LAMPIT

Warnings and Precautions, Embryo-Fetal Toxicity ( 5.2 ) 2/2023

1 INDICATIONS AND USAGE LAMPIT is indicated in pediatric patients (birth to less than 18 years of age and weighing at least 2.5 kg) for the treatment of Chagas disease (American Trypanosomiasis) caused by Trypanosoma cruzi [see Clinical Studies ( 14 )]. LAMPIT is a nitrofuran antiprotozoal, indicated in pediatric patients (birth to less than 18 years of age and weighing at least 2.5 kg) for the treatment of Chagas disease (American Trypanosomiasis), caused by Trypanosoma cruzi . ( 1 )

2 DOSAGE AND ADMINISTRATION • LAMPIT tablets must be taken with food ( 2.1 ) Dosage of LAMPIT in Pediatric Patients (birth a to less than 18 years of age) (2.2) Body Weight Group Total Daily Dose of nifurtimox (mg/kg) 41 kg or greater 8 to 10 Less than 41 kg 10 to 20 a Term newborn with body weight greater than or equal to 2.5 kg • Administer LAMPIT tablets orally, three times daily with food for 60 days. ( 2.2 ) • Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with LAMPIT ( 2.3 , 8.3 ) . • See Full Prescribing Information for additional important administration instructions. ( 2.1 , 2.2 , 2.4, 2.5 ) 2.1 Important Administration Instructions • LAMPIT (30 mg and 120 mg) tablets are for oral use and must be taken with food. • LAMPIT tablets are dosed by body weight of the patient [see Dosage and Administration ( 2.2 )] . • LAMPIT (30 mg and 120 mg) tablets are functionally scored tablets which can be split into one-half (15 mg and 60 mg respectively) at the scored lines by hand. Do not break LAMPIT tablets mechanically with a tablet splitting device [see Dosage and Administration ( 2.4 ) and Instructions for Use] . • LAMPIT 30 mg and 120 mg tablets can be made into a slurry as an alternative method of administration for patients who cannot swallow the tablets [see Dosage and Administration ( 2.5 )] . • Discontinue consumption of alcohol during treatment with LAMPIT [see Contraindications ( 4 ) and Drug Interactions ( 7 )] . • Complete the full course of treatment to prevent recurrence of the infection. • If a dose is missed, take the missed dose as soon as possible together with food. However, if it is within 3 hours of the next scheduled dose, skip the missed dose and continue treatment as prescribed. Do not take a double dose to make up for a missed dose. 2.2 Recommended Dosage in Pediatric Patients • Administer LAMPIT (30 mg and 120 mg) tablets orally three times a day with food. • Total daily recommended dosages of LAMPIT are based on the body weight of the patient (see Table 1 ). • Adjust LAMPIT dosage accordingly if body weight decreases during treatment [see Warnings and Precautions ( 5.4 )]. • The recommended duration of treatment with LAMPIT is 60 days. Table 1: Total Daily Recommended Dosages of LAMPIT Based on Body Weight Age Body weight group Total daily dose of nifurtimox (mg/kg) Birth a to less than 18 years 41 kg or greater 8 to 10 Less than 41 kg 10 to 20 a Term newborn with body weight of greater than or equal to 2.5 kg Table 2: Individual Dosages Based on Body Weight in Pediatric Patients (Birth a to Less than 18 years of age) Body weight (kg) Dose (mg) Number of LAMPIT 30 mg tablets per dose (3 x Daily) Number of LAMPIT 120 mg tablets per dose (3 x Daily) 2.5 kg to 4.5 kg 15 mg 1⁄2 tablet — 4.6 kg to less than 9 kg 30 mg 1 tablet — 9 kg to less than 13 kg 45 mg 1 1⁄2 tablets — 13 kg to less than 18 kg 60 mg 2 tablets 1⁄2 tablet 18 kg to less than 22 kg 75 mg 2 1⁄2 tablets — 22 kg to less than 27 kg 90 mg 3 tablets — 27 kg to less than 35 kg 120 mg 4 tablets 1 tablet 35 kg to less than 41 kg 180 mg — 1 1⁄2 tablets 41 kg to less than 51 kg 120 mg — 1 tablet 51 kg to less than 71 kg 180 mg — 1 1⁄2 tablets 71 kg to less than 91 kg 240 mg — 2 tablets 91 kg or greater 300 mg — 2 1⁄2 tablets a Term newborn with body weight of greater than or equal to 2.5 kg 2.3 Pregnancy Testing Prior to Initiating LAMPIT Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with LAMPIT [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.3 )]. 2.4 Instructions for Splitting LAMPIT Tablets Do not break LAMPIT tablets mechanically with a tablet splitting device. A functional score line is used to divide the tablet by hand as follows: • To split LAMPIT tablet, place the tablet on a flat surface with the score line facing up. • With the tablet resting on the flat surface, apply enough downward pressure with the index finger centered on …

