Nifurtimox (Systemic)

VA CLASSIFICATION
Primary: AP109

Commonly used brand name(s): Lampit.

Another commonly used name is
Bayer 2502 . ^{{08} {19}}
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^*Not commercially available in the U.S.

^†Not commercially available in Canada.

Category:


Antiprotozoal (systemic)^{01}{08}—

Indications

Note: Because nifurtimox is not commercially available in the U.S. or Canada, the bracketed information and the use of the superscript 1 in this monograph reflect the lack of labeled (approved) indications for this medication in these countries.

Accepted

[Trypanosomiasis, American (treatment)]¹—Nifurtimox is used as a primary agent in the treatment of American trypanosomiasis (Chagas' disease) caused by Trypanosoma cruzi , especially in the acute, early stage of the disease. ^{{01} {06} {07} {08} {09} {10} {19} {20} {22} {23} {25}} In the chronic stage, the therapeutic benefit of this agent is less certain. ^{{08} {09} {11} {21} {24} {27}} The efficacy of nifurtimox in the treatment of chronic Chagas' disease varies from one country to another, possibly due to variation in the sensitivity of different strains of the organism. ^{{09} {28}}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Synthetic nitrofuran compound. ^{{01} {03}}
Molecular weight—
    287.30 ^{12}

Mechanism of action/Effect:

Trypanocidal. Two hypotheses may explain the mechanism of action of nifurtimox. One involves the ability of this agent to form a nitro-anion radical metabolite, which reacts with the nucleic acids of the parasite, causing a significant breakage in the deoxyribonucleic acid (DNA). This mechanism is similar to that proposed for the antibacterial action of other nitrofuran agents. ^{{09} {11}} The other involves the production of superoxide anions, and hence, hydrogen peroxide (both of which are very toxic to the parasite) and inhibition of trypanothione reductase, which is a parasite-specific antioxidant defense enzyme. Another enzyme, ascorbate-linked peroxidase, is also present but at relatively low levels in the organism. Lack of these enzymes leads to the accumulation of hydrogen peroxide to cytotoxic levels, resulting in death of the parasite. ^{{03} {09} {11} {14}}

Absorption:

Rapidly absorbed from the gastrointestinal tract. ^{{01} {08}}

Distribution:

Low concentrations of the unchanged substance appear in the serum and plasma following oral administration of nifurtimox in healthy volunteers. ^{{07} {13}}

Apparent volume of distribution (Vol _D)—755.3±283.8 L. ^{02}

Biotransformation:

Rapidly and extensively metabolized ^{01} in the liver where it undergoes nitroreduction involving cytochrome P-450 and P-450 reductase. Interindividual variability was noted suggesting that metabolism of nifurtimox may be under genetic control. The extensive hepatic metabolism probably accounts for the low serum concentration of nifurtimox in healthy volunteers following a single oral dose of 15 mg per kg of body weight (mg/kg). ^{{02} {04}}

Half-life:

Elimination half-life—2.95±1.19 hours in healthy volunteers following a single oral dose of 15 mg/kg. ^{02}

Time to peak concentration:

About 2 hours. ^{02}

Peak serum concentration:


Following a single oral dose of 15 mg/kg in healthy volunteers:

Mean concentration: 787 nanograms per mL. ^{02}

Peak serum concentration was found to be significantly higher in patients with renal failure (1290 nanograms per mL); this may be caused by either an increase in the systemic bioavailability of the medication or by a decrease in the distribution volume secondary to renal failure. ^{03}


Elimination:
    Renal—Very little nifurtimox (less than 1%) ^{07} is excreted in the urine, ^{{01} {07} {13}} with an apparent clearance of 193.4±93.2 L per hour in healthy volunteers following a single oral dose of 15 mg/kg. ^{02} Patients with renal failure were found to have a 50% lower clearance. This may be due to a reduction in the metabolic clearance of nifurtimox due to altered hepatic enzyme reactions caused by the chronic renal disease itself. ^{03}


