ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious or otherwise important adverse reactions are discussed elsewhere in the labeling:oPotential for Genotoxicity, Carcinogenicity, and Mutagenicity [see Warnings and Precautions (5.1)] oWorsening of Neurological and Psychiatric Conditions [see Warnings and Precautions (5.3)]oHypersensitivity [see Warnings and Precautions (5.4)]oDecreased Appetite and Weight Loss [see Warnings and Precautions (5.5)]oPorphyria [see Warnings and Precautions (5.6)]. oPotential for Genotoxicity, Carcinogenicity, and Mutagenicity [see Warnings and Precautions (5.1)] oWorsening of Neurological and Psychiatric Conditions [see Warnings and Precautions (5.3)]. oHypersensitivity [see Warnings and Precautions (5.4)]. oDecreased Appetite and Weight Loss [see Warnings and Precautions (5.5)]. oPorphyria [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 1-888-842-293 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 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 2:1 fashion to 60-day (n=219) or 30-day (n=111) LAMPIT treatment regimen and were followed up for one year after end of treatment. LAMPIT was administered three times day with food using 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 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 Adverse Reactions Reported in (>=1%) Pediatric Patients with Chagas Disease in Trial Treated with LAMPIT for 60 daysSystem Organ ClassAdverse ReactionsIncidence Blood and lymphatic system disordersAnemiaEosinophilia2.7%2.3%Gastrointestinal disordersVomiting Abdominal paina NauseaDiarrhea14.6%13.2%8.2%4.6%General disorders and administration site conditionsPyrexia7.3%InvestigationsWeight decreased2.7%Metabolism and nutrition disordersDecreased appetite10.5%Nervous system disordersHeadacheDizziness12.8%2.7%Skin and subcutaneous tissue disordersRashb Urticaria5.5%2.3%a Abdominal pain includes abdominal pain and abdominal pain upperb 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Table 4:Postmarketing Adverse Reactions Reported in Pediatric and Adult Populations Treated with NifurtimoxSystem Organ Class Adverse ReactionImmune system disordersHypersensitivity reactions, including anaphylaxisEar and labyrinth disordersVertigoSkin and subcutaneous tissue disordersAngioedemaDrug reaction with eosinophilia and systemic symptoms (DRESS)Musculoskeletal, connective tissue and bone disordersMuscle weaknessNervous system disorders AmnesiaPolyneuropathyPsychiatric disorders ApathyAgitationPsychotic behaviorSleep disorderBlood and lymphatic system disordersThrombocytopenia.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Adequate long-term carcinogenicity studies for nifurtimox have not been performed. Nitrofurans, which have similar chemical structures to nifurtimox have been reported to be carcinogenic in mice and rats.Genetic ToxicityThe genotoxicity of nifurtimox has been demonstrated in vitro in several bacterial species and mammalian cell systems and in vivo in mammals.Nifurtimox was mutagenic in strains of S. typhimurium (TA 98, 100, and 1537) in an Ames assay.Nifurtimox was genotoxic in human lymphocytes in an in vitro micronucleus assay.In vivo, nifurtimox was shown to be positive for genotoxicity in mouse micronucleus assay, mouse sister-chromatid exchange assay, and human chromosome aberration assay. However, in sister-chromatid exchange study in humans, oral doses of nifurtimox did not cause significant increase in the frequency of sister-chromatid exchange in blood lymphocytes.. Impairment of Fertility In study examining the effects of nifurtimox on testicular morphology, male mice fed 0.08% or 0.16% nifurtimox in animal feed for 14 weeks experienced dose-dependent testicular toxicity including complete inhibition of spermatogenesis with the highest dose, evidence of arrested mitosis, signs of pyknosis, and no mature sperm. However, interstitial cells were unchanged, and fibrosis and inflammatory infiltrates were not observed. Nine weeks after the end of nifurtimox exposure, all testicular effects were almost entirely reversed.In male and female fertility study in rats, nifurtimox was administered in dietary feed at doses of 150 ppm (equivalent to 7-15 mg/kg), 300 ppm (equivalent to 15-30 mg/kg/day), and 600 ppm (equivalent to 30-60 mg/kg/day) for 10 weeks before mating. Male fertility was completely inhibited in rats administered 30-60 mg/kg/day nifurtimox, but female fertility was not affected for the same dosing regimen. In recovery study, 11 weeks after the end of dosing, fertility was still inhibited in 75% of male rats administered nifurtimox for 32 weeks indicating lack of complete reversibility. The nifurtimox dose in male rats that was not associated with inhibition of fertility was considered to be <=30 mg/kg/day which is approximately equivalent to 0.5 times the MRHD for fertile males based on body surface area comparison.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Nifurtimox is an antiprotozoal drug [see Microbiology (12.4)].. 12.2 Pharmacodynamics Nifurtimox exposure-response relationships and the time course of pharmacodynamics response are unknown. Cardiac Electrophysiology At the recommended dose, nifurtimox treatment does not result in large mean increases (>20 ms) in the QTc interval.. 