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On August 6, 2020, the U.S. Food and Drug Administration (FDA) approved LAMPIT (nifurtimox) for the treatment of Chagas disease (American Trypanosomiasis), caused by Trypanosoma cruzi, in pediatric patients (birth to less than 18 years of age and weighing at least 2.5 kg). This indication is approved under accelerated approval based on the number of treated patients who became immunoglobulin G (IgG) antibody negative or who showed an at least 20% decrease in optical density on two different IgG antibody tests against antigens of T. cruzi. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
The approved recommended dosage of LAMPIT in pediatric patients (birth to less than 18 years of age and weighing at least 2.5 kg) based on body weight is:
- 40 kg or greater: 8 mg/kg to 10 mg/kg
- Less than 40 kg: 10 mg/kg to 20 mg/kg
Administer LAMPIT tablets orally three times daily with food for 60 days. Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with LAMPIT. Additional information regarding dosage and administration as well as warnings and precautions about the potential for genotoxicity and carcinogenicity, embryo-fetal toxicity, worsening of neurological and psychiatric conditions, hypersensitivity, decreased appetite and weight loss, and porphyria can be found in the full prescribing information linked below.
Mechanism of Action (MOA) and Pharmacokinetics (PK)
MOA: Nifurtimox is an antiprotozoal drug.
General PK: The mean (%CV) nifurtimox AUC estimates ranged between 1676-2670 μg∙h/L (19 - 32%) and Cmax estimates ranged between 425-568 μg/L (26 - 50%) following administration of single dose 120 mg nifurtimox with food in adult Chagas patients. No clinically significant differences in nifurtimox AUC or Cmax at the 120 mg dose were observed when using two tablet strengths (30 and 120 mg) or administered as whole or dissolved tablets under fed conditions.
Absorption: The median time to reach maximum concentration (Tmax) of nifurtimox under fed conditions was 4 hours (range: 2 to 8 hours).
Effect of Food: Following administration of a single oral dose of 120 mg LAMPIT in adult Chagas patients, nifurtimox Cmax increased 68%, AUC increased 71%, and Tmax increased by 1 hour with a high-fat meal (800–1000 calorie, approximately 60% fat) compared to fasted conditions.
Distribution: Nifurtimox passes the blood brain barrier as well as the placental barrier. The plasma protein binding of nifurtimox is 42%.
Elimination: The mean (%CV) estimates for elimination half-life of nifurtimox ranged between 2.4–3.6 hours (12–37%).
Metabolism: Metabolism of nifurtimox is primarily mediated via nitroreductases. Exploratory investigations identified two major pharmacologically inactive metabolites (M-4, M-6) and several other minor metabolites in pooled human plasma. M-4 is a rearranged cysteine conjugate of nifurtimox with a half-life of approximately 28 hours, and M-6 is postulated to be formed by hydrolytic cleavage of the hydrazone moiety with a half-life of approximately 10 hours.
Excretion: Following administration of nifurtimox under fed and fasted conditions, approximately 44% and 27% of the dose was recovered in urine mainly as metabolites, respectively. Biliary and fecal elimination of nifurtimox and its metabolites has not been evaluated.
Drug Interactions
Concomitant use of LAMPIT with alcohol may increase the incidence and severity of undesirable effects similar to other nitrofurans and nitroheterocyclic compounds. LAMPIT is contraindicated in patients who consume alcohol during treatment.
Use in Specific Populations
The effect of renal or hepatic impairment on the pharmacokinetics of nifurtimox is unknown. Published literature indicates blood concentrations of nifurtimox increased in patients with ESRD requiring hemodialysis. Administer LAMPIT in patients with renal or hepatic impairment under close medical supervision.
Efficacy and Safety
The efficacy of LAMPIT for the treatment of Chagas disease in pediatric patients birth to <18 years of age and weighing at least 2.5 kg was demonstrated in one prospective, randomized, double-blind trial conducted in Argentina, Bolivia and Colombia. Serological response to treatment was defined as ≥20% decrease in optical density measured by lysate and recombinant ELISA in subjects >8 months to <18 years or seroconversion to negative (defined as negative immunoglobulin G concentration in all patients) at 1-year post-treatment follow-up. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.
The most frequently reported adverse reactions (≥5%) are vomiting, abdominal pain, headache, decreased appetite, nausea, pyrexia, and rash.
Full prescribing information is available at https://go.usa.gov/xfs49.
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.
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