LAMPIT Film-coated tablet Ref.[10150] Active ingredients: Nifurtimox

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 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 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.

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)]

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:

^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.

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:

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)].

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 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 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 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) 6 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 a dose of 50 mg/kg/day or in rats at a 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 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 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).

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 mother’s clinical need for LAMPIT and any potential adverse effects on the breastfed infant from LAMPIT or from the underlying maternal condition.

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 a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with LAMPIT and for 6 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 3 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)].

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.

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.

The effect of hepatic impairment on the pharmacokinetics of nifurtimox is unknown [Clinical Pharmacology (12.3)]. Administer LAMPIT under close medical supervision.