A Comprehensive Pharmacological and Clinical Monograph on Nifurtimox (DB11820)

Executive Summary

Nifurtimox is a nitrofuran antiprotozoal agent primarily indicated for the treatment of Chagas disease (American Trypanosomiasis) caused by the parasite Trypanosoma cruzi.[1] Developed by Bayer and in medical use since 1965, it recently gained renewed prominence with its accelerated approval by the U.S. Food and Drug Administration (FDA) in August 2020 for use in pediatric patients from birth to less than 18 years of age.[3] It is also a critical component of combination therapy for second-stage Human African Trypanosomiasis (sleeping sickness) caused by

Trypanosoma brucei gambiense.[3]

The mechanism of action of nifurtimox, while not fully elucidated, involves its function as a prodrug that is selectively activated within the parasite. Parasitic nitroreductases convert the drug into a nitro-anion radical, which initiates a redox cycle that generates a cascade of cytotoxic reactive oxygen species (ROS). This overwhelming oxidative stress leads to widespread damage to parasitic DNA, lipids, and proteins, ultimately causing cell death.[3] This same mechanism of DNA damage, however, underpins the drug's most significant safety concerns, including a demonstrated potential for genotoxicity in humans and a theoretical risk of carcinogenicity based on data from structurally related compounds.[6]

The clinical profile of nifurtimox is defined by its efficacy in the acute phase of Chagas disease, supported by the pivotal Phase 3 CHICO trial (NCT02625974), which led to its pediatric approval based on serological endpoints.[8] The standard treatment course is a demanding 60-day, three-times-daily regimen that is often complicated by a high incidence of adverse effects, particularly gastrointestinal and neurological symptoms. These tolerability issues are more pronounced in adults and frequently lead to treatment discontinuation, representing a major barrier to its effective use.[2]

Regulatory recognition of nifurtimox includes its designation as an Essential Medicine by the World Health Organization (WHO) and its recent FDA approval, which was granted under an accelerated pathway contingent on confirmatory trials.[3] Key safety considerations detailed in its prescribing information include warnings for embryo-fetal toxicity, requiring stringent contraception measures, and an absolute contraindication against concurrent alcohol consumption due to the risk of severe reactions.[6] Nifurtimox represents a critical, albeit imperfect, tool in the limited armamentarium against neglected tropical diseases, with ongoing research focused on optimizing its use and exploring its potential as a repurposed agent in pediatric oncology.

Drug Identity and Physicochemical Properties

A precise understanding of the chemical and physical characteristics of nifurtimox is fundamental to its application in pharmacology and clinical medicine. This section details its nomenclature, structural properties, and formulation characteristics.

Nomenclature and Identifiers

Nifurtimox is identified by a variety of names and unique codes across chemical, pharmacological, and regulatory databases.

• Generic Names: Nifurtimox, Nifurtimoxum.[1]
• Brand Name: The drug is marketed globally under the brand name Lampit®.[1]
• Synonyms and Code Names: During its development and in research literature, it is often referred to by its code names, including BAY-2502, BAY-A-2502, and Bayer 2502.[11]
• Systematic (IUPAC) Names: The formal chemical names for the compound are 3-methyl-4-(((5-nitrofuran-2-yl)methylene)amino)thiomorpholine 1,1-dioxide and (E)-N-(3-methyl-1,1-dioxo-1,4-thiazinan-4-yl)-1-(5-nitrofuran-2-yl)methanimine.[5]
• Database Identifiers: Key registry numbers that ensure unambiguous identification include:
• DrugBank ID: DB11820 [1]
• CAS Number: 23256-30-6 [1]
• EC Number: 245-531-0 [13]
• KEGG Drug ID: D00833 [3]
• KEGG Compound ID: C08002 [3]

Chemical and Physical Properties

Nifurtimox is a small molecule synthetic organic compound belonging to several chemical classes.

• Chemical Classification: It is classified as a nitrofuran, a class of compounds containing a furan ring substituted with a nitro group. It is also categorized as a nitrofuran derivative, a nitro compound, a sulfur compound, and a thiazine.[1]
• Molecular Formula: The empirical formula for nifurtimox is C10​H13​N3​O5​S.[13]
• Molecular Weight: The calculated molecular weight is 287.29 g/mol.[13]
• Structural Identifiers:
• InChI: 1S/C10H13N3O5S/c1-8-7-19(16,17)5-4-12(8)11-6-9-2-3-10(18-9)13(14)15/h2-3,6,8H,4-5,7H2,1H3/b11-6+ [11]
• InChIKey: ARFHIAQFJWUCFH-IZZDOVSWSA-N [11]
• Canonical SMILES: CC1CS(CCN1/N=C/C2=CC=C([N+]([O-])=O)O2)(=O)=O [12]
• Physical Appearance and Solubility: Nifurtimox is a yellow to orange crystalline powder.[13] It is a Biopharmaceutics Classification System (BCS) Class 2 compound, indicating it has low aqueous solubility and high permeability.[16] Its solubility is poor in water but higher in organic solvents such as dimethyl sulfoxide (DMSO), with reported values ranging from >5 mg/mL to ≥13 mg/mL, sometimes requiring warming.[12]

Formulation and Presentation

The formulation of Lampit® tablets reflects a modern, patient-centric approach to drug delivery, particularly for its target pediatric population.

