Skip to Content

Melarsoprol (Systemic)


VA CLASSIFICATION
Primary: AP109

Commonly used brand name(s): Arsobal.

Other commonly used names are
Mel B and Melarsen Oxide-BAL . {01} {02}
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)—

Indications

Note: Because melarsoprol 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, African (treatment)]1—Melarsoprol is used as a primary agent {04} {06} in the treatment of African trypanosomiasis (African sleeping sickness; trypanosome fever) caused by Trypanosoma brucei gambiense or T. b. rhodesiense in patients with late or chronic disease with central nervous system (CNS) involvement. {01} {02} {03} {04} {05} {13} {14} {17} {19} Another agent used for trypanosomiasis is eflornithine, which is effective against T. b. gambiense infections. {04} {20} However, eflornithine has variable efficacy against T. b. rhodesiense infections. {04}

—Not all species or strains of a particular organism may be susceptible to melarsoprol.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:


Chemical
    Trivalent arsenical derivative. {01} {05} {06}
Molecular weight—
    398.33 {07}

Mechanism of action/Effect:

Trypanocidal; {03} {05} melarsoprol is believed to work by disruption of energy generation in the trypanosome parasite due to the high affinity of melarsoprol for sulfhydryl groups. These groups form the active sites of many enzymes (especially the kinases), and are involved in the maintenance of the secondary and tertiary structures of proteins. Once inside the trypanosome, melarsoprol inactivates the enzyme, pyruvate kinase, which is present in the cytoplasm. This causes inhibition of the synthesis of adenosine triphosphate (ATP), which is the energy required for the survival of the parasite. The trypanosome eventually dies as a result of diminished energy production. {02}

Selectivity of melarsoprol is thought to be related to 3 factors, namely: efficient binding of melarsoprol to the trypanosome rather than the mammalian host enzyme, some concentration of the medication in the trypanosome, and total dependence of the trypanosome on glycolysis for energy (ATP) generation. {02}

Absorption:

Fairly well absorbed after oral administration but is not normally given by this route; usually given parenterally. {01}

Distribution:

Crosses the blood-brain barrier; {01} {03} {08} cerebrospinal fluid (CSF) concentration is about 50-fold lower than that in the serum; significant variability has been shown when CSF concentration was measured 24 hours after the last injection of each therapeutic course and 120 hours after the very last injection; maximum CSF concentration is about 260 ng per mL (ng/mL) and the minimum CSF concentration is below the limit of detection; mean CSF concentration is about 30 ng/mL. {08}

Volume of distribution (Vol D)—>100 L per kg. {08}

Half-life:

Mean terminal elimination half-life—About 35 hours. {08}

Peak serum concentration

Most serum concentrations are between 2 and 4 mcg per mL (mcg/mL) 24 hours after initial administration and are still ³ 0.1 mcg/mL after 120 hours; maximum serum concentration is in the range of 5 to 6 mcg/mL after the fourth injection of the therapeutic courses; mean value is 0.22 mcg/mL (±0.08 mcg/mL) 120 hours after the very last injection of the therapeutic courses; between the courses of treatment, the serum concentration of melarsoprol drops to almost zero. {08}

Elimination:
    Renal—Rapidly excreted in the urine {02} {03} {05} within days of administration; total clearance is about 50 mL per minute. {08}


Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in humans.

Studies have not been done in animals. {03} {09}

Breast-feeding

It is not known whether melarsoprol is distributed into breast milk. However, problems in humans have not been documented. {03}

Pediatrics

Appropriate studies on the relationship of age to the effects of melarsoprol have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date.


Geriatrics


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

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
» Febrile episodes    (melarsoprol has been associated with an increased incidence of reactive arsenical encephalopathy [RAE] when given to febrile patients; {10} {12} {19} its use is contraindicated during epidemics of influenza {01} {10} because of heightened probability of febrile episodes in influenza {21} {22})


» Glucose-6-phosphate dehydrogenase (G6PD) deficiency    (melarsoprol may cause severe hemolytic reactions in G6PD deficient patients {01} {03} {09} {10} {19})


» Hypersensitivity to melarsoprol{01}{03}{10}{19}
Leprosy    (melarsoprol may precipitate erythema nodosum in lepromatous patients {01} {03} {10} {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):