12.3 Pharmacokinetics Absorption The mean (%CV) nifurtimox AUC estimates ranged between 1676-2670 ugh/L (19-32%) and Cmax estimates ranged between 425-568 ug/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. The median time to reach maximum concentration (Tmax) of nifurtimox under fed conditions was hours (range: to hours).. Effect of Food Following administration of single oral dose of 120 mg LAMPIT in adult Chagas patients, nifurtimox Cmax increased 68%, AUC increased 71%, and Tmax increased by hour with 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 proteins 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 rearranged cysteine conjugate of nifurtimox with half-life of approximately 28 hours, and M-6 is postulated to be formed by hydrolytic cleavage of the hydrazone moiety with 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.. Specific Populations The effect of renal or hepatic impairment on the pharmacokinetics of nifurtimox is unknown. Blood concentrations of nifurtimox increased in patients with ESRD.. Drug Interaction Studies Clinical Studies No clinical studies evaluating the drug interaction potential of nifurtimox have been conducted.. In Vitro Studies Cytochrome P450 Enzymes (CYPs): Nifurtimox is not substrate of CYPs. Nifurtimox and its metabolites (M-4 or M-6) are not inhibitors or inducers of CYPs.Transporter Systems: Nifurtimox is not substrate or inhibitor of P-glycoprotein (P-gp) or breast cancer resistant protein (BCRP), and is not an inhibitor of organic anion transporting polypeptide (OATPs), multidrug and toxin extrusion (MATE) proteins (MATE1/MATE2-K), organic anion transporter 1/3 (OAT1/OAT3), or organic cation transporter (OCT2). Major metabolites (M-4 or M-6) of nifurtimox are not inhibitors of P-gp, BCRP, OATPs, MATE1, MATE2K, OAT1, OAT3, or OCT2 at clinically relevant concentrations. 12.4 Microbiology Mechanism of Action The mechanism of action of nifurtimox is not fully understood. Studies suggest that nifurtimox is metabolized/activated, by Type (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.. Antimicrobial Activity Nifurtimox is active against all three stages, trypomastigotes, amastigotes, and epimastigotes, of T. cruzi. However, the sensitivity of T. cruzi strains to nifurtimox, from different geographic regions, may vary.. Resistance In vitro studies suggest the potential for development of resistance in T. cruzi against nifurtimox.The mechanism of resistance to nifurtimox appears to be multifactorial. Trypanosomal nitroreductase is defined as key resistance determinate. Either loss of gene copy, mutation of gene or down-regulation of gene expression are sufficient to cause decreased susceptibility of T. cruzi against nitroheterocyclic drugs like nifurtimox. In addition, other mechanisms of resistance like lower drug influx or higher drug efflux are described. However, the clinical relevance of these findings is not known.. Cross-resistance Nonclinical studies suggest cross-resistance between nifurtimox and benznidazole. This appears to be due to down regulation of Type NTR localized in the mitochondria.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oLAMPIT tablets must be taken with food (2.1)Dosage of LAMPIT in Pediatric Patients (birtha to less than 18 years of age) (2.2)Body Weight GroupTotal Daily Dose of nifurtimox(mg/kg)41 kg or greater8 to 10Less than 41 kg10 to 20aTerm newborn with body weight greater than or equal to 2.5 kgoAdminister LAMPIT tablets orally, three times daily with food for 60 days. (2.2)oObtain pregnancy test in females of reproductive potential prior to initiating treatment with LAMPIT (2.3, 8.3).oSee Full Prescribing Information for additional important administration instructions. (2.1, 2.2, 2.4, 2.5). oLAMPIT tablets must be taken with food (2.1). oAdminister LAMPIT tablets orally, three times daily with food for 60 days. (2.2). oObtain pregnancy test in females of reproductive potential prior to initiating treatment with LAMPIT (2.3, 8.3).. oSee Full Prescribing Information for additional important administration instructions. (2.1, 2.2, 2.4, 2.5). 2.1 Important Administration Instructions oLAMPIT (30 mg and 120 mg) tablets are for oral use and must be taken with food. oLAMPIT tablets are dosed by body weight of the patient [see Dosage and Administration (2.2)].oLAMPIT (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 tablet splitting device [see Dosage and Administration (2.4) and Instructions for Use].oLAMPIT 30 mg and 120 mg tablets can be made into slurry as an alternative method of administration for patients who cannot swallow the tablets [see Dosage and Administration (2.5)].oDiscontinue consumption of alcohol during treatment with LAMPIT [see Contraindications (4) and Drug Interactions (7)]. oComplete the full course of treatment to prevent recurrence of the infection.oIf dose is missed, take the missed dose as soon as possible together with food. However, if it is within hours of the next scheduled dose, skip the missed dose and continue treatment as prescribed. Do not take double dose to make up for missed dose. oLAMPIT (30 mg and 120 mg) tablets are for oral use and must be taken with food. oLAMPIT tablets are dosed by body weight of the patient [see Dosage and Administration (2.2)].. oLAMPIT (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 tablet splitting device [see Dosage and Administration (2.4) and Instructions for Use].. oLAMPIT 30 mg and 120 mg tablets can be made into slurry as an alternative method of administration for patients who cannot swallow the tablets [see Dosage and Administration (2.5)].. oDiscontinue consumption of alcohol during treatment with LAMPIT [see Contraindications (4) and Drug Interactions (7)]. oComplete the full course of treatment to prevent recurrence of the infection.. oIf dose is missed, take the missed dose as soon as possible together with food. However, if it is within hours of the next scheduled dose, skip the missed dose and continue treatment as prescribed. Do not take double dose to make up for missed dose. 2.2 Recommended Dosage in Pediatric Patients oAdminister LAMPIT (30 mg and 120 mg) tablets orally three times day with food. oTotal daily recommended dosages of LAMPIT are based on the body weight of the patient (see Table 1). oAdjust LAMPIT dosage accordingly if body weight decreases during treatment [see Warnings and Precautions (5.4)].oThe recommended duration of treatment with LAMPIT is 60 days. Table 1: Total Daily Recommended Dosages of LAMPIT Based on Body WeightAgeBody weight groupTotal daily dose of nifurtimox (mg/kg)Birtha to less than 18 years41 kg or greater8 to 10Less than 41 kg10 to 20aTerm newborn with body weight of greater than or equal to 2.5 kgTable 2: Individual Dosages Based on Body Weight in Pediatric Patients (Birtha to Less than 18 years of age)Body weight (kg)Dose (mg)Number of LAMPIT 30 mg tablets per dose (3 Daily)Number of LAMPIT120 mg tablets per dose(3 Daily)2.5 kg to 4.5 kg15 mg 1/2 tablet--4.6 kg to less than kg30 mg1 tablet--9 kg to less than 13 kg45 mg1 1/2 tablets--13 kg to less than 18 kg60 mg2 tablets 1/2 tablet18 kg to less than 22 kg75 mg2 1/2 tablets--22 kg to less than 27 kg90 mg3 tablets--27 kg to less than 35 kg120 mg4 tablets1 tablet35 kg to less than 41 kg180 mg--1 1/2 tablets41 kg to less than 51 kg120 mg--1 tablet51 kg to less than 71 kg180 mg--1 1/2 tablets71 kg to less than 91 kg240 mg--2 tablets91 kg or greater300 mg--2 1/2 tabletsaTerm newborn with body weight of greater than or equal to 2.5 kg. oAdminister LAMPIT (30 mg and 120 mg) tablets orally three times day with food. oTotal daily recommended dosages of LAMPIT are based on the body weight of the patient (see Table 1). oAdjust LAMPIT dosage accordingly if body weight decreases during treatment [see Warnings and Precautions (5.4)].. oThe recommended duration of treatment with LAMPIT is 60 days. 2.3 Pregnancy Testing Prior to Initiating LAMPIT Obtain 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 tablet splitting device. functional score line is used to divide the tablet by hand as follows: oTo split LAMPIT tablet, place the tablet on flat surface with the score line facing up. oWith 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. oTo split LAMPIT tablet, place the tablet on flat surface with the score line facing up. oWith 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 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. oPlace approximately 2.5 mL of water into spoon.oPlace the prescribed dose into the water. oAllow the tablet(s) to disintegrate (typically less than 30 seconds).oA slurry (liquid suspension) is formed.oTake the slurry immediately with food.. oPlace approximately 2.5 mL of water into spoon.. oPlace the prescribed dose into the water. oAllow the tablet(s) to disintegrate (typically less than 30 seconds).. oA slurry (liquid suspension) is formed.. oTake the slurry immediately with food.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use).Embryo Fetal ToxicityoAdvise pregnant women and females of reproductive potential of the potential risk of LAMPIT to fetus and to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.2), Use in Specific Populations (8.1, 8.3) and Nonclinical Toxicology (13.1)].oAdvise females of reproductive potential to use effective contraception while taking LAMPIT and for months after the last dose [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].oAdvise male patients with female partners of reproductive potential to use condoms during treatment with LAMPIT and for months after the final dose of LAMPIT [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].LactationAdvise nursing mothers to monitor infants exposed to LAMPIT through breast milk for vomiting, rash, decreased appetite, fever, and irritability [Use in Specific Populations (8.2)]. InfertilityAdvise males of reproductive potential that LAMPIT may impair fertility [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].Worsening of Neurological and Psychiatric ConditionsAdvise patients with history of brain injury, seizures, psychiatric disease, serious behavioral alterations or if neurological and/or psychiatric drug reactions occur, that LAMPIT tablets should be administered only under close medical supervision [see Warnings and Precautions (5.1)].HypersensitivityInform patients that hypersensitivity could be reaction caused by LAMPIT or an immune response triggered by Chagas disease during treatment. Hypersensitivity reactions could include hypotension, angioedema (including laryngeal or facial edema), dyspnea, pruritus, rash or other severe skin reactions [see Warnings and Precautions (5.2)]. Alcohol ConsumptionAdvise patients to discontinue alcohol use during treatment with LAMPIT. LAMPIT is contraindicated in patients who consume alcohol during treatment [see Contraindications (4)].Decreased Appetite and Weight LossInform patients that LAMPIT can cause decreased appetite and weight loss. Body weight should be checked every 14 days, as the dosage may have to be adjusted [see Warnings and Precautions (5.5)].PorphyriaAdvise patients with porphyria that treatment with nitrofuran derivatives, such as LAMPIT, may precipitate acute attacks of porphyria. Administer LAMPIT tablets under close medical supervision in patients with porphyria. [see Warnings and Precautions (5.6)].Important Administration InstructionsAdvise patients to take LAMPIT with food.Advise patients not to break LAMPIT tablets mechanically with tablet splitting device [see Dosage and Administration (2.4)].For patients who cannot swallow tablets, LAMPIT can be dispersed in water and administered as slurry, taken with food [see Dosage and Administration (2.1, 2.2, 2.5)].Ability to Operate Vehicles or MachineryInform patients that if muscle weakness or tremors occur during treatment with LAMPIT they should not drive, cycle or use any tools or machines [see Adverse Reactions (6.1]. Manufactured for: Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ 07981 USA(C) 2020 Bayer HealthCare Pharmaceuticals Inc. For more information, call Bayer HealthCare Pharmaceuticals Inc. at Bayer at 1-888-842-2937 or go to www.LAMPIT.com. oAdvise pregnant women and females of reproductive potential of the potential risk of LAMPIT to fetus and to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.2), Use in Specific Populations (8.1, 8.3) and Nonclinical Toxicology (13.1)].. oAdvise females of reproductive potential to use effective contraception while taking LAMPIT and for months after the last dose [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].. oAdvise male patients with female partners of reproductive potential to use condoms during treatment with LAMPIT and for months after the final dose of LAMPIT [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].. For more information, call Bayer HealthCare Pharmaceuticals Inc. at Bayer at 1-888-842-2937 or go to www.LAMPIT.com.

