HAT. Patients (n=394) were randomized in a 2:1 ratio to a 10-day treatment regimen of either Fexinidazole Tablets (n=264) or nifurtimox-eflornithine combination therapy (NECT) (n=130). The mean age was 35 years (range 15 to 71) and 61% were male. The fexinidazole tablet group received 1,800 mg of Fexinidazole Tablets orally once daily on Days 1 through 4, followed by 1,200 mg orally once daily on Days 5 through 10, with all dosing in the fed state. The NECT control arm received nifurtimox tablets 15 mg/kg/day in three divided doses for 10 days as well as eflornithine injectable solution 400 mg/kg/day in two divided doses for 7 days. Patients were hospitalized throughout their treatment and were allowed to leave the hospital from Day 13 onwards if their clinical status was satisfactory. Patients were followed up at 3, 6, 12, 18, and 24 months after the end of treatment visit. HAT symptoms reported at baseline in >50% of patients included headache, pruritus, sleepiness, weight loss, and asthenia. The median CSF WBC count was 157 cells/µL.
The outcome at 18 months was considered a success if patients were classified as a cure or probable cure as defined below:
- Cure: Patient is alive with no evidence of trypanosomes in any body fluid and CSF WBC ≤20 cells/µL.
- Probable cure for patients who refused a lumbar puncture (or who had a hemorrhagic CSF sample) at 18 months: No parasites in the blood or lymph and a satisfactory clinical condition without clinical signs or symptoms (or clinical status is unlikely to be due to HAT), CSF WBC <50 cells/µL at 6 and/or 12 months and not increasing at 12 months, as long as there was no indication of a relapse up to 24 months and no definitive failure (presence of trypanosomes) had been observed before in any body fluid.
Success rates at 18 months are shown in Table 6 for the modified intention-to-treat (mITT) population, which consisted of all randomized patients who received at least one dose of study treatment but excluded 5 randomized patients due to geopolitical unrest. The success rate in the fexinidazole treatment arm was lower than in the NECT arm. Additionally, more deaths occurred in the fexinidazole treatment arm at 24 months (n=9, 3.4%) compared to the NECT treatment arm (n=2, 1.6%). This decreased efficacy and increased mortality was noted in the subgroup of patients who had CSF-WBC >100 cells/µL at baseline [see Warnings and Precautions (5.1)]. The results at 24 months were consistent with the results at 18 months with 24-month success rates of 89.7% (235/262) in the fexinidazole treatment arm and 97.6% (124/127) in the NECT arm.
Table 6: Success Rates at 18 Months (mITT population) in Trial 1
|Fexinidazole||NECT||Difference (97% CI|
Analysis adjusted for interim analysis to control the overall Type I error at two-sided 0.05.)
|Success at 18 months|
Two fexinidazole treated patients were considered as failures due to loss to follow-up and consent withdrawal prior to 18 months.
|239 (91.2%)||124 (97.6%)||-6.4% (-11.6%, -0.1%)|
|Success at 18 months by baseline CSF-WBC|
CSF-WBC represents white blood cell count in cerebrospinal fluid at baseline.
| Baseline CSF-WBC ≤100 cells/µL||100/102 (98.0%)||47/49 (95.9%)||–|
| Baseline CSF-WBC >100 cells/µL||139/160 (86.9%)||77/78 (98.7%)||–|
Trial 2 and Trial 3
Additional supportive evidence for efficacy in early stage HAT due to T. brucei gambiense, and in pediatric patients was obtained from two single-arm trials: a single-arm trial in adults (Trial 2, NCT02169557), and a single-arm trial in pediatric patients aged 6 to 15 years old and weighing at least 20 kg (Trial 3, NCT02184689). In Trial 2, the mean age of patients was 34 years and 82% of patients had evidence of first-stage HAT (evidence of trypanosomes in the blood or lymph, no trypanosomes in the CSF, and CSF WBC ≤5 cells /µL). In Trial 3, the mean age of patients was 11 years and 55% of patients had evidence of first-stage HAT. Fexinidazole Tablets 1,200 mg, was given in fed condition once a day on Days 1 through 4, followed by 600 mg on Days 5 through 10 to patients weighing <35 kg, and all other patients received the adult dosing regimen. Treatment success proportions in all patients with first- or late-stage HAT were 98.7% (227/230, 95% CI [96.2%, 99.7%]) at 12 months in Trial 2 and 97.6% (122/125, 95% CI [93.1%, 99.5%]) at 12 months in Trial 3. The results at 18 months were consistent with the results at 12 months.
Administration with Food
Advise the patient that Fexinidazole Tablets must be taken with food each day at about the same time of the day (e.g., during or immediately after the main meal of the day), to make sure it is adequately absorbed [see Dosage and Administration (2.1, 2.2)].
Advise patients not to consume alcoholic beverages during treatment with Fexinidazole Tablets and for at least 48 hours after completing Fexinidazole Tablets therapy [see Dosage and Administration (2.1) and Warnings and Precautions (5.6)].
Advise the patient not to administer an additional dose if vomiting occurs after the administration of Fexinidazole Tablets but continue with the next scheduled dose the following day. If a second event of vomiting occurs after administration of any other dose of Fexinidazole Tablets, counsel the patient on the importance of contacting the healthcare provider immediately [see Dosage and Administration (2.1)].
Advise patients that 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. Counsel the patient on the importance of contacting the health care practitioner immediately if a second scheduled dose is missed [see Dosage and Administration (2.1)].
Neuropsychiatric Adverse Reactions
Counsel patients and their caregivers of the risk for neuropsychiatric adverse reactions, such as insomnia, headache, tremor, mood changes, psychiatric disorders (such as agitation, anxiety, abnormal behavior, depression, nightmares, hallucination, and personality change) and suicidal ideation [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]. If such adverse reactions occur, advise the patients and their caregivers to contact their healthcare provider immediately.
Counsel the patient that they should not drive or use machines if they feel tired or dizzy. Dizziness, fatigue, asthenia, and somnolence have been reported following treatment with Fexinidazole Tablets [see Adverse Reactions (6.1)].
Advise patients to disclose to their healthcare provider all other medications, including herbal medicines, the patient is currently taking while being treated with fexinidazole tablets [see Drug Interactions (7)].
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