» Cerebrospinal fluid (CSF) examination{09}{14}{16}    (should be done prior to, during, and after treatment with melarsoprol to monitor the effects of therapy; increased CSF leukocyte count, CSF protein content, and the presence of trypanosomes in the CSF are determinants of the risk of encephalopathy)




Side/Adverse Effects

Note: Reactive arsenical encephalopathy (RAE) has been attributed to the toxic effect of melarsoprol, or to a Jarisch-Herxheimer-type reaction resulting from the release of antigen from trypanosomes killed in the brain. It may also be due to the combination of melarsoprol toxicity and the host's immune response. {01} {10} {11} {12} {13} {14} RAE occurs in about 10 {01} {02} {04} {06} to 12% of patients {13} and is usually seen between the end of the first 3-day course of treatment and the start of the second course of treatment. {01} {10} {12} {13} {14}
Peripheral neuropathy is thought to be due to a direct toxic effect of the arsenic content of melarsoprol on neural tissues. {06} It occurs in about 9% of patients {06} {11} and may be seen within 2 to 5 weeks after intravenous administration. {11}
Cutaneous reactions occur in about 4 to 5% of patients. {13}
Renal or hepatic dysfunction may be dose-related and occurs in about 3% of patients. It is usually seen during the last phase of treatment. {03}
Allergic or hypersensitivity reactions occur particularly during the second or subsequent courses of treatment. {03}

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 more frequent
    
Jarisch-Herxheimer-like reaction (chills; fever; general feeling of illness or discomfort; headache; rigidity; sweating){10}{13}
    
local swelling at injection site{13}
    
peripheral neuropathy (numbness, tingling, pain, or weakness of hands or feet){01}{03}{06}{10}{11}
    
phlebitis (pain at injection site){13}
    
reactive arsenical encephalopathy (confusion; convulsions; fever; headache; loss of consciousness; restlessness; slurring of speech; tremors){01}{02}{03}{06}{08}{09}{10}{11}{12}{13}{14}

Incidence less frequent
    
Cutaneous reactions, such as exfoliative dermatitis (red, thickened, or scaly skin), or urticaria (skin rash or itching){01}{03}{06}{09}{13}
    
hepatic dysfunction (fever with or without chills; yellow eyes or skin){01}{03}{10}{13}
    
hypertension (increased blood pressure){03}{09}{10}
    
myocardial toxicity (irregular heartbeat){03}{09}{10}
    
renal dysfunction (cloudy urine){01}{03}{10}{13}

Incidence rare
    
Allergic or hypersensitivity reactions (changes in facial skin color; fainting or loss of consciousness; fast or irregular breathing; fever; puffiness or swelling of the eyelids or around the eyes; shortness of breath, trouble in breathing, tightness in chest, and/or wheezing; skin rash and/or itching){01}{03}{09}{10}
    
blood dyscrasias, such as agranulocytosis (fever with or without chills; sore/ulcers, or white spots on lips or mouth; sore throat){09}, aplastic anemia (shortness of breath, trouble in breathing, tightness in chest, and/or wheezing; sores, ulcers, or white spots on lips or in mouth; swollen and/or painful glands; unusual bleeding or bruising; unusual tiredness or weakness){03}, or thrombocytopenia (black, tarry stools; blood in urine or stools; pinpoint red spots on skin; unusual bleeding or bruising){03}
    
hemorrhagic encephalopathy (fever; sudden loss of consciousness){13}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Arthralgia (joint pain){13}

Incidence less frequent
    
Gastrointestinal disturbances (abdominal or stomach pain; diarrhea; nausea; vomiting){01}{03}{09}{10}{11}{13}





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

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

Before receiving this medication
»   Conditions affecting use, especially:
Hypersensitivity to melarsoprol
Other medical problems, especially febrile episodes and glucose-6-phosphate (G6PD) deficiency

Proper use of this medication
Importance of receiving this medication in the hospital for full course of therapy and on a regular schedule

» Proper dosing

Precautions while receiving this medication
Receiving this medication in the supine position and in a fasting state to minimize gastrointestinal disturbances; remaining in the supine position after injection of the medication and continuing fasting for at least 5 hours


Side/adverse effects
Signs of potential side effects, especially Jarisch-Herxheimer-like reaction; local swelling at injection site; peripheral neuropathy; phlebitis; reactive arsenical encephalopathy; cutaneous reactions, such as exfoliative dermatitis or urticaria; hepatic dysfunction; hypertension; myocardial toxicity; renal dysfunction; allergic or hypersensitivity reactions; blood dyscrasias, such as agranulocytosis, aplastic anemia, or thrombocytopenia; hemorrhagic encephalopathy


