DRUG INTERACTIONS- summary

­ • Avoid use of herbal medicines and supplements.

 • See full prescribing information for complete list of clinically significant drug interactions. 

DRUG INTERACTIONS- details-                                                                                              

1. Pharmacodynamic 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 ß-blockers) should be avoided

U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 29

Name of the Drug-    FEXINIDAZOLE

Active Ingredient -   Fexinidazole

Pharmacological Classification- To treat human African trypanosomiasis caused                                                            by the parasite Trypanonosoma brucei                                                                          gambiense                                                                                                                                                                               

 Date of Approval-          7/16/2021             

HIGHLIGHTS OF PRESCRIBING INFORMATION                                                           

These highlights do not include all the information needed to use FEXINIDAZOLE TABLETS safely and effectively.

See full prescribing information for FEXINIDAZOLE TABLETS. FEXINIDAZOLE tablets, for oral use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE

 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.

 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.

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ADVERSE REACTIONS-

­ 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.

CONTRAINDICATIONS-

­ • Known hypersensitivity to fexinidazole, and/or nitroimidazole drugs

 • Patients with hepatic impairment

WARNINGS AND PRECAUTIONS-

­ • Decreased Efficacy in Severe Human African Trypanosomiasis caused by Trypanosoma brucei gambiense. 

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.

 • 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.

 • 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.

 • Potential for Hepatotoxicity:                                                                                    Evaluate liver-related laboratory tests at the start and during treatment.

 • 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.

 • 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). ------------------------------ADVERSE REACTIONS------------------------------­ 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 rep

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.

 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

DOSAGE FORMS AND STRENGTHS-

­ Tablets: 600 mg 

PATIENT COUNSELING INFORMATION 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)]. Alcohol Consumption 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)]. Vomiting 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)]. Missed Doses 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. Dizziness Reference ID: 4827304 18 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)]. Drug Interactions 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)].

Manufactured for: Drugs for Neglected Diseases initiative 15 Chemin Camille-Vidart 1202 Geneva Switzerland Distributed by: sanofi-aventis U.S. LLC Bridgewater, NJ 08807 A SANOFI COMPANY ©2021 sanofi-aventis U.S. LL

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                          Fexinidazole is an antiprotozoal drug 

2. Pharmacodynamics-                                                                                          Cardiac Electrophysiology 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 

Absorption- Median Tmax (Range) on Day 4, hours 4 (0-9) 4 (0-6) 6 (0-24)

Effect of Food* The AUC of fexinidazole, M1, and M2 were approximately 4 to 5-fold higher following administration with food compared to the fasted state.

Distribution -Apparent Volume of Distribution on Day 4, L 3222 (±1199) NA NA Plasma Protein Binding 98% 41% 57% Mean (Range) CSF concentrations at 24 hours after the last fexinidazole dose on Day 10, mcg/mL† NA 1.39 (0-4.5) 6.45 (0.3-14.9) Mean (Range) CSF to DBS Ratios† NA 0.53 (0.1-2.2) 0.36 (0.1-0.8)

Elimination- Mean (±SD) Day 10 Half-life, hours 15 (±6) 16 (±6) 23 (±4) Mean (±SD) Apparent Clearance on Day 4, L/hour 161 (±37) NA NA

Metabolism-                                                                                                   • Fexinidazole is metabolized to M1 by several CYP450 enzymes, including CYP3A4 and flavin monooxygenases. 

• Several CYP450 enzymes including, CYP3A4 and flavin monooxygenases, are involved in the metabolism of M1 to M2. • M2 is not further metabolized.

• The AUC0-24 of M1 and M2 are 11 and 34-fold higher, respectively, than that of fexinidazole.

Excretion- Urine Less than 3.2% of a given dose of Fexinidazole Tablets, primarily as M1 and M2 metabolites Cmax = maximum plasma concentration; Tmax = time to maximum concentration; CSF = cerebrospinal fluid; CYP = cytochrome P450 enzymes; AUC0-24 hours = area under the plasma concentration-time curve from time zero to 24 hours, AUC0-t = area under the plasma concentration-time curve from time zero to the last timepoint with measurable analyte concentrations; DBS = dried blood spot NA: Not available or not applicable

* The effect of food following administration of a single 1,200 mg dose with a meal containing approximately 963 Kcal with 62% of total calories from fat, 17% from protein, and 21% from carbohydrate (n=12). † From study in patient with HAT. Reference ID: 4827304

Specific Populations-                                                                                                      Elderly patients 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.

Pediatric patients -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.

Hepatic impairment- 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

Renal Impairment -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 

Race/ethnicity- 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 

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 BCR

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                      There are risks to the mother and fetus associated with untreated HAT due to T. brucei gambiense during pregnancy 

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.

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 Reference ID: 4827304 9 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.

2. Lactation Risk Summary-                                                                                         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 

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.

 3.Pediatric Use -                                                                                                           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 

4. Geriatric Use-                                                                                                               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.

5.Renal Impairment-                                                                                                        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 

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.

6.Hepatic Impairment -                                                                                                  The pharmacokinetics of fexinidazole in patients with hepatic impairment is unknown. Since fexinidazole is extensively metabolized by the liver, Fexinidazole Tablets are contraindicated in patients with hepatic impairment

 OVERDOSAGE

Randomized, controlled clinical studies were conducted in normal adult male volunteers 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 

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.