• Dosage Forms: Nifurtimox is available for oral administration as 30 mg and 120 mg tablets.[2]
• Tablet Characteristics: A key feature of the Lampit® formulation is its design for ease of administration in children. The tablets are functionally scored, which allows them to be accurately split by hand into halves (providing 15 mg and 60 mg doses, respectively). The prescribing information explicitly advises against the use of mechanical pill-cutting devices, highlighting the reliability of the manual scoring.[1] Furthermore, the tablets are specially formulated to be dispersible. They can be placed in a small volume of water (2.5 mL) to form a slurry, which facilitates administration to infants and children who have difficulty swallowing whole or half tablets.[6]

The development of such a sophisticated, user-friendly formulation for a drug that has been in use for over half a century is noteworthy. Typically, medications for neglected tropical diseases, which disproportionately affect populations in low-resource settings, do not receive this level of investment in formulation science. The recent FDA approval for a pediatric indication likely provided the regulatory and commercial impetus for Bayer to develop a product that overcomes practical administration challenges. This design directly addresses the needs of caregivers administering medication to infants, where accurate dosing is critical and specialized tools like pill crushers or cutters may be unavailable or unhygienic. This investment in a dividable, dispersible tablet is a crucial element in enhancing the feasibility of the demanding 60-day treatment course and improving the potential for therapeutic adherence and success in a vulnerable patient population.

Table 1: Nifurtimox Identification and Key Properties

Property	Details
Generic Name	Nifurtimox 1
Brand Name	Lampit® 3
Chemical Class	Nitrofuran Antiprotozoal 1
IUPAC Name	3-methyl-4-(((5-nitrofuran-2-yl)methylene)amino)thiomorpholine 1,1-dioxide 14
CAS Number	23256-30-6 1
DrugBank ID	DB11820 1
Molecular Formula	C10​H13​N3​O5​S 15
Molecular Weight	287.29 g/mol 15
Physical Appearance	Yellow to orange powder 13
Formulation	30 mg and 120 mg functionally scored, dispersible oral tablets 17

Pharmacology and Mechanism of Action

Nifurtimox exerts its therapeutic effects through a complex biochemical mechanism that results in selective toxicity to trypanosomal parasites. Its activity is not limited to protozoa, as it has also been investigated for its potential as an antineoplastic agent.

Pharmacodynamics and Spectrum of Activity

Nifurtimox is a broad-spectrum antiprotozoal agent with potent trypanocidal properties.

• Primary Activity: Its principal therapeutic use is against the protozoan parasite Trypanosoma cruzi, the etiological agent of Chagas disease. Nifurtimox demonstrates activity against both the extracellular trypomastigote and the intracellular amastigote forms of the parasite, which is crucial for eradicating the infection from the host.[1]
• Other Activity: Nifurtimox is also clinically effective against Trypanosoma brucei gambiense, one of the subspecies of parasites that cause Human African Trypanosomiasis (sleeping sickness). Its ability to cross the blood-brain barrier makes it particularly useful in the second, meningoencephalitic stage of the disease, when the central nervous system (CNS) is involved.[3]

Molecular Mechanism of Action

The precise molecular mechanism of nifurtimox has not been fully elucidated, but a multi-step process involving reductive activation and the generation of oxidative stress is the widely accepted model.[1]

• Prodrug Activation: Nifurtimox functions as a prodrug that requires metabolic activation to exert its cytotoxic effects. This activation is initiated by the bioreduction of its 5-nitro group, a reaction catalyzed by parasitic NADH-dependent type I (oxygen-insensitive) and type II (oxygen-sensitive) nitroreductases (NTRs).[1] The relative absence of these specific enzymes in mammalian cells provides a degree of selective toxicity, forming the basis of its therapeutic window.[2]
• Generation of Cytotoxic Species: The single-electron reduction of the nitro group produces a highly reactive nitro-anion radical metabolite.[3] In the presence of molecular oxygen, this radical undergoes redox cycling, transferring its electron to oxygen to regenerate the parent nifurtimox molecule and produce a superoxide radical ( O2−​). This process can repeat, leading to the accumulation of a cascade of reactive oxygen species (ROS), including superoxide and, subsequently, hydrogen peroxide (H2​O2​).[3]
• Cellular Damage: T. cruzi possesses less robust antioxidant defense mechanisms compared to mammalian cells. The massive production of ROS overwhelms the parasite's capacity to neutralize these toxic species, which is reliant on enzymes like trypanothione reductase.[3] The resulting state of severe oxidative stress leads to widespread, lethal cellular damage, including lipid peroxidation of membranes, depletion of essential thiols (e.g., glutathione), and significant damage to parasite nucleic acids, causing DNA strand breaks.[3]
• Enzyme Inhibition: In addition to the oxidative stress model, other mechanisms have been proposed. Nifurtimox has been reported to inhibit parasite dehydrogenase activity, specifically the glycosomal glyceraldehyde-3-phosphate dehydrogenase, which is vital for glycolysis in the parasite.[1] Inhibition of trypanothione reductase, a key enzyme unique to the parasite's antioxidant system, has also been suggested as a potential target, which would synergize with the ROS-generating effects.[19]

The very mechanism that confers nifurtimox its therapeutic efficacy—the generation of DNA-damaging radicals—is also the source of its most significant, long-term safety concern. The process of radical formation and subsequent reaction with nucleic acids is not perfectly confined to the parasite. This leads to a risk of off-target effects on host cell DNA. This connection is not merely theoretical; it is explicitly acknowledged in the FDA-approved prescribing information, which includes a prominent warning for the "Potential for Genotoxicity and Carcinogenicity".[6] This warning highlights that genotoxicity has been demonstrated in human subjects, with a study in pediatric patients showing a 13-fold increase in chromosomal aberrations following treatment.[7] Furthermore, other structurally related nitrofuran agents have shown carcinogenicity in chronic rodent studies.[7] This establishes a direct link between the drug's intended pharmacodynamic effect and a major safety liability, framing the clinical decision to use nifurtimox as a critical risk-benefit assessment. The life-threatening potential of untreated Chagas disease in children is deemed to justify the use of an agent with these risks, but it simultaneously underscores the importance of its controlled use and the need for long-term safety monitoring.