General Dosing Information
Because melarsoprol is toxic, patients undergoing therapy with this medication should be treated in the hospital. {01} {02} {03} {08} {09} {10} {12} Dosage should be based upon clinical assessment or the general condition of the patient other than body weight. {01} {10}

Treatment protocols for melarsoprol may vary. Usually, this medication is given in short courses of 3 or 4 days' duration and separated by `rest periods' of 7 to 10 days. {01} {03} {10} In children and debilitated patients, melarsoprol should be given in low doses initially, then gradually increased to the maximum daily dose of 3.6 mg per kg of body weight. {01}

Melarsoprol should be administered by slow intravenous injection as a 3.6% solution in propylene glycol. {01} {03} {09} Because melarsoprol injection is intensely irritating due to its propylene glycol content, care should be taken to avoid leakage into the surrounding tissues. Extravasation during intravenous administration may result in extreme local tissue damage and destruction. {01} {09}

Gastrointestinal disturbances may be reduced by slowly injecting melarsoprol in the supine, fasting patient. After the injection, the patient should remain supine and should not eat for at least 5 hours. {01} {03} {10}

Preliminary treatment with suramin or pentamidine 24 to 48 hours prior to melarsoprol treatment is recommended {06} to reduce febrile Jarisch-Herxheimer-like reactions that may occur, particularly in debilitated patients with high levels of parasitemia. {01} {03} {04} {06} {09}

Desensitization may be attempted to prevent hypersensitivity reactions from occurring. This may be done by starting treatment with small doses and gradually increasing the doses of melarsoprol. {01} {03} {13} However, some medical authorities believe giving small doses of melarsoprol may increase the risk of resistance. {01} Concomitant administration of corticosteroids may help to control symptoms during desensitization. {01} {03} {13}

Corticosteroids also have been used to prevent and treat potentially fatal reactions, especially reactive arsenical encephalopathy (RAE). {06} {12} {15} However, conclusive evidence of their value has not been demonstrated. {06} {09} In view of their high cost and doubtful evidence, routine use of corticosteroids is not recommended by the World Health Organization (WHO) Expert Committee on Trypanosomiasis. {06} {09}

Intercurrent infections, such as pneumonia and malaria, should be treated prior to melarsoprol therapy. Malnutrition should be corrected with a protein-rich diet. {03} {09}

Any neurological symptom that may appear during the course of treatment necessitates temporary interruption of treatment. {03} Most clinicians also would suspend treatment during episodes of RAE. {09}

Needles and syringes must be sterilized by dry heat because solution of melarsoprol is incompatible with water. {03}

After melarsoprol treatment, patients should be followed up every 6 months for 2 {09} to 3 years {06} and the CSF examined on each occasion. An increase in the leukocytes and protein content or reappearance of trypanosomes in the CSF is indicative of relapse. In this case, a second complete course of treatment with melarsoprol may be administered, although it is rarely successful. Other agents, such as eflornithine, may be a more effective alternative to melarsoprol, {09} especially in T. b. gambiense infections. However, the effectiveness of eflornithine in T. b. rhodesiense infections has been variable. {04}

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

   • For RAE—Temporary cessation of melarsoprol, administration of anticonvulsants and sedatives to control seizures, {01} {03} {06} {09} {12} hypertonic solutions (mannitol 25% 150 mL by rapid intravenous infusion followed by mannitol 10% 500 mL by slow intravenous infusion), as well as diuretics, to reduce cerebral edema. {01} {03} {09} {12} Corticosteroids {01} {06} {12} {15} and subcutaneous epinephrine {01} {06} {12} have been reported to be useful in the prevention and treatment of RAE. {01} {06} {12} {15} Dimercaprol (British antilewisite [BAL]) has been given based on the assumption that encephalopathy resulted from arsenic poisoning, but giving BAL has not generally been of benefit. {01} {06} {14} For psychotic reactions due to RAE, major neuroleptics, such as chlorpromazine or haloperidol, may be given. {12}


Parenteral Dosage Forms

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

MELARSOPROL FOR INJECTION

Usual adult dose
[Trypanosomiasis, African (treatment)]1
Intravenous, 3.6 mg per kg per day for three days. {02} {03} {04} {05} {19} This three-day regimen can be repeated three or four times with an interval of one week between courses of treatment. {03} {04} {19}