Precautions to Consider

Carcinogenicity

Long-term bioassays in rats given nifurtimox at a total dose of 11.7 grams per kg of body weight for 625 days showed no carcinogenic effects. ^{18} However, one study mentioned another investigation that showed an increased incidence of malignant lymphomas in mice given nifurtimox at a dose of 80 mg per kg of body weight (mg/kg) per day for 60 days. ^{17}

Mutagenicity

A cytogenetic analysis performed in blood lymphocytes of children given nifurtimox for treatment of Chagas' disease resulted in a thirteen-fold increase in chromosomal aberrations (CA). This finding showed the genotoxic effect of nifurtimox in humans. ^{17}

The above study also mentioned several investigations of the mutagenicity of nifurtimox in bacteria and animals. Results of these investigations showed nifurtimox to be mutagenic in bacterial systems for Escherichia coli and for Salmonella typhimurium ; nifurtimox exhibited genotoxic effects on Drosophila melanogaster and Allium cepa , and it caused a significant increase in the number of chromosomal aberrations in rat bone marrow cells; nifurtimox also increased micronucleus formation in the bone marrow of mice and sister-chromatid exchange (SCE) formation in splenic lymphocytes of mice after in vivo exposure. ^{17}

Pregnancy/Reproduction
Fertility—
Studies in rats and mice given nifurtimox in repeated doses from 100 mg/kg resulted in a disturbance of spermatogenesis as shown by blockage, degeneration and atrophy of the seminal epithelium. Mice were given nifurtimox in doses of up to 224 mg/kg for 14 days and rats were given doses of up to 400 mg/kg for 3 weeks; after a treatment-free period of up to 10 weeks, the changes in the seminal epithelium disappeared. ^{{07} {16}}

Fertility and reproductive ability were not impaired in male and female rats given a dose of up to 300 parts per million (ppm) (corresponding to 15 to 30 mg/kg) per day for 10 weeks. However, a dose of 600 ppm (corresponding to 30 to 60 mg/kg) inhibited reproduction. Cross-mating between untreated female rats and treated male rats, and vice versa, showed that inhibition of reproduction due to decreased fertility occurred only in the males. During further mating after treatment-free periods of 4 and 11 weeks, only about 25% of the male rats had recovered, while about 75% remained infertile. ^{{05} {07}}

Pregnancy—
Studies have not been done in humans. ^{{07} {15}}

Studies in pregnant rats given doses of up to 20 mg/kg per day and in pregnant mice given doses of up to 50 mg/kg per day showed no inhibition of embryonic and fetal development. However, doses over 50 mg/kg per day in rats and 125 mg/kg per day in mice resulted in retarded growth of the fetuses. In both species, there was no evidence of teratogenicity. ^{{05} {07}}

Breast-feeding

It is not known whether nifurtimox is distributed into breast milk. However, problems in humans have not been documented. ^{04}

Pediatrics

Appropriate studies on the relationship of age to the effects of nifurtimox have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date. ^{{04} {22} {23}}


Geriatrics


Appropriate studies on the relationship of age to the effects of nifurtimox have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date. ^{04}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol    (concurrent use may enhance the occurrence of side effects ^{{01} {04} {07}})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Alcohol and/or drug abuse, chronic, or history of or
Allergies, especially of the skin, or history of or
» Peripheral neuropathy, or history of or^{28}
» Seizures and cerebral impairment, such as behavioral disorders, epilepsy, or psychoses, or history of    (nifurtimox may aggravate these conditions ^{{07} {19}})


» Hepatic function impairment    (nifurtimox is metabolized in the liver; hepatic function impairment may increase blood concentrations of this medication, increasing the risk of side effects ^{02})


» Renal function impairment    (nifurtimox is excreted via the kidneys; impaired elimination may increase blood concentrations of this medication, resulting in toxicity ^{{03} {07} {19}})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Body weight    (should be checked at least every 14 days because the patient can lose appetite during treatment resulting in weight loss; dosage should be adjusted if body weight decreases during treatment; for patients who are overweight [10% or more above the recommended weight for the patient's height], dosing should be based on ideal body weight; body weight will be regained with return of appetite soon after termination of treatment ^{{07} {19}})




Side/Adverse Effects

Note: Symptoms of Chagas' disease and the adverse effects of nifurtimox are often alike. Therefore, the cause of adverse effects can be difficult to establish. ^{19}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Skin rash ^{22}{25}—about 5%^{25}