Investigational Antineoplastic Activity

The unique activation mechanism of nifurtimox has led to its investigation as a potential anticancer agent, representing a scientifically coherent drug repurposing strategy.

• Hypoxia-Activated Cytotoxicity: The solid tumor microenvironment is often characterized by regions of severe hypoxia (low oxygen). Nifurtimox has been identified as a hypoxia-activated cytotoxin, meaning it can be preferentially reduced and activated to its toxic form in these low-oxygen conditions, which are known to upregulate certain reductive enzymes.[11] This offers a potential mechanism for targeting tumor cells while sparing well-oxygenated normal tissues.
• Oncological Targets: Research has primarily focused on its application in difficult-to-treat pediatric cancers. Preclinical studies have demonstrated that nifurtimox can induce apoptosis and reduce tumor growth in both in vitro and in vivo models of neuroblastoma.[5] This has led to its evaluation in early-phase clinical trials for patients with relapsed or refractory neuroblastoma and medulloblastoma (e.g., NCT00486564, NCT00601003).[3]
• Mechanism in Cancer Cells: In neuroblastoma cell lines, nifurtimox has been shown to exert multiple anticancer effects. It can reduce the expression of the N-Myc oncogene, a key driver of neuroblastoma progression. It also disrupts cancer cell metabolism by inhibiting aerobic glycolysis via a reduction in lactate dehydrogenase (LDH) activity. These actions contribute to its overall effect of reducing cell viability, inducing cell cycle arrest, and promoting apoptosis.[12] This repurposing is not a random screening effort but a targeted strategy based on a shared biological principle—reductive activation in a specific microenvironment—that bridges its antiparasitic and potential antineoplastic activities.

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of nifurtimox is characterized by absorption that is highly dependent on food, broad distribution, extensive metabolism, and a relatively short elimination half-life, all of which have significant implications for its clinical use.

Absorption

The oral bioavailability of nifurtimox is critically influenced by the presence of food.

• Effect of Food: Administration of nifurtimox with food is mandatory for optimal absorption. A clinical study in adult patients demonstrated that a high-fat meal (800-1000 calories) increased the peak plasma concentration (Cmax) by 68% and the total drug exposure (AUC) by 71% when compared to administration under fasted conditions.[24] Food also delays the time to reach peak concentration by approximately one hour.[24] This substantial food effect is the basis for the clinical directive to always administer the drug with meals.[1]
• Pharmacokinetic Parameters:
• Time to Peak Concentration (Tmax): Following oral administration in the fed state, the median Tmax is 4 hours, with a range of 2 to 8 hours.[1]
• Area Under the Curve (AUC): Average AUC estimates following a single 120 mg dose with food range from 1676 to 2670 µg∙h/L.[1] One study in healthy volunteers reported an AUC of 5430 ng∙mL⁻¹∙h.[1]
• Peak Concentration (Cmax): Cmax values range from 425 to 568 µg/L after a single 120 mg dose with food.[1]
• First-Pass Metabolism: Low serum concentrations observed in some studies suggest that nifurtimox may undergo a significant first-pass effect in the liver following oral absorption.[1]

Distribution

Nifurtimox distributes widely throughout the body, including into protected compartments like the central nervous system.

• Protein Binding: In plasma, nifurtimox is approximately 42% bound to proteins, with albumin being the primary binding protein.[1]
• Tissue Penetration: The drug is known to cross both the blood-brain barrier and the placenta.[1] This property is clinically relevant, as it allows the drug to reach parasites within the central nervous system, making it effective for second-stage African trypanosomiasis. However, its ability to cross the placenta is also the basis for concerns about potential embryo-fetal toxicity.[6]

Metabolism

Nifurtimox is extensively metabolized into inactive compounds before elimination.

• Primary Pathway: The metabolism of nifurtimox is primarily mediated by nitroreductase enzymes, consistent with its mechanism as a prodrug activated by reduction.[1]
• Metabolites: Two major pharmacologically inactive metabolites have been identified in human plasma: M-4 and M-6. M-4 is a rearranged cysteine conjugate of nifurtimox, while M-6 is believed to be formed by the hydrolytic cleavage of the drug's hydrazone moiety.[1] These metabolites have significantly longer half-lives (M-4: ~28 hours; M-6: ~10 hours) than the parent drug.[24] Several other minor metabolites have also been detected.[1]

Elimination

The parent drug is cleared from the body relatively quickly, with metabolites being the primary form excreted in the urine.