3 DOSAGE FORMS AND STRENGTHS LAMPIT tablets are available as 30 mg and 120 mg tablets. • 30 mg, yellow, round, biconvex tablets, functionally scored on one side for the division of the tablet into equal doses and marked with ‘30’ on the other side. • 120 mg, yellow, round, biconvex tablets, functionally scored on one side for the division of the tablet into equal doses and marked with ‘120’ on the other side • Tablets: 30 mg (functionally scored) ( 3 ) • Tablets: 120 mg (functionally scored) ( 3 )

4 CONTRAINDICATIONS LAMPIT tablets are contraindicated in: • Patients with known hypersensitivity to nifurtimox or any of the excipients in LAMPIT [see Warnings and Precautions ( 5.4 )]. • Patients who consume alcohol during treatment [see Drug Interactions ( 7 )] • Known hypersensitivity to nifurtimox or to any of the excipients in LAMPIT. ( 4 ) • Alcohol consumption during treatment. (4)

6 ADVERSE REACTIONS The following serious or otherwise important adverse reactions are discussed elsewhere in the labeling: • Potential for Genotoxicity, Carcinogenicity, and Mutagenicity [see Warnings and Precautions ( 5.1 )] • Worsening of Neurological and Psychiatric Conditions [see Warnings and Precautions ( 5.3 )] • Hypersensitivity [see Warnings and Precautions ( 5.4 )] • Decreased Appetite and Weight Loss [see Warnings and Precautions ( 5.5 )] • Porphyria [see Warnings and Precautions ( 5.6 )] The most frequently reported adverse reactions (≥5%) are vomiting, abdominal pain, headache, decreased appetite, nausea, pyrexia, and rash. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 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. The safety data described below reflect exposure to LAMPIT in one prospective, randomized, double-blind trial (Trial 1). 330 pediatric patients with serologic evidence of T. cruzi infection and without Chagas disease-related cardiac or gastrointestinal symptoms were randomly assigned in a 2:1 fashion to a 60-day (n=219) or a 30-day (n=111) LAMPIT treatment regimen and were followed up for one year after end of treatment. LAMPIT was administered three times a day with food using a body weight-based dosing. The median treatment duration was 61 days for subjects in the 60-day regimen. The majority (86.7%) of the study population was ≥2 to <18 years of age at randomization. Discontinuation of LAMPIT due to adverse reactions occurred in 14 of 330 (4.2%) patients overall, 12 of 219 (5.5%) patients in the 60-day arm, and 2 of 111 (1.8%) patients in the 30-day arm. Adverse reactions were reported for 213 of 330 (64.5%) patients. The proportion of patients with adverse reactions was higher in the 60-day regimen (67.1%) compared with the 30-day regimen (59.5%). Most patients with adverse reactions had mild (76.5%) or moderate (22.0%) reactions. The most frequently reported adverse reactions in patients treated with LAMPIT for 60 days were vomiting (14.6%), abdominal pain (13.2%), headache (12.8%), decreased appetite (10.5%), nausea (8.2%), pyrexia (7.3%), rash (5.5%). Adverse reactions occurring in ≥1% of LAMPIT-treated patients are shown in Table 3 . Table 3 Adverse Reactions Reported in (≥1%) Pediatric Patients with Chagas Disease in Trial 1 Treated with LAMPIT for 60 days System Organ Class Adverse Reactions Incidence Blood and lymphatic system disorders Anemia Eosinophilia 2.7% 2.3% Gastrointestinal disorders Vomiting Abdominal pain a Nausea Diarrhea 14.6% 13.2% 8.2% 4.6% General disorders and administration site conditions Pyrexia 7.3% Investigations Weight decreased 2.7% Metabolism and nutrition disorders Decreased appetite 10.5% Nervous system disorders Headache Dizziness 12.8% 2.7% Skin and subcutaneous tissue disorders Rash b Urticaria 5.5% 2.3% a Abdominal pain includes abdominal pain and abdominal pain upper b Rash includes rash, rash macular, rash maculo-papular, rash morbilliform, and rash papular. Other adverse reactions occurring in 0.1% to less than 1% of patients treated with LAMPIT for 60 days included asthenia, vertigo, arthralgia, myalgia, paresthesia, tremor, irritability, anxiety, pruritus, fatigue, somnolence, seizure, syncope, neutropenia, leukopenia. 6.2 Postmarketing Experience The following safety data were derived during postmarketing surveillance of nifurtimox from outside the United States, including literature data for all age groups (pediatric and adult populations). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish …

7 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 [see Dosage and Administration ( 2.2 ) Contraindications ( 4 )].