INSTRUCTIONS FOR USE SECTION.

Instructions for Use INSTRUCTIONS FOR USELAMPIT (LAM-pit)(nifurtimox)tablets, for oral useThis Instructions for Use contains information on how to split LAMPIT tablets and how to prepare tablet and water mixture (called slurry) if whole tablets or half tablets cannot be swallowed. Read this Instructions for Use before you start taking LAMPIT and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.LAMPIT 30 mg tabletsLAMPIT 120 mg tabletsImportant Information You Need to Know Before Taking LAMPIToDo not take more LAMPIT than prescribed by your healthcare provider.oTake LAMPIT with food.oSplit LAMPIT tablets by hand. Do not split LAMPIT tablets using tablet splitting device. See the instructions below for splitting tablets by hand.oIf you cannot swallow LAMPIT tablets or you are giving LAMPIT to child who cannot swallow the tablets, you can dissolve the tablet in water and give the mixture with food. See the instructions below for preparing tablet and water mixture (slurry).How to Take LAMPIToTake LAMPIT times day with food.oYour healthcare provider may need to change your dose of LAMPIT during treatment as needed. Take your LAMPIT dose exactly as prescribed by your healthcare provider. oLAMPIT 30 mg tablets and 120 mg tablets have scored line on one side and can be taken whole or broken at the scored line.oIf you miss dose of LAMPIT, take the missed dose as soon as possible with food. If it is within hours of the next scheduled dose, skip the missed dose and take the next dose at your regular time. Do not take doses to make up for missed dose.How to Split LAMPIT Tablets by HandStep 1: To split the tablet, place the tablet on flat surface with the scored line facing up (See Figure A).Figure AStep 2: With the tablet still on the flat surface, apply enough pressure down on the center of the tablet with your index finger to split it in half along the scored line (See Figure B).Figure BStep 3: LAMPIT tablets can be split in half along the scored line (See Figure C).Figure CStep 4: Only use tablet that has been broken at the scored line (See Figure D).Figure DDo not split LAMPIT tablets in any other way.Preparing Tablet and Water Mixture (Slurry)For people who are not able to swallow whole tablets or half tablets, LAMPIT can be mixed in water. Step 1: Place approximately one-half teaspoonful (2.5 ml) of water into spoon (See Figure E).Figure EStep 2: Place the prescribed dose into the water (See Figure F).Figure FStep 3: Allow the tablet to dissolve in the water. This should take less than 30 seconds (See Figure G).Figure GStep 4: tablet and water mixture (slurry) will form (See Figure H).Figure HGive the tablet and water mixture (slurry) right away with food. Do not mix more than the prescribed dose.Storing LAMPIToStore LAMPIT at room temperature between 68F to 77F (20C to 25C).oKeep LAMPIT in the bottle with child-resistant cap that it comes with. Do not remove the packet that helps to keep your medicine dry (desiccant).oKeep the bottle tightly closed and protect from moisture.Keep LAMPIT and all medicines out of the reach of children.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured for: Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ 07981 USA(C) 2020 Bayer HealthCare Pharmaceuticals Inc. For more information, call Bayer HealthCare Pharmaceuticals Inc. at Bayer at 1-888-842-2937 or go to www.LAMPIT.com Issued: 8/2020. oDo not take more LAMPIT than prescribed by your healthcare provider.. oTake LAMPIT with food.. oSplit LAMPIT tablets by hand. Do not split LAMPIT tablets using tablet splitting device. See the instructions below for splitting tablets by hand.. oIf you cannot swallow LAMPIT tablets or you are giving LAMPIT to child who cannot swallow the tablets, you can dissolve the tablet in water and give the mixture with food. See the instructions below for preparing tablet and water mixture (slurry).. oTake LAMPIT times day with food.. oYour healthcare provider may need to change your dose of LAMPIT during treatment as needed. Take your LAMPIT dose exactly as prescribed by your healthcare provider. oLAMPIT 30 mg tablets and 120 mg tablets have scored line on one side and can be taken whole or broken at the scored line.. oIf you miss dose of LAMPIT, take the missed dose as soon as possible with food. If it is within hours of the next scheduled dose, skip the missed dose and take the next dose at your regular time. Do not take doses to make up for missed dose.. oStore LAMPIT at room temperature between 68F to 77F (20C to 25C).. oKeep LAMPIT in the bottle with child-resistant cap that it comes with. Do not remove the packet that helps to keep your medicine dry (desiccant).. oKeep the bottle tightly closed and protect from moisture.. INSTRUCTIONS FOR USE. 30 mg tablets. 120 mg tablets. tablet. press. split in half. split tab. spoon water. spoon tablets. tablet in water. dissolving. slurry.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Adequate long-term carcinogenicity studies for nifurtimox have not been performed. Nitrofurans, which have similar chemical structures to nifurtimox have been reported to be carcinogenic in mice and rats.Genetic ToxicityThe genotoxicity of nifurtimox has been demonstrated in vitro in several bacterial species and mammalian cell systems and in vivo in mammals.Nifurtimox was mutagenic in strains of S. typhimurium (TA 98, 100, and 1537) in an Ames assay.Nifurtimox was genotoxic in human lymphocytes in an in vitro micronucleus assay.In vivo, nifurtimox was shown to be positive for genotoxicity in mouse micronucleus assay, mouse sister-chromatid exchange assay, and human chromosome aberration assay. However, in sister-chromatid exchange study in humans, oral doses of nifurtimox did not cause significant increase in the frequency of sister-chromatid exchange in blood lymphocytes.. Impairment of Fertility