Incidence rare
    
CNS toxicity including disorientation (confusion^{20}), disturbances of equilibrium such as ataxia (clumsiness or unsteadiness), and nystagmus (uncontrolled back-and-forth and/or rolling eye movements^{20}{26}), excitation^{23}{25}
forgetfulness^{07}{24}
insomnia (trouble in sleeping^{{03}{07}{24}{25}}), irritability ^{03}{07}{24}
psychosis (mood or mental changes^{{07}{11}{20}{23}}), seizures (convulsions^{{03}{07}{11}{24}{25}{26}}), and tremors^{07}
    
eosinophilia ^{22}(fever)
    
impotence ^{24}(decreased sexual drive or ability)
    
leukopenia (fever; chills or sore throat)—occurs with excessively high doses but disappears spontaneously after withdrawal of the medication^{07}{21}
    
muscle weakness^{07}{11}
    
peripheral neuropathy (numbness, tingling, pain, or weakness in hands or feet)—usually occurs at the end of the treatment period^{07}{11}{24}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Gastrointestinal disturbances, such as anorexia with weight loss (loss of appetite^{{07}{11}{20}{22}{23}{24}{25}{26}}), epigastric pain (abdominal or stomach pain^{07}{25}), nausea^{{07}{11}{23}{25}{26}}
and/or vomiting^{{07}{11}{23}{25}} —about 20 to 80%^{25}
    
headache —about 10%^{25}
    
vertigo (dizziness)—about 12%^{20}{25}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Nifurtimox (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergy to nifurtimox ^{{07} {19} {29}}



Mutagenicity—
Studies showed a thirteen-fold increase in chromosomal aberrations in children given nifurtimox for treatment of Chagas' disease ^{17}
Other medications, especially alcohol ^{{01} {04} {07}}
Other medical problems, especially hepatic function impairment, ^{02} peripheral neuropathy, renal function impairment ^{{03} {07} {19}} and seizures and cerebral impairment ^{{07} {19}}

Proper use of this medication
Taking with meals to minimize gastrointestinal irritation ^{{07} {10} {19}}

» Compliance with full course of therapy

When treating infants, crushing the tablets and mixing with food at beginning of meal ^{07}

» Proper dosing
Missed dose

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress and body weight ^{{07} {19}}

» Checking with physician if symptoms get worse

» Avoiding use of alcoholic beverages or other alcohol-containing preparations while taking this medication ^{{01} {04} {07}}


Side/adverse effects
Signs of potential side effects, especially skin rash; CNS toxicity including disorientation, disturbances of equilibrium such as ataxia and nystagmus, excitation, forgetfulness, insomnia, irritability, psychosis, seizures, and tremors; eosinophilia; impotence; leukopenia; muscle weakness; and peripheral neuropathy ^{{03} {07} {11} {20} {21} {22} {23} {24} {25} {26}}


General Dosing Information
Nifurtimox is better tolerated by younger patients. ^{{20} {23}}

To minimize gastrointestinal irritation, nifurtimox should be taken after meals in 3 or 4 divided doses. ^{{07} {10} {19}}

When treating infants, nifurtimox tablets should be crushed and mixed into some food at the beginning of a meal. ^{07}

Treatment is considered successful when both parasitemia and serological tests become negative and remain so for at least 1 year after end of treatment. Serological tests tend to become negative 6 to 8 months after treatment. ^{32}

For treatment of adverse effects
Recommended treatment consists of the following:

   • Antacids to minimize gastrointestinal disturbances. ^{07}
   • Anticonvulsants for seizures. ^{{07} {19} {20} {26}}


Oral Dosage Forms

Note: Because nifurtimox is not commercially available in the U.S. or Canada, the bracketed uses and the use of superscript 1 in the Dosage Forms section reflect the lack of labeled (approved) indications for this product in these countries.

