LAMPIT

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 ½ tablet — 4.6 kg to less than 9 kg 30 mg 1 tablet — 9 kg to less than 13 kg 45 mg 1 ½ tablets — 13 kg to less than 18 kg 60 mg 2 tablets ½ tablet 18 kg to less than 22 kg 75 mg 2 ½ 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 ½ tablets 41 kg to less than 51 kg 120 mg — 1 tablet 51 kg to less than 71 kg 180 mg — 1 ½ tablets 71 kg to less than 91 kg 240 mg — 2 tablets 91 kg or greater 300 mg — 2 ½ 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 the top of the tablet to break it along the score line. 2.5 Preparation of a Slurry of LAMPIT as an Alternate Method of Administration For patients who are unable to swallow whole or half tablets, LAMPIT tablet can be dispersed in water and administered as outlined below. • Place approximately 2.5 mL of water into a spoon. • Place the prescribed dose into the water. • Allow the tablet(s) to disintegrate (typically less than 30 seconds). • A slurry (liquid suspension) is formed. • Take the slurry immediately with food.

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)

5 WARNINGS AND PRECAUTIONS • Potential for Genotoxicity and Carcinogenicity. ( 5.1 ) • Embryo-Fetal Toxicity: May cause fetal harm. Pregnancy testing is recommended for females of reproductive potential. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. Advise males to use condoms with female partners of reproductive potential. ( 2.3 , 5.2 , 8.1 , 8.3 ) • Worsening Neurological and Psychiatric Conditions: Patients with a history of brain injury, seizures, psychiatric disease, serious behavioral alterations may experience worsening of their conditions when receiving LAMPIT. Administer LAMPIT under close medical supervision in these patients or if neurological disturbances or psychiatric drug reactions occur. ( 5.3 ) • Hypersensitivity: Hypersensitivity reactions including hypotension, angioedema, dyspnea, pruritus, rash or other severe skin reactions have been reported with the use of nifurtimox, discontinuation of treatment is recommended. ( 5.4 ) • Decreased Appetite and Weight Loss: Check body weight every 14 days as dosage may need to be adjusted. ( 5.5 ) • Porphyria: Treatment with nitrofuran derivatives, such as LAMPIT, may precipitate acute attacks of porphyria. Administer LAMPIT under close medical supervision in patients with porphyria. ( 5.6 ) 5.1 Potential for Genotoxicity and Carcinogenicity Genotoxicity Genotoxicity of LAMPIT has been demonstrated in humans, in vitro in several bacterial species and mammalian cell systems, and in vivo in rodents [see Nonclinical Toxicology ( 13.1 )] . A study evaluating the cytogenetic effect of nifurtimox in pediatric patients ranging from 7 months to 14 years of age with Chagas disease demonstrated a 13-fold increase in chromosomal aberrations. Carcinogenicity Carcinogenicity has been observed in mice and rats treated chronically with nitrofuran agents which are structurally similar to nifurtimox. Similar data have not been reported for LAMPIT [see Nonclinical Toxicology ( 13.1 )] . It is not known whether LAMPIT is associated with carcinogenicity in humans. 5.2 Embryo-Fetal Toxicity Based on findings from animal studies, LAMPIT can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, nifurtimox administered orally to pregnant rats, and rabbits during organogenesis was associated with reduced maternal body weights in rats, and abortions, fetal death, and smaller litter sizes in rabbits at doses approximately equivalent to and 2-times, respectively, the maximum recommended human dose (MRHD) of 10 mg/kg/day. Fetal malformations were observed in pregnant rabbits administered nifurtimox doses less than the MRHD [see Use in Specific Populations ( 8.1 )]. Advise pregnant women of the potential risk to a fetus. Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with LAMPIT [see Dosage and Administration ( 2.3 )] . Advise females of reproductive potential to use effective contraception during treatment with LAMPIT and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use condoms during treatment and for 3 months after the last dose of LAMPIT [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.3 )]. 5.3 Worsening of Neurological and Psychiatric Conditions Patients with a history of brain injury, seizures, psychiatric disease, or serious behavioral alterations may experience worsening of their conditions when receiving LAMPIT. Administer LAMPIT under close medical supervision in these patients and in patients who develop neurological disturbances or psychiatric drug reactions. 5.4 Hypersensitivity Cases of hypersensitivity have been reported in patients receiving therapy with nifurtimox. The hypersensitivity could be a reaction induced by nifurtimox or an immune response triggered by Chagas disease during treatment. Hypersensitivity reactions could be accompanied by hypotension, angioedema (including laryngeal or facial edema), dyspnea, pruritus, rash or other severe skin reactions. At the first sign of serious hypersensitivity, discontinue treatment with LAMPIT [see Contraindications ( 4 )]. 5.5 Decreased Appetite and Weight Loss Decreased appetite and weight loss were reported in patients treated with LAMPIT in the clinical trials. During treatment with LAMPIT, patients can lose their appetite or experience nausea/vomiting which can result in weight loss. Check body weight every 14 days, as the dosage may have to be adjusted [see Dosage and Administration ( 2.2 )]. 5.6 Porphyria Treatment with nitrofuran derivatives, such as LAMPIT, may precipitate acute attacks of porphyria. Administer LAMPIT tablets under close medical supervision in patients with porphyria.

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 )].

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 a causal relationship to drug exposure. Table 4: Postmarketing Adverse Reactions Reported in Pediatric and Adult Populations Treated with Nifurtimox System Organ Class Adverse Reaction Immune system disorders Hypersensitivity reactions, including anaphylaxis Ear and labyrinth disorders Vertigo Skin and subcutaneous tissue disorders Angioedema Drug reaction with eosinophilia and systemic symptoms (DRESS) Musculoskeletal, connective tissue and bone disorders Muscle weakness Nervous system disorders Amnesia Polyneuropathy Psychiatric disorders Apathy Agitation Psychotic behavior Sleep disorder Blood and lymphatic system disorders Thrombocytopenia

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 number of live fetuses/litter and the percent of live fetuses per total implantations per group were significantly lower in the mid- and high-dose groups compared to the control group. Nifurtimox administration was associated with increased fetal and litter incidences of a skeletal malformation (fusion of caudal vertebral bodies) in fetuses in the low-dose group receiving 5 mg/kg/day (approximately equivalent to 0.2-times the MRHD based on body surface area comparison). No maternal toxicity was observed at 15 mg/kg/day which is approximately equivalent to 0.5 times the MRHD based on body surface area comparison. In a pre-postnatal study, pregnant female rats were orally administered 15, 30, and 60 mg/kg/day nifurtimox during organogenesis and lactation [GD 6 to lactation day (LD) 21]. Maternal findings included reduced maternal body weights in high-dose dams during gestation and to a lesser degree during lactation. In first-generation offspring, body weights were significantly reduced in males and females in the high-dose group during the lactation and post-lactation periods. Physical development, neurological function, and reproduction of first-generation offspring were not substantially changed in the nifurtimox treatment groups, but 5–20% of male offspring in all the nifurtimox treatment groups exhibited slightly small testes. No adverse maternal effects or fetal effects on first-generation female offspring occurred at 30 mg/kg/day, and no adverse fetal effects on the development of male offspring occurred at 15 mg/kg/day (respectively approximately 0.5- and 0.2-times the MRHD based on body surface area comparison).