• Route of Excretion: The primary route of elimination is renal. Following administration in the fed state, approximately 44% of the dose is recovered in the urine, almost entirely in the form of metabolites.[1] Biliary and fecal elimination pathways have not been formally evaluated.[1]
• Elimination Half-Life: The elimination half-life of the parent nifurtimox compound is short, with estimates ranging from 2.4 to 3.6 hours.[1]
• Clearance: The systemic clearance of nifurtimox has been reported to be approximately 99.7 L/h in patients without renal failure.[1]

The combination of a short elimination half-life (~3 hours) and a significant adverse effect profile creates a substantial therapeutic challenge. The short half-life necessitates a rigorous three-times-daily dosing schedule to maintain plasma concentrations within the therapeutic range over the full 60-day course of treatment.[5] This high pill burden, for a drug known to frequently cause gastrointestinal and neurological side effects like nausea, vomiting, and dizziness, is a classic formula for poor patient adherence.[10] The literature confirms that adverse effects often "compromise the continuity of the treatment," making it difficult for patients to complete the full course.[5] This intrinsic link between the drug's fundamental pharmacokinetic properties and its primary clinical limitation (tolerability) highlights why research into alternative dosing strategies (such as the 30-day regimen, which proved less effective in the CHICO trial) and novel, sustained-release formulations is a critical area of focus for improving the management of Chagas disease.[5]

Table 2: Summary of Nifurtimox Pharmacokinetic Parameters

Parameter	Value	Clinical Significance / Comments
Absorption (Tmax)	Median: 4 hours (range: 2-8 h) 1	Reached several hours after oral administration with food.
Food Effect	AUC increases by ~71%; Cmax increases by ~68% with a high-fat meal.24	Administration with food is mandatory to ensure adequate drug exposure.
Distribution	Crosses blood-brain barrier and placenta.1	Effective for CNS infections (sleeping sickness) but poses a risk of fetal harm.
Protein Binding	~42% (primarily to albumin).1	Moderate protein binding suggests a reasonable fraction of free, active drug.
Metabolism	Extensively metabolized by nitroreductases to inactive metabolites.1	Functions as a prodrug; parent compound is largely cleared via metabolism.
Elimination Half-Life	2.4 - 3.6 hours.1	The short half-life necessitates a three-times-daily dosing regimen to maintain therapeutic levels.
Route of Elimination	Primarily renal excretion of metabolites (~44% of dose in urine).1	Dose adjustments may be needed in severe renal impairment.

Clinical Efficacy and Therapeutic Applications

Nifurtimox is a key therapeutic agent for two major neglected tropical diseases caused by trypanosomal parasites. Its approval and use are supported by clinical trials, though its application is nuanced by disease stage and patient population.

Approved Indication: Pediatric Chagas Disease (T. cruzi)

The primary FDA-approved indication for nifurtimox is for the treatment of Chagas disease in the pediatric population.

• FDA Approval: On August 6, 2020, nifurtimox (Lampit®) was granted accelerated approval for the treatment of Chagas disease in pediatric patients from birth to less than 18 years of age and weighing at least 2.5 kg.[4] This approval addressed a significant unmet need for a safe and effective treatment in this vulnerable population.
• Pivotal Clinical Evidence (CHICO Trial): The approval was primarily based on the results of the CHICO trial (NCT02625974), a prospective, randomized, double-blind, historically controlled Phase 3 study conducted in Argentina, Bolivia, and Colombia.[8]
• Study Design: The trial enrolled 330 pediatric patients with Chagas disease. Patients were randomized in a 2:1 ratio to receive a new pediatric formulation of nifurtimox for either 60 days or 30 days. The primary efficacy analysis compared the outcomes in the 60-day treatment arm against a well-documented historical placebo control group, as a concurrent placebo was deemed unethical.[6]
• Primary Endpoint: Due to the long, asymptomatic chronic phase of Chagas disease, which makes traditional clinical endpoints impractical, the FDA agreed to an accelerated approval based on a surrogate endpoint. This endpoint was the proportion of patients who achieved serological response, defined as becoming immunoglobulin G (IgG) antibody negative or demonstrating at least a 20% decrease in optical density on two different IgG antibody tests against T. cruzi antigens one year after treatment completion.[4]
• Key Results: The study successfully demonstrated the superiority of the 60-day nifurtimox regimen over the historical placebo control based on the serological endpoint. The 30-day treatment arm was found to be less effective and is therefore not an approved dosing regimen.[6]
• Long-Term Follow-up (CHICO SECURE): A subsequent 4-year follow-up of the CHICO cohort, known as the CHICO SECURE study, provided further evidence of the long-term effectiveness and safety of the 60-day regimen.[9] The study observed a continued decrease in anti- T. cruzi antibodies over time, with a small percentage of patients achieving complete seronegative conversion. This outcome was significantly more likely in children who were younger (<2 years old) at the start of treatment. Importantly, over 90% of evaluable patients maintained persistently negative quantitative PCR (qPCR) results for T. cruzi DNA, indicating sustained parasite clearance.[9]
• Clinical Context: Nifurtimox is most effective when administered during the early, acute phase of infection.[5] Its efficacy in the late chronic phase, where organ damage may have already begun, is considered more variable and less certain.[5] In the United States, benznidazole is also approved for Chagas disease (in children aged 2-12), and nifurtimox may be considered a second-line option in some contexts; however, it is the only recommended drug for infants under 2 years of age.[3]

The regulatory strategy employed for the pediatric approval of nifurtimox serves as a compelling case study in addressing the challenges of drug development for neglected tropical diseases. The decades-long latency of Chagas disease makes randomized controlled trials with clinical endpoints like prevention of cardiomyopathy logistically and ethically untenable, especially in children. Recognizing this barrier, the FDA adopted a pragmatic approach by granting accelerated approval based on a surrogate endpoint—serological response—that is reasonably likely to predict long-term clinical benefit. This decision was a result of extensive discussion between the sponsor and the agency, as documented in meeting minutes.[16] This regulatory flexibility allowed for timely access to a potentially life-saving medication for a vulnerable population. However, it comes with the critical obligation for the sponsor to conduct post-marketing confirmatory trials to formally verify and describe the clinical benefit, ensuring that the initial promise based on the surrogate marker translates into tangible, long-term health outcomes.[1]

Use in Human African Trypanosomiasis (T. b. gambiense)

Nifurtimox plays a crucial role in the management of the advanced stage of West African sleeping sickness.