In study examining the effects of nifurtimox on testicular morphology, male mice fed 0.08% or 0.16% nifurtimox in animal feed for 14 weeks experienced dose-dependent testicular toxicity including complete inhibition of spermatogenesis with the highest dose, evidence of arrested mitosis, signs of pyknosis, and no mature sperm. However, interstitial cells were unchanged, and fibrosis and inflammatory infiltrates were not observed. Nine weeks after the end of nifurtimox exposure, all testicular effects were almost entirely reversed.In male and female fertility study in rats, nifurtimox was administered in dietary feed at doses of 150 ppm (equivalent to 7-15 mg/kg), 300 ppm (equivalent to 15-30 mg/kg/day), and 600 ppm (equivalent to 30-60 mg/kg/day) for 10 weeks before mating. Male fertility was completely inhibited in rats administered 30-60 mg/kg/day nifurtimox, but female fertility was not affected for the same dosing regimen. In recovery study, 11 weeks after the end of dosing, fertility was still inhibited in 75% of male rats administered nifurtimox for 32 weeks indicating lack of complete reversibility. The nifurtimox dose in male rats that was not associated with inhibition of fertility was considered to be <=30 mg/kg/day which is approximately equivalent to 0.5 times the MRHD for fertile males based on body surface area comparison.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Absorption The mean (%CV) nifurtimox AUC estimates ranged between 1676-2670 ugh/L (19-32%) and Cmax estimates ranged between 425-568 ug/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. The median time to reach maximum concentration (Tmax) of nifurtimox under fed conditions was hours (range: to hours).. Effect of Food Following administration of single oral dose of 120 mg LAMPIT in adult Chagas patients, nifurtimox Cmax increased 68%, AUC increased 71%, and Tmax increased by hour with 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 proteins 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 rearranged cysteine conjugate of nifurtimox with half-life of approximately 28 hours, and M-6 is postulated to be formed by hydrolytic cleavage of the hydrazone moiety with 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.. Specific Populations The effect of renal or hepatic impairment on the pharmacokinetics of nifurtimox is unknown. Blood concentrations of nifurtimox increased in patients with ESRD.. Drug Interaction Studies Clinical Studies No clinical studies evaluating the drug interaction potential of nifurtimox have been conducted.. In Vitro Studies Cytochrome P450 Enzymes (CYPs): Nifurtimox is not substrate of CYPs. Nifurtimox and its metabolites (M-4 or M-6) are not inhibitors or inducers of CYPs.Transporter Systems: Nifurtimox is not substrate or inhibitor of P-glycoprotein (P-gp) or breast cancer resistant protein (BCRP), and is not an inhibitor of organic anion transporting polypeptide (OATPs), multidrug and toxin extrusion (MATE) proteins (MATE1/MATE2-K), organic anion transporter 1/3 (OAT1/OAT3), or organic cation transporter (OCT2). Major metabolites (M-4 or M-6) of nifurtimox are not inhibitors of P-gp, BCRP, OATPs, MATE1, MATE2K, OAT1, OAT3, or OCT2 at clinically relevant concentrations.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary Based on animal studies, LAMPIT may cause fetal harm when administered to pregnant woman. Published postmarketing reports on nifurtimox use during pregnancy are insufficient to inform 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 mice, rats, and rabbits during organogenesis was associated with reduced fetal body weights in mice, reduced maternal and fetal 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 rodents and 2-times the MRHD in rabbits. An increased incidence of fetal skeletal malformation (fusion of caudal vertebral bodies) occurred in rabbits at nifurtimox doses approximately 0.2 times the MRHD. In 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 fetus.There is pregnancy safety study for LAMPIT. If LAMPIT is administered during pregnancy, or if 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 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 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 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 case-by-case basis.. Data Animal Data In preliminary embryo-fetal studies, pregnant mice and rats were administered 20, 50, and 125 mg/kg/day nifurtimox during the period of organogenesis [gestation day (GD) to GD 15 for both species]. Maternal body weights were significantly reduced in the 50 and 125 mg/kg/day dose groups in rats, but not in mice. No fetal malformations were reported for either species, but mean fetal weights were significantly reduced in the 125 mg/kg/day dose group in mice and in the 50 and 125 mg/kg/day dose groups in rats. No maternal toxicity was observed in mice at 125 mg/kg/day or in rats at 20 mg/kg/day (respectively approximately equal to or 0.3-times the MRHD based on body surface area comparison). No adverse fetal effects were observed in mice at dose of 50 mg/kg/day or in rats at dose of 20 mg/kg/day (respectively equivalent to 0.4-times or 0.3-times the MRHD based on body surface area comparison).In pregnant rabbits administered 5, 15, and 60 mg/kg/day nifurtimox during the period of organogenesis (GD 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 skeletal malformation (fusion of caudal vertebral bodies) in fetuses in the low-dose group receiving 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 pre-postnatal study, pregnant female rats were administered 15, 30, and 60 mg/kg/day nifurtimox during organogenesis and lactation [GD to lactation day (LD) 21]. Maternal findings included reduced maternal body weights in high-dose dams during gestation and to 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).