Usual adult prescribing limits
Up to 180 mg per day. {02} {03} {05} {13} {19} However, up to 200 mg per day was used in one study. {06}

Usual pediatric dose
[Trypanosomiasis, African (treatment)]1
Intravenous, 18 to 25 mg per kg total over one month given as follows: initially, 0.36 mg per kg per day, gradually increasing to 3.6 mg per kg per day at intervals of one to five days, for a total of nine to ten doses. {04} {19}

Note: Some medical authorities recommend 1.8 mg per kg per day for three days. This three-day regimen can be repeated three or four times with an interval of one week between courses of treatment. {05} {19}



Size(s) usually available:
U.S.—
Not commercially available.

Note: Although melarsoprol 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]). {04}


Canada—
Not commercially available.

Note: Although melarsoprol 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). {18}


Other (France)—


180 mg per 5 mL (Rx) [Arsobal (propylene glycol)]

Packaging and storage:
Store ampules below 25 °C (77 °F). Protect from light. {03} {09} Protect from freezing.

Stability:
Melarsoprol ampules are stable for three years at temperatures below 25 °C (77 °F). {03}

Incompatibilities:
Melarsoprol is incompatible with water. {03}



Developed: 12/20/1994



References
  1. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 29th ed. London: The Pharmaceutical Press, 1989: 515.
  1. Gutteridge WE. Existing chemotherapy and its limitations. Br Med Bull 1985; 41(2): 162-8.
  1. Arsobal product monograph (Specia—France) and label box, Rec 3/94.
  1. Abramowicz M, editor. Drugs for parasitic infections. Med Lett Drugs Ther 1993; 35(911): 111-22.
  1. Van Voorhis WC. Therapy and prophylaxis of systemic protozoan infections. Drugs 1990; 40(20): 176-202.
  1. Pepin J, Guerin C, Ethier L, et al. Trial of prednisolone for the prevention of melarsoprol-induced encephalopathy in gambiense sleeping sickness. Lancet 1989: 1246-50.
  1. Fleeger CA, editor. USAN 1995. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1994: 410.
  1. Burri C, Baltz T, Giroud C, et al. Pharmacokinetic properties of the trypanocidal drug melarsoprol. Chemotherapy 1993; 39: 225-34.
  1. WHO Model Prescribing Information: Drugs used in parasitic diseases. Geneva: World Health Organization, 1990: 68-70.
  1. Gilman AG, Rall TW, Nies AS, Taylor P, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990: 1009-10.
  1. Dukes MNG, editor. Meyler's side effects of drugs. An encyclopedia of adverse reactions and interactions. 12th ed. Amsterdam: Elsevier, 1992: 708.
  1. Haller L, Adams H, Merouze F, et al. Clinical and pathological aspects of human African trypanosomiasis (T. b. gambiense) with particular reference to reactive arsenical encephalopathy. Am J Trop Med Hyg 1986; 35(1): 94-9.
  1. Robertson DHH. The treatment of sleeping sickness (mainly due to Trypanosoma rhodesiense) with melarsoprol. Trans R Soc Trop Med Hyg 1963; 57(2): 122-33.
  1. Pepin J, Milord F. African trypanosomiasis and drug-induced encephalopathy: risk factors and pathogenesis. Trans R Soc Trop Med Hyg 1991; 85: 222-4.
  1. Foulkes JR. An evaluation of prednisolone for the prevention of melarsoprol-induced encephalopathy in gambiense sleeping sickness. Lancet 1989: 1246-50.
  1. Hamon JF, Seri B, Doua F, et al. Effects of Mel B Arsobal and alpha-difluoromethylornithine on the awakening electroencephalogram of humans with gambiense trypanosomiasis disease: preliminary report. Pharmacol Biochem Behav 1990; 36: 831-5.
  1. Wellde BT, Chumo DA, Reardon MJ, et al. Treatment of Rhodesian sleeping sickness in Kenya. Ann Trop Med Parasitol 1989; 83 (suppl. 1): 99-109.
  1. Personal communication, Marilyn Bullen (HPB Health Canada), 8/12/94.
  1. Panel consensus, 10/94.
  1. Panel comment, 10/94.
  1. Panel comment, 10/94.
  1. Panel comment, 10/94.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Hide