• Indication: It is used to treat the second, meningoencephalitic stage of the disease, which is defined by the invasion of the central nervous system by the parasite.[3] Its ability to penetrate the blood-brain barrier is essential for this indication.
• Combination Therapy (NECT): Nifurtimox is a cornerstone of the Nifurtimox-Eflornithine Combination Therapy (NECT) regimen. This regimen, which combines 10 days of oral nifurtimox with 7 days of intravenous eflornithine, has been recommended by the WHO as a first-line treatment for second-stage T. b. gambiense infection.[3] Clinical trials, such as NCT00146627, demonstrated that NECT is safer, easier to administer (with a shorter duration of IV therapy), and equally or more effective than the previous standard of eflornithine monotherapy.[3]

Off-Label and Investigational Uses

Beyond its approved indications, nifurtimox has been used in other patient populations and is being investigated for new therapeutic applications.

• Adult Chagas Disease: Although not specifically FDA-approved for adults in the US, nifurtimox has a long history of off-label use in this population and is licensed for adults in other countries.[3] However, clinical experience and studies have consistently shown that adverse events are far more frequent and severe in adults compared to children. This leads to poor tolerability and high rates of treatment discontinuation, with one study of US immigrant patients reporting that 21% were unable to complete the full course of therapy.[2]
• Pediatric Oncology: Based on its preclinical activity as a hypoxia-activated cytotoxin, nifurtimox is being investigated as a repurposed agent for pediatric cancers. It has completed Phase 1 (NCT00486564) and Phase 2 (NCT00601003) clinical trials to evaluate its safety, tolerability, and potential efficacy in children with refractory or relapsed neuroblastoma and medulloblastoma.[3]

Dosage, Administration, and Patient Monitoring

The safe and effective use of nifurtimox requires strict adherence to weight-based dosing, proper administration techniques, and diligent patient monitoring throughout the course of therapy.

Recommended Dosing Regimens (Pediatric Chagas Disease)

The dosage of nifurtimox is tailored to the individual patient's body weight and is administered over a fixed duration.

• Treatment Duration: The recommended and approved duration of treatment is 60 days.[6] Completing the full course is essential to maximize the chance of parasite eradication and prevent relapse.[17]
• Frequency: The total daily dose should be divided and administered three times a day, typically every 8 hours.[5]
• Weight-Based Dosing: The total daily dosage is calculated based on the patient's body weight, with different mg/kg recommendations for different weight brackets [17]:
• Patients weighing 41 kg or greater: 8 to 10 mg/kg/day.
• Patients weighing less than 41 kg (but at least 2.5 kg): 10 to 20 mg/kg/day.

Method of Administration

Proper administration is crucial for ensuring optimal drug absorption and patient adherence.

• Administration with Food: Nifurtimox must be taken with food. Co-administration with food significantly enhances its absorption and overall bioavailability.[1]
• Tablet Handling: The 30 mg and 120 mg tablets are functionally scored and can be split into halves by hand along the scored line. The use of a mechanical tablet-splitting device is explicitly discouraged, as it may lead to inaccurate dosing.[17]
• Slurry Preparation for Administration: For infants and patients who cannot swallow tablets, an alternative administration method is available. The prescribed dose (whole or half tablets) should be placed into a spoon containing approximately one-half teaspoon (2.5 mL) of water. The tablet(s) will disintegrate in about 30 seconds, forming a slurry (liquid suspension). This slurry must be administered immediately with food.[17]
• Management of Missed Doses: If a patient misses a dose, it should be taken as soon as possible with food. However, if the next scheduled dose is due in less than 3 hours, the missed dose should be skipped, and the patient should resume the normal dosing schedule. A double dose should not be taken to make up for a missed one.[17]

Essential Patient Monitoring

Given the potential for adverse effects, regular monitoring is a key component of nifurtimox therapy.

• Body Weight: Decreased appetite and subsequent weight loss are very common side effects. Therefore, it is mandatory to check the patient's body weight every 14 days during the 60-day treatment course. If significant weight loss occurs, the dosage of nifurtimox may need to be adjusted accordingly by the prescribing physician.[6]
• Neurological and Psychiatric Status: Patients should be monitored for any new or worsening neurological or psychiatric symptoms, such as dizziness, tremor, seizures, irritability, or mood changes. This is especially critical for patients with a pre-existing history of brain injury, seizure disorders, or psychiatric conditions, who should be under close medical supervision.[6]
• Pregnancy Status: For females of reproductive potential, a negative pregnancy test must be confirmed before initiating nifurtimox therapy due to the risk of embryo-fetal toxicity.[20]
• Monitoring of Breastfed Infants: If a mother is taking nifurtimox while breastfeeding, the infant should be closely observed for potential adverse effects, including vomiting, rash, decreased appetite, fever, and irritability. The appearance of any of these symptoms should be reported to a healthcare provider.[20]

Table 3: Weight-Based Dosing Schedule for Pediatric Chagas Disease

Adapted from FDA Prescribing Information for Lampit®.17 Doses are administered three times daily with food for 60 days.