NIFURTIMOX TABLETS^{15}

Usual adult dose
[Trypanosomiasis, American]¹
For acute and chronic infections: Oral, 8 to 10 mg per kg of body weight per day in three ^{{07} {31}} or four ^{10} divided doses after meals, for ninety ^{{07} {31}} to one hundred twenty days. ^{{10} {19} {27}}


Usual pediatric dose
[Trypanosomiasis, American]¹


Children up to 10 years of age:
For acute infection—Oral, 15 to 20 mg per kg of body weight per day in three ^{{07} {31}} or four divided doses after meals, for ninety days. ^{{07} {10} {19} {31}}

For chronic infection—Oral, 15 to 20 mg per kg of body weight per day in three ^{{07} {31}} or four divided doses after meals, for one hundred twenty days. ^{{07} {19} {27} {31}}



Children 11 to 16 years of age:
For acute infection—Oral, 12.5 to 15 mg per kg of body weight per day in three ^{{07} {31}} or four divided doses after meals, for ninety days. ^{{07} {10} {19} {31}}

For chronic infection—Oral, 12.5 to 15 mg per kg of body weight per day in three ^{{07} {31}} or four divided doses after meals, for one hundred twenty days. ^{{07} {19} {27} {31}}



Children 17 years of age and over:
See Usual adult dose. ^{{07} {10} {19} {31}}


Note: The following table has also been given by the manufacturer: ^{07}

	Body Weight (kg)	Number of Tablets
		30 mg	120 mg
Children	3–4	1/2
	5–6	1
	7–9	11/2
	10–12	2
	13–15	21/2
	15–18	3
	19–21	31/2
	22–26	4	1
	27–32		11/4
Adolescents	33–39		11/4
	40–46		11/2
	47–54		13/4
	55–60		2
Adults	45–49		1
	50		1
	50		11/4
	51–60		11/4
	61		11/4
	61		11/2
	62–72		11/2
	73		11/2
	73		13/4
	74–84		13/4
	85–94		2
	95–100		21/4

Strength(s) usually available
U.S.—
Not commercially available.

Note: Although nifurtimox is not commercially available in the U.S., it can be obtained from the Parasitic Disease Drug Service, Centers for Disease Control and Prevention, Atlanta, Georgia 30333 (telephone nos.: 404-639-3670; 404-639-2888 on evenings, weekends, or holidays [emergencies only]). ^{10}


Canada—
Not commercially available.

Note: Although nifurtimox is not commercially available in Canada, it is made available with authorization from the Bureau of Human Prescription Drugs (BHPD), Health Protection Branch (HPB), Health Canada, Tower B, 3rd Floor, 1600 Scott Street, Ottawa, Ontario K1A 0L2 (telephone no.: 613-941-2108). ^{30}


Other—


30 mg (Rx) [Lampit^{07}{31} (Argentina^{31}) (Germany^{07})]


120 mg (Rx) [Lampit^{07}{31} (Argentina^{31}) (Germany^{07})]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F) in a well-closed container ^{01}, unless otherwise specified by manufacturer. Protect from light. ^{01}

Revised: 04/25/1995

References

1. WHO Model Prescribing Information: Drugs used in parasitic diseases. Geneva: World Health Organization, 1990: 71-4.
   

2. Paulos C, Paredes J, Vasquez I, et al. Pharmacokinetics of a nitrofuran compound, nifurtimox, in healthy volunteers. Int J Clin Pharmacol, Therapy and Toxicology 1989; 27(9): 454-7.
   

3. Gonzalez-Martin G, Thambo S, Paulos C, et al. The pharmacokinetics of nifurtimox in chronic renal failure. Eur J Clin Pharmacol 1992; 671-3.
   

4. Dollery C, editor. Therapeutic drugs. Edinburgh: Churchill Livingstone, 1991: 87-93.
   

5. Lorke D. Embryotoxicity studies of nifurtimox in rats and mice and studies of fertility and general reproductive performance. Arzneimittelforschung 1972; 22(9a): 1603-7.
   

6. Cerisola JA. Chemotherapy of Chagas infection in man. In: Proceedings of an international symposium held in conjunction with the fifth international congress on protozoology; 1977 June 27; New York (NY): 35-47. (PAHO Scientific Publication No. 347).
   