SPL PATIENT PACKAGE INSERT SECTION.

Patient Package Insert PATIENT INFORMATIONLAMPIT(R) (LAM-pit)(nifurtimox)tablets, for oral useWhat is LAMPITLAMPIT is prescription medicine used to treat Chagas disease caused by the parasite Trypanosoma cruzi in children less than 18 years of age weighing at least 5.5 pounds (2.5 kg).It is not known if LAMPIT is safe and effective in children weighing less than 5.5 pounds (2.5 kg).Do not take LAMPIT if you:oare allergic to nifurtimox, or any of the ingredients in LAMPIT. See the end of this Patient Information leaflet for complete list of ingredients in LAMPIT.oplan to drink alcohol during treatment with LAMPIT.Before taking LAMPIT, tell your healthcare provider about all your medical conditions, including if you:ohave history of brain injury, seizures, mental health problems, or behavior changes.ohave kidney problems or are on dialysis.ohave liver problems.ohave genetic problem called porphyria. Taking LAMPIT can make your symptoms of porphyria including dark urine, severe stomach pain, muscle pain, tingling, numbness, mental changes or skin sensitivity to light worse.oare pregnant, plan to become pregnant, or think you may be pregnant. LAMPIT can harm your unborn baby. For females who are able to become pregnant:oYour healthcare provider should do pregnancy test before you start taking LAMPIT to make sure that you are not pregnant.oYou should use effective forms of birth control during treatment with LAMPIT and for months after your last dose of LAMPIT. Talk to your healthcare provider about what forms of birth control may be right for you.oCall your healthcare provider right away if you become pregnant or think you are pregnant during treatment with LAMPIT. For males:oLAMPIT may cause fertility problems in males. This may affect your ability to father child. Talk to your healthcare provider if you have concerns about fertility.oYou should use condom with female partners who are able to become pregnant, during treatment with LAMPIT and for months after your last dose of LAMPIT. oare breastfeeding or plan to breastfeed. LAMPIT can pass into breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby during treatment with LAMPIT. If you take LAMPIT and breastfeed, monitor your baby for vomiting, rash, decreased appetite, fever, and irritability. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep list of them with you to show to your healthcare provider and pharmacist when you get new medicine.How should take LAMPITSee the detailed Instructions for Use that comes with LAMPIT for information about how to split LAMPIT tablets and how to take LAMPIT if whole tablets or half tablets cannot be swallowed.oTake LAMPIT exactly as your healthcare provider tells you. oYour healthcare provider may change your dose if needed.oTake your prescribed dose of LAMPIT times day with food.oLAMPIT tablets are marked with scored line. LAMPIT tablets can be taken whole or split at the scored line. oLAMPIT tablets should be split by hand at the scored line. Do not split LAMPIT tablets using tablet splitting device. oIf you cannot swallow LAMPIT tablets or you are giving LAMPIT to child who cannot swallow the tablets, be sure to read the Instructions for Use that come with LAMPIT. LAMPIT tablets can be dissolved in water if whole tablets or half tablets cannot be swallowed. oIf you miss dose of LAMPIT, take it as soon as possible with food. If it is within hours of your next scheduled dose, skip the missed dose and take the next dose at your regular time. Do not take doses to make up for missed dose. What are the possible side effects of LAMPITLAMPIT may cause serious side effects, including:oWorsening of symptoms related to brain injury, seizures, mental health problems or behavior changes in people with history of these problems. Call your healthcare provider right away if any of these problems get worse during treatment with LAMPIT.oAllergic reactions. Allergic reactions can happen when taking nifurtimox, the active ingredient in LAMPIT, or with changes in your immune system caused by Chagas disease during treatment with LAMPIT. These allergic reactions can include low blood pressure, swelling of the face and tongue (angioedema), shortness of breath, itching, rash or other skin problems. Call your healthcare provider or get emergency medical help if you get any of these signs and symptoms of an allergic reaction during treatment with LAMPIT.oLoss of appetite and weight loss. Your healthcare provider should check your weight every 14 days to see if your dose of LAMPIT may need to be changed.The most common side effects of LAMPIT include:oheadacheovomitingonauseaorashodecreased appetiteoabdominal painofeverThese are not all the possible side effects of LAMPIT.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store LAMPIToStore LAMPIT at room temperature between 68F to 77F (20C to 25C).oKeep LAMPIT in the bottle that it comes in with the child-resistant cap on the bottle. Do not remove the packet that helps to keep your medicine dry (desiccant).oKeep the bottle tightly closed and protect from moisture.Keep LAMPIT and all medicines out of the reach of children.General information about the safe and effective use of LAMPIT.