Body Weight (kg)	Dose per Administration (mg)	Number of LAMPIT 30 mg Tablets per Dose	Number of LAMPIT 120 mg Tablets per Dose
2.5 to 4.5	15	½ tablet	—
4.6 to < 9	30	1 tablet	—
9 to < 13	45	1 ½ tablets	—
13 to < 18	60	2 tablets	½ tablet
18 to < 22	75	2 ½ tablets	—
22 to < 27	90	3 tablets	—
27 to < 35	120	4 tablets	1 tablet
35 to < 41	180	—	1 ½ tablets
41 to < 51	120	—	1 tablet
51 to < 71	180	—	1 ½ tablets
71 to < 91	240	—	2 tablets
91 or greater	300	—	2 ½ tablets

Comprehensive Safety Profile

The clinical utility of nifurtimox is significantly influenced by its safety and tolerability profile. Adverse reactions are common and necessitate careful patient monitoring, and several important warnings and contraindications must be observed.

Adverse Drug Reactions (ADRs)

Adverse reactions to nifurtimox are frequent, generally reversible, and often dose-related. Their incidence and severity tend to increase with the patient's age, being notably more pronounced in adults than in children.[2]

• Most Common ADRs (≥5% incidence): The most frequently reported adverse reactions in clinical trials were primarily gastrointestinal and neurological.[7]
• Gastrointestinal: Vomiting (14.6%), abdominal pain (13.2%), decreased appetite (10.5%), and nausea (8.2%).
• Neurological: Headache (12.8%).
• Systemic: Pyrexia (fever) (7.3%).
• Dermatological: Rash (5.5%).
• Other Common ADRs (1-10% incidence):
• Gastrointestinal: Diarrhea (4.6%), decreased weight (2.7%).
• Neurological: Dizziness (2.7%).
• Hematological: Anemia (2.7%), eosinophilia (2.3%).
• Dermatological: Urticaria (2.3%).[19]
• Less Common and Rare ADRs (<1% and Postmarketing): A wide range of less frequent but potentially serious adverse events have been reported.[17]
• Neurological/Psychiatric: Vertigo, paresthesia ("pins and needles"), tremor, amnesia, polyneuropathy, muscle weakness, seizure, anxiety, irritability, agitation, sleep disorders, and psychotic behavior.
• Musculoskeletal: Arthralgia (joint pain), myalgia (muscle pain).
• Hematological: Leukopenia (low white blood cell count), neutropenia, thrombocytopenia (low platelet count).
• Hypersensitivity: Anaphylaxis, angioedema (swelling of the face, lips, tongue), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

Warnings and Precautions

The FDA-approved prescribing information for Lampit® includes several critical warnings and precautions that guide its safe use.

• Potential for Genotoxicity and Carcinogenicity: Nifurtimox has demonstrated genotoxic effects in various assay systems, including in vitro bacterial and mammalian cells, in vivo in rodents, and in humans. A study in pediatric patients with Chagas disease reported a 13-fold increase in chromosomal aberrations after treatment. While carcinogenicity data for nifurtimox itself are not available, structurally similar nitrofuran agents have been shown to be carcinogenic in rodents. The potential for carcinogenicity in humans is unknown.[6]
• Embryo-Fetal Toxicity: Based on findings from animal reproduction studies, nifurtimox can cause fetal harm. Oral administration during organogenesis was associated with reduced fetal body weights in rodents and abortions, fetal death, and malformations in rabbits at doses equivalent to or less than the maximum recommended human dose (MRHD). Consequently, nifurtimox is not recommended for use during pregnancy.[2]
• Contraception Requirements: Due to this risk, stringent contraception is required. Females of reproductive potential must use an effective form of birth control during treatment and for 6 months after the final dose. Male patients with female partners of reproductive potential must use condoms during treatment and for 3 months after the final dose.[6]
• Worsening of Neurological and Psychiatric Conditions: Patients with a history of brain injury, seizures, psychiatric disease, or serious behavioral alterations may experience an exacerbation of their conditions while taking nifurtimox. These patients require close medical supervision.[3]
• Hypersensitivity: Serious hypersensitivity reactions, including anaphylaxis, angioedema, and severe skin reactions, have been reported. These reactions may be directly induced by nifurtimox or may represent an immune response triggered by the release of antigens from dying parasites during treatment (a phenomenon similar to a Jarisch-Herxheimer reaction). Treatment should be discontinued immediately at the first sign of a serious hypersensitivity reaction.[3]
• Decreased Appetite and Weight Loss: These are very common adverse reactions that can be significant. Regular monitoring of body weight every 14 days is mandatory, as dosage adjustments may be necessary to manage this side effect.[6]
• Porphyria: As a nitrofuran derivative, nifurtimox may precipitate acute attacks of porphyria in susceptible individuals. It should be administered under close medical supervision in patients with this genetic disorder.[6]

Contraindications

Nifurtimox is strictly contraindicated in the following situations:

• Patients with a known hypersensitivity to nifurtimox or any of the excipients in the Lampit® formulation.[6]
• Patients who consume alcohol during treatment. This is an absolute contraindication due to the risk of a severe interaction.[6]
• Some sources also list severe liver or kidney disease and a history of certain neurological or psychiatric disorders as contraindications, though the official US label lists these as conditions requiring caution.[3]

Overdose

Information on nifurtimox overdose is limited. Symptoms are expected to be an exaggeration of the known adverse effects, including severe weight loss, anorexia, nausea, vomiting, vertigo, headache, nervous excitation, insomnia, convulsions, and disorientation.[1] Management is supportive, as there is no specific antidote.