8 USE IN SPECIFIC POPULATIONS Patients with Renal and or Hepatic Impairment: Administer LAMPIT under close medical supervision. ( 8.6 , 8. 7) 8.1 Pregnancy Risk Summary Based on animal studies, LAMPIT may cause fetal harm when administered to a pregnant woman. Published postmarketing reports on nifurtimox use during pregnancy are insufficient to inform a drug-associated risk of birth defects and miscarriage. There are risks to the fetus associated with Chagas disease ( see Clinical Considerations). Nifurtimox administered orally to pregnant rats, and rabbits during organogenesis was associated with reduced maternal body weights in rats, and abortions, reduced maternal weight gain, and reduced numbers of live fetuses in rabbits when nifurtimox was administered orally during organogenesis at doses approximately equal to the MRHD in rats and 2-times the MRHD in rabbits. An increased incidence of a fetal skeletal malformation (fusion of caudal vertebral bodies) occurred in rabbits at nifurtimox doses approximately 0.2 times the MRHD. In a pre-postnatal study, maternal body weights and fetal body weights of first-generation offspring were reduced at doses approximately equal to or 0.5 times the MRHD, respectively, and several male offspring in the nifurtimox treatment groups exhibited slightly small testes at doses ≥0.2 times the MRHD ( see Data) . Advise pregnant women of the potential risk to a fetus. There is a pregnancy safety study for LAMPIT. If LAMPIT is administered during pregnancy, or if a patient becomes pregnant while receiving LAMPIT or within six months following the last dose of LAMPIT, healthcare providers should report LAMPIT exposure by calling 1-888-842-2937. 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. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk Published data from case-control and observational studies on chronic Chagas disease during pregnancy are inconsistent in their findings. Some studies showed an increased risk of pregnancy loss, prematurity and neonatal mortality in pregnant women who have chronic Chagas disease while other studies did not demonstrate these findings. Chronic Chagas disease is usually not immediately life-threatening. Since pregnancy findings are inconsistent, treatment of chronic Chagas disease during pregnancy is not recommended due to risk of embryo-fetal toxicity from LAMPIT. Acute symptomatic Chagas disease is rare in pregnant women; however, symptoms may be serious or life-threatening. If a pregnant woman presents with acute symptomatic Chagas disease, the risks versus benefits of treatment with LAMPIT to the mother and the fetus should be evaluated on a case-by-case basis. Data Animal Data In an embryo-fetal toxicity study in pregnant rats, 15, 30, and 60 mg/kg/day nifurtimox were administered orally during the period of organogenesis (GD 6 to GD 17). Maternal body weights, body weight gain, and food consumption were reduced in the 60 mg/kg/day dose group. Treatment with nifurtimox did not produce fetal toxicity and no nifurtimox-related fetal malformations were observed. No maternal toxicity was observed at 30 mg/kg/day nifurtimox (approximately 0.5 times the MRHD based on body surface area comparison) and no adverse fetal effects were observed at 60 mg/kg/day nifurtimox (approximately equivalent to the MRHD based on body surface area comparison). In pregnant rabbits orally administered 5, 15, and 60 mg/kg/day nifurtimox during the period of organogenesis (GD 6 to GD 20), the high dose was associated with maternal toxicity including reduced body weights and food consumption, and abortions in 8/20 high-dose dams. The mean n …

12.1 Mechanism of Action Nifurtimox is an antiprotozoal drug [see Microbiology ( 12.4 )] .

Mechanism of Action The mechanism of action of nifurtimox is not fully understood. Studies suggest that nifurtimox is metabolized/activated, by Type I (oxygen insensitive) and Type II (oxygen sensitive) nitoreductases (NTR) leading to production of toxic intermediate metabolites and/or reactive oxygen species that induce DNA damage and cell death of both intracellular and extracellular forms of T. cruzi .

11 DESCRIPTION LAMPIT contains nifurtimox, an antiprotozoal. The chemical name is (E)-N-(3-Methyl-1,1-dioxidothiomorpholin-4-yl)-1-(5-nitro-2-furyl)methanimine. The molecular weight is 287.29 and the molecular formula is C 10 H 13 N 3 O 5 S. The structural formula is: LAMPIT (nifurtimox) tablets are yellow round, biconvex tablets, each containing 30 mg or 120 mg of nifurtimox, intended for oral use. The 30 mg tablets are functionally scored on one side and marked with ‘30’ on the other side. The 120 mg tablets are functionally scored on one side and marked with ‘120’ on the other side. The inactive ingredients of the tablets are as follows: calcium hydrogen phosphate dihydrate, magnesium stearate, maize starch, silica colloidal anhydrous and sodium lauryl sulfate. Chemical Structure

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied LAMPIT tablets are supplied as follows: • 30 mg, yellow, round, biconvex tablets, functionally scored on one side and marked with ‘30’ on the other side. • 120 mg, yellow, round, biconvex tablets, functionally scored on one side and marked with ‘120’ on the other side. LAMPIT tablets 30 mg are supplied as bottles of 100 tablets with child-resistant closures (NDC 50419-750-01). LAMPIT tablets 120 mg are supplied as bottles of 100 tablets with child-resistant closures (NDC 50419-751-01). 16.2 Storage and Handling Store at controlled room temperature 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature]. Store LAMPIT tablets in the original bottle with child-resistant closures and do not remove the desiccant. Keep bottle with child-resistant closures tightly closed and protect from moisture.