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use LAMPIT for condition for which it was not prescribed. Do not give LAMPIT to other people, even if they have the same symptoms that you have. It may harm them.You can ask your healthcare provider or pharmacist for information about LAMPIT that is written for health professionals.What are the ingredients in LAMPITActive ingredient: nifurtimoxInactive ingredients: calcium hydrogen phosphate dihydrate, magnesium stearate, maize starch, silica colloidal anhydrous, and sodium lauryl sulfate.Manufactured for: Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ 07981 USA(C) 2020 Bayer HealthCare Pharmaceuticals Inc. For more information, call Bayer HealthCare Pharmaceuticals Inc. at Bayer at 1-888-842-2937 or go to www.LAMPIT.com This Patient Information has been approved by the U.S. Food and Drug AdministrationIssued: 8/202020 oare allergic to nifurtimox, or any of the ingredients in LAMPIT. See the end of this Patient Information leaflet for complete list of ingredients in LAMPIT.. oplan to drink alcohol during treatment with LAMPIT.. ohave history of brain injury, seizures, mental health problems, or behavior changes.. ohave kidney problems or are on dialysis.. ohave liver problems.. ohave genetic problem called porphyria. Taking LAMPIT can make your symptoms of porphyria including dark urine, severe stomach pain, muscle pain, tingling, numbness, mental changes or skin sensitivity to light worse.. oare pregnant, plan to become pregnant, or think you may be pregnant. LAMPIT can harm your unborn baby. For females who are able to become pregnant:oYour healthcare provider should do pregnancy test before you start taking LAMPIT to make sure that you are not pregnant.oYou should use effective forms of birth control during treatment with LAMPIT and for months after your last dose of LAMPIT. Talk to your healthcare provider about what forms of birth control may be right for you.oCall your healthcare provider right away if you become pregnant or think you are pregnant during treatment with LAMPIT.. oYour healthcare provider should do pregnancy test before you start taking LAMPIT to make sure that you are not pregnant.. oYou should use effective forms of birth control during treatment with LAMPIT and for months after your last dose of LAMPIT. Talk to your healthcare provider about what forms of birth control may be right for you.. oCall your healthcare provider right away if you become pregnant or think you are pregnant during treatment with LAMPIT.. For males:. oLAMPIT may cause fertility problems in males. This may affect your ability to father child. Talk to your healthcare provider if you have concerns about fertility.. oYou should use condom with female partners who are able to become pregnant, during treatment with LAMPIT and for months after your last dose of LAMPIT. oare breastfeeding or plan to breastfeed. LAMPIT can pass into breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby during treatment with LAMPIT. If you take LAMPIT and breastfeed, monitor your baby for vomiting, rash, decreased appetite, fever, and irritability. oTake LAMPIT exactly as your healthcare provider tells you. oYour healthcare provider may change your dose if needed.. oTake your prescribed dose of LAMPIT times day with food.. oLAMPIT tablets are marked with scored line. LAMPIT tablets can be taken whole or split at the scored line. oLAMPIT tablets should be split by hand at the scored line. Do not split LAMPIT tablets using tablet splitting device. oIf you cannot swallow LAMPIT tablets or you are giving LAMPIT to child who cannot swallow the tablets, be sure to read the Instructions for Use that come with LAMPIT. LAMPIT tablets can be dissolved in water if whole tablets or half tablets cannot be swallowed. oIf you miss dose of LAMPIT, take it as soon as possible with food. If it is within hours of your next scheduled dose, skip the missed dose and take the next dose at your regular time. Do not take doses to make up for missed dose. oWorsening of symptoms related to brain injury, seizures, mental health problems or behavior changes in people with history of these problems. Call your healthcare provider right away if any of these problems get worse during treatment with LAMPIT.. oAllergic reactions. Allergic reactions can happen when taking nifurtimox, the active ingredient in LAMPIT, or with changes in your immune system caused by Chagas disease during treatment with LAMPIT. These allergic reactions can include low blood pressure, swelling of the face and tongue (angioedema), shortness of breath, itching, rash or other skin problems. Call your healthcare provider or get emergency medical help if you get any of these signs and symptoms of an allergic reaction during treatment with LAMPIT.. oLoss of appetite and weight loss. Your healthcare provider should check your weight every 14 days to see if your dose of LAMPIT may need to be changed.. oheadache. ovomiting. onausea. orash. odecreased appetite. oabdominal pain. ofever. oStore LAMPIT at room temperature between 68F to 77F (20C to 25C).. oKeep LAMPIT in the bottle that it comes in with the child-resistant cap on the bottle. Do not remove the packet that helps to keep your medicine dry (desiccant).. oKeep the bottle tightly closed and protect from moisture.. This Patient Information has been approved by the U.S. Food and Drug AdministrationIssued: 8/202020.

SPL UNCLASSIFIED SECTION.