Black Box Warning

The provided prescribing information and regulatory documents do not indicate that nifurtimox carries a Black Box Warning from the FDA.[26]

Table 4: Summary of Common and Serious Adverse Reactions

Part A: Adverse Reactions by Frequency
Common (≥10%)
Less Common (1% to <10%)
Rare (<1%) & Postmarketing
Part B: Major Warnings and Precautions
Warning
Potential for Genotoxicity and Carcinogenicity
Embryo-Fetal Toxicity
Worsening of Neurological/Psychiatric Conditions
Hypersensitivity
Decreased Appetite and Weight Loss
Porphyria

Drug and Disease Interactions

The safety of nifurtimox therapy can be affected by interactions with other substances, particularly alcohol, as well as by the patient's underlying medical conditions.

Drug-Drug Interactions

The interaction profile of nifurtimox is not extensive, but one major interaction is of paramount clinical importance.

• Alcohol (Ethanol): The concurrent use of alcohol and nifurtimox is contraindicated.[6] This is classified as a major, highly clinically significant interaction that must be avoided entirely.[37] The consumption of alcohol during treatment may increase the incidence and severity of adverse effects.[1] This is a known class effect for nitrofuran and other nitroheterocyclic compounds, which can cause a disulfiram-like reaction. This type of pharmacodynamic interaction results from the inhibition of aldehyde dehydrogenase, leading to the accumulation of acetaldehyde and causing symptoms such as flushing, dizziness, nausea, and headache. Given the absolute contraindication, comprehensive patient education on the importance of complete abstinence from all alcoholic beverages and alcohol-containing products throughout the 60-day treatment course is a critical safety mandate.
• Other Interactions: A limited number of other potential drug interactions have been identified, most of which are classified as moderate.[37] These include:
• Major Interactions: Ritonavir, Tipranavir.
• Moderate Interactions: Various live microbiota and probiotic products (e.g., Lactobacillus, Bifidobacterium), fecal microbiota products, and black cohosh. The mechanisms and clinical significance of these interactions are not well-defined in the available literature, and their management would typically involve careful monitoring or consideration of alternatives under specialist guidance.

Drug-Food Interactions

Unlike typical adverse drug-food interactions, the interaction between nifurtimox and food is beneficial and essential for its therapeutic effect.

• Positive Interaction: Food significantly increases the rate and extent of nifurtimox absorption, with a high-fat meal increasing total exposure (AUC) by approximately 71%.[24] Therefore, nifurtimox must be administered with food to ensure adequate bioavailability and therapeutic efficacy.[1]

Disease Interactions (Use in Specific Populations)

The use of nifurtimox requires caution and close supervision in patients with certain pre-existing medical conditions.

• Renal Impairment: Nifurtimox should be used with caution in patients with kidney disease. Published literature suggests that blood concentrations of the drug may be increased in patients with end-stage renal disease (ESRD) requiring hemodialysis. While specific dose adjustments are not provided, close medical supervision is recommended.[3]
• Hepatic Impairment: The pharmacokinetics of nifurtimox have not been studied in patients with liver disease. Given that the drug is extensively metabolized, caution and close medical supervision are advised for patients with hepatic impairment.[3]
• Neurological and Psychiatric Conditions: As detailed in the Warnings and Precautions, nifurtimox can exacerbate underlying neurological or psychiatric disorders, including a history of brain injury, seizures, or serious behavioral alterations. Its use in these patients necessitates careful risk assessment and close monitoring.[3]
• Porphyria: Nifurtimox, as a nitrofuran derivative, may precipitate acute attacks of porphyria. Close medical supervision is required when administering it to patients with this condition.[20]
• Pregnancy and Lactation:
• Pregnancy: Nifurtimox is not recommended during pregnancy due to evidence of fetal harm in animal studies.[3]
• Lactation: The drug is known to pass into breast milk. While some sources do not consider it an absolute contraindication, it is recommended that the breastfed infant be monitored closely for adverse effects such as irritability, decreased appetite, vomiting, rash, and fever. Other guidelines recommend withholding treatment while breastfeeding.[3]
• Male Fertility: Nifurtimox may impair male fertility. This potential for decreased fertility or infertility should be discussed with male patients before initiating therapy.[20]

Regulatory Status and History

Nifurtimox has a long history of use globally, but its formal regulatory journey in major markets like the United States is relatively recent, culminating in a specific pediatric approval.