7. Lampit product monograph (Bayer—Germany), Rec 12/93.
   

8. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 28th ed. London: The Pharmaceutical Press, 1982: 508, 522.
   

9. Gutteridge WE. Existing chemotherapy and its limitations. Br Med Bull 1985; 41(2): 162-8.
   

10. Abramowicz M, editor. Drugs for parasitic infections. Med Lett Drugs Ther 1993; 35(911): 111-22.
    

11. Marr JJ, Docampo R. Chemotherapy for Chagas disease: a perspective of current therapy and considerations for future research. Rev Infect Dis 1986; 8(6): 884-903.
    

12. Fleeger CA, editor. USP dictionary of USAN and international drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1995: 468.
    

13. Medenwald H, Brandau K, Schlossmann K. Quantitative determination of nifurtimox in body fluids of rat, dog and man. Arzneimittelforschung 1972; 22(9a): 1613-17.
    

14. Van Voorhis WC. Therapy and prophylaxis of systemic protozoan infections. Drugs 1990; 40(20): 176-202.
    

15. Panel consensus on monograph draft of Nifurtimox (2/95).
    

16. Hoffman K. Toxicological investigations on the tolerability of nifurtimox. Arzneimittelforschung 1972; 22(9a): 1590-1603.
    

17. Gorla NB, Ledesma OS, Barbieri GP, et al. Thirteenfold increase of chromosomal aberrations non-randomly distributed in chagasic children treated with nifurtimox. Mutat Res 1989; 224: 263-7.
    

18. Steinhoff D, Grundmann E. Test for carcinogenicity of nifurtimox on oral and subcutaneous administration to rats. Arzneimittelforschung 1972; 22(9a): 1607-12.
    

19. Wegner DHG, Rohwedder RW. The effect of nifurtimox in acute Chagas' infection. Arzneimittelforschung 1972; 22(9a): 1624-35.
    

20. Bocca Tourres CL. La enfermedad de Chagas en periodo agudo y su tratamiento con el Bay 2502. Bol Chil Parasitol 1969; 24(1-2): 24-7.
    

21. Cancado JR, Marra UD, Lopes M, et al. Toxicidad y valor terapeutico del Bay 2502 en la enfermedad de Chagas cronica en tres esquemas posologicos. Bol Chil Parasitol 1969; 24(1-2): 28-32.
    

22. Rubio M, Donoso F. Enfermedad de Chagas en niños y tratamiento con Bay 2502. Bol Chil Parasitol 1972; 24(1-2): 43-8.
    

23. Cichero JA, Segura E, Quatrochi JC. Evolucion clinico-parasitologica y tolerancia a la droga de 33 niños con infeccion chagasica cronica tratados con Bay 2502. Bol Chil Parasitol 1969: 24(1-2): 59-62.
    

24. Maekelt GA. Evaluacion clinica y serologica de la droga Bay 2502 en pacientes con infeccion chagasica cronica. Bol Chil Parasitol 1969; 24(1-2): 95-6.
    

25. Lugones HS, Peralta F, Feijoo DC, et al. Evolucion de la sintomatologia clinica y la funcion hepatica en la enfermedad de Chagas aguda tratada con Bay 2502. Bol Chil Parasitol 1969; 24(1-2): 19-24.
    

26. Pepin J, Milord F, Mpia B, et al. An open clinical trial of nifurtimox for arseno-resistant Trypanosoma brucei gambiense sleeping sickness in central Zaire. Trans R Soc Trop Med Hyg 1989; 83: 514-7.
    

27. Wegner DHG, Rohwedder RW. Experience with nifurtimox in chronic Chagas' infection. Arzneimittelforschung 1972; 22(9a): 1635-42.
    

28. Panel comment, 2/95.
    

29. Panel comment, 2/95.
    

30. Personal communication, Ian Mackay (HPB Health Canada), 12/16/94.
    

31. Lampit package insert (Bayer—Argentina), Rec 12/93.
    

32. WHO. Control of Chagas' disease: report of a WHO expert committee. WHO Tech Rep Ser 811 1991. Cited by Reynolds JEF, editor. Martindale, the extra pharmacopeia. 28th ed. London: The Pharmaceutical Press, 1982: 522.