2.1 Important Administration Instructions oLAMPIT (30 mg and 120 mg) tablets are for oral use and must be taken with food. oLAMPIT tablets are dosed by body weight of the patient [see Dosage and Administration (2.2)].oLAMPIT (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 tablet splitting device [see Dosage and Administration (2.4) and Instructions for Use].oLAMPIT 30 mg and 120 mg tablets can be made into slurry as an alternative method of administration for patients who cannot swallow the tablets [see Dosage and Administration (2.5)].oDiscontinue consumption of alcohol during treatment with LAMPIT [see Contraindications (4) and Drug Interactions (7)]. oComplete the full course of treatment to prevent recurrence of the infection.oIf dose is missed, take the missed dose as soon as possible together with food. However, if it is within hours of the next scheduled dose, skip the missed dose and continue treatment as prescribed. Do not take double dose to make up for missed dose. oLAMPIT (30 mg and 120 mg) tablets are for oral use and must be taken with food. oLAMPIT tablets are dosed by body weight of the patient [see Dosage and Administration (2.2)].. oLAMPIT (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 tablet splitting device [see Dosage and Administration (2.4) and Instructions for Use].. oLAMPIT 30 mg and 120 mg tablets can be made into slurry as an alternative method of administration for patients who cannot swallow the tablets [see Dosage and Administration (2.5)].. oDiscontinue consumption of alcohol during treatment with LAMPIT [see Contraindications (4) and Drug Interactions (7)]. oComplete the full course of treatment to prevent recurrence of the infection.. oIf dose is missed, take the missed dose as soon as possible together with food. However, if it is within hours of the next scheduled dose, skip the missed dose and continue treatment as prescribed. Do not take double dose to make up for missed dose.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Patients with Renal and or Hepatic Impairment: Administer LAMPIT under close medical supervision. (8.6, 8.7). 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 pregnant woman. Published postmarketing reports on nifurtimox use during pregnancy are insufficient to inform 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 mice, rats, and rabbits during organogenesis was associated with reduced fetal body weights in mice, reduced maternal and fetal 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 rodents and 2-times the MRHD in rabbits. An increased incidence of fetal skeletal malformation (fusion of caudal vertebral bodies) occurred in rabbits at nifurtimox doses approximately 0.2 times the MRHD. In 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 fetus.There is pregnancy safety study for LAMPIT. If LAMPIT is administered during pregnancy, or if 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 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 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 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 case-by-case basis.. Data Animal Data In preliminary embryo-fetal studies, pregnant mice and rats were administered 20, 50, and 125 mg/kg/day nifurtimox during the period of organogenesis [gestation day (GD) to GD 15 for both species]. Maternal body weights were significantly reduced in the 50 and 125 mg/kg/day dose groups in rats, but not in mice. No fetal malformations were reported for either species, but mean fetal weights were significantly reduced in the 125 mg/kg/day dose group in mice and in the 50 and 125 mg/kg/day dose groups in rats. No maternal toxicity was observed in mice at 125 mg/kg/day or in rats at 20 mg/kg/day (respectively approximately equal to or 0.3-times the MRHD based on body surface area comparison). No adverse fetal effects were observed in mice at dose of 50 mg/kg/day or in rats at dose of 20 mg/kg/day (respectively equivalent to 0.4-times or 0.3-times the MRHD based on body surface area comparison).In pregnant rabbits administered 5, 15, and 60 mg/kg/day nifurtimox during the period of organogenesis (GD 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 skeletal malformation (fusion of caudal vertebral bodies) in fetuses in the low-dose group receiving 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 pre-postnatal study, pregnant female rats were administered 15, 30, and 60 mg/kg/day nifurtimox during organogenesis and lactation [GD to lactation day (LD) 21]. Maternal findings included reduced maternal body weights in high-dose dams during gestation and to 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).. 8.2 Lactation Risk Summary Published literature demonstrates that nifurtimox is present in human breast milk with an estimated infant daily dose of less than 15% of the recommended daily dose for pediatric patients with Chagas disease. There were no reports of adverse effects on the small number of infants who were breastfed by mothers taking nifurtimox. There is no information on the effects of nifurtimox on milk production. Monitor infants exposed to LAMPIT through breast milk for vomiting, rash, decreased appetite, pyrexia and irritability.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for LAMPIT and any potential adverse effects on the breastfed infant from LAMPIT or from the underlying maternal condition.. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with LAMPIT.. Contraception Females LAMPIT may cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with LAMPIT and for months after the final dose. Males Due to the potential for genotoxicity, advise male patients with female partners of reproductive potential to use condoms during treatment and for months after the final dose of LAMPIT [see Nonclinical Toxicology (13.1)]. Infertility Males Based on findings in rodents, LAMPIT may impair fertility in males of reproductive potential. These effects on fertility were not reversible in 75% of the animals at 11 weeks after dosing [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of LAMPIT have been established for the treatment of Chagas disease (American Trypanosomiasis) caused by Trypanosoma cruzi in pediatric patients from birth to less than 18 years of age weighing at least 2.5 kg. The safety and effectiveness of LAMPIT has not been established in pediatric patients weighing less than 2.5 kg. 8.6 Renal Impairment The effect of renal impairment on the pharmacokinetics of nifurtimox is unknown [see Clinical Pharmacology (12.3)]. Published literature suggests that blood concentrations of nifurtimox were increased in patients with End Stage Renal Disease (ESRD) requiring hemodialysis [see, Clinical Pharmacology (12.3)]. Administer LAMPIT under close medical supervision.. 8.7 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of nifurtimox is unknown [Clinical Pharmacology (12.3)]. Administer LAMPIT under close medical supervision.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oPotential for Genotoxicity and Carcinogenicity. (5.1)oEmbryo-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 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)oWorsening Neurological and Psychiatric Conditions: Patients with 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)oHypersensitivity: 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)oDecreased Appetite and Weight Loss: Check body weight every 14 days as dosage may need to be adjusted. (5.5)oPorphyria: 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). oPotential for Genotoxicity and Carcinogenicity. (5.1). oEmbryo-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 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). oWorsening Neurological and Psychiatric Conditions: Patients with 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). oHypersensitivity: 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). oDecreased Appetite and Weight Loss: Check body weight every 14 days as dosage may need to be adjusted. (5.5). oPorphyria: 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 months to 14 years of age with Chagas disease demonstrated 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 pregnant woman. In animal reproduction studies, nifurtimox administered orally to pregnant mice, rats, and rabbits during organogenesis was associated with reduced fetal body weights in rodents, 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 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 months after the last dose. Advise male patients with female partners of reproductive potential to use condoms during treatment and for 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 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 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.