Historical Context

Nifurtimox was developed by Bayer and first came into medical use in 1965.[3] For decades, it was one of only two drugs, alongside benznidazole, available for the treatment of Chagas disease, primarily used in endemic regions of Latin America and often accessed in other parts of the world through special programs or clinical protocols.[32]

U.S. Food and Drug Administration (FDA)

In the United States, nifurtimox was considered a New Molecular Entity (NME) prior to its approval, as it had not been previously marketed in the country.[39]

• Orphan Drug Designation: Recognizing the rarity of Chagas disease in the US, the FDA Office of Orphan Products Development granted nifurtimox Orphan Drug Designation for the "treatment of Chagas Disease (American Trypanosomiasis) caused by T. cruzi" on August 5, 2010.[39]
• Accelerated Approval: On August 6, 2020, the FDA granted accelerated approval to Lampit® (nifurtimox).[4]
• Approved Indication: The approval is specifically for pediatric patients from birth to less than 18 years of age and weighing at least 2.5 kg for the treatment of Chagas disease caused by T. cruzi.[4]
• Post-Marketing Commitment: The accelerated approval was based on a surrogate endpoint (serological response). As a condition of this approval, continued approval for this indication may be contingent upon the verification and description of clinical benefit in a confirmatory trial.[1]

European Medicines Agency (EMA)

Nifurtimox does not currently hold a centralized marketing authorization from the EMA. However, regulatory steps are underway to potentially support a future application.

• Paediatric Investigation Plan (PIP): On March 11, 2022, the EMA's Paediatric Committee (PDCO) agreed to a Paediatric Investigation Plan (PIP) for nifurtimox (EMEA-003134-PIP01-21) for the treatment of Chagas disease.[41] A PIP is a mandatory development plan required to ensure that the necessary data are obtained through studies in children to support the authorization of a medicine for the pediatric population. The agreement of a PIP is a critical prerequisite for filing a marketing authorization application in the European Union. The plan, submitted by Bayer AG, also included a waiver for the use of nifurtimox in preterm newborn infants, as Chagas disease does not typically occur in this specific subset.[42]

Other Regulatory and Public Health Bodies

Nifurtimox has long been recognized as a critical medicine by global health organizations and is licensed in several countries.

• World Health Organization (WHO): Nifurtimox is included on the WHO's Model List of Essential Medicines for the treatment of both Chagas disease and, in combination with eflornithine, for African trypanosomiasis.[3] The WHO also plays a crucial role in procuring and distributing the drug for free in many endemic countries where it would otherwise be inaccessible.[3]
• Other National Approvals: Nifurtimox is licensed for use in various other countries, particularly those where Chagas disease is endemic, such as Argentina. It is also licensed in some non-endemic countries, including Germany and Turkey.[3]

Conclusion and Future Directions

Nifurtimox stands as a vital but challenging therapeutic agent in the global fight against neglected tropical diseases. For over half a century, it has been a cornerstone of therapy for Chagas disease and, more recently, for second-stage sleeping sickness. Its utility, however, is constrained by a significant adverse effect profile that frequently compromises treatment adherence, a demanding 60-day dosing regimen necessitated by its short pharmacokinetic half-life, and evidence of variable efficacy, particularly in the chronic phase of Chagas disease. The recent development and approval of a pediatric-friendly, dividable, and dispersible formulation represents a major advancement, directly addressing long-standing administration barriers and improving the feasibility of treating the most vulnerable patient population.

The future of nifurtimox and the broader field of Chagas disease therapy is pointed in several key directions, driven by the need to optimize current treatments and explore new applications.

• Confirmatory Clinical Trials: The most immediate regulatory and clinical necessity is the completion of confirmatory trials for the pediatric Chagas disease indication. These trials must demonstrate that the serological response observed in the pivotal CHICO study—the basis for its accelerated FDA approval—translates into a tangible, long-term clinical benefit, such as the prevention of cardiac and gastrointestinal sequelae.[4]
• Therapeutic Optimization: The high rate of adverse events and the long duration of therapy remain significant hurdles. Ongoing research, such as the TESEO study, is focused on optimizing the regimens of existing drugs, including both nifurtimox and benznidazole.[43] These studies are exploring whether shorter treatment durations or different dosing strategies can maintain efficacy while improving tolerability and adherence, a critical step in making these life-saving treatments more accessible and successful in real-world settings.
• Addressing Data Gaps in Special Populations: Significant gaps in knowledge persist, particularly regarding the safety of nifurtimox during pregnancy. A planned Phase 4 observational pregnancy safety study (NCT03784391) is a crucial step toward collecting prospective data on maternal and fetal outcomes, which will help inform clinical guidance for a common and difficult treatment dilemma in endemic areas.[44]
• Drug Repurposing in Oncology: The potential of nifurtimox as a hypoxia-activated anticancer agent remains a promising area of investigation. Its unique mechanism offers a rational basis for its use against solid tumors characterized by hypoxic microenvironments. Further clinical trials in pediatric cancers like neuroblastoma and medulloblastoma are needed to determine if this preclinical promise can be translated into a meaningful therapeutic role, potentially as an adjunct to standard chemotherapy regimens.[3]
• Development of Novel Formulations: The inherent biopharmaceutical limitations of nifurtimox, such as its poor solubility and rapid metabolism, are drivers for innovation in drug delivery. Research into novel formulations, such as self-emulsifying drug delivery systems (SEDDS), aims to improve its pharmacokinetic profile, potentially enhancing bioavailability, reducing dosing frequency, and improving efficacy in the difficult-to-treat chronic phase of Chagas disease.[5]

In conclusion, nifurtimox is a paradigmatic drug for the field of neglected diseases. It is an older compound that has been revitalized through modern formulation science, rigorous clinical evaluation, and flexible regulatory pathways to meet an urgent pediatric need. Yet, its limitations serve as a constant reminder of the pressing, unmet need for the discovery and development of next-generation therapies that are safer, more effective, and simpler to administer for the world's most vulnerable populations.

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