melarsoprol

Melarsoprol is a medication administered intravenously to treat human African trypanosomiasis, also known as sleeping sickness. Melarsoprol is a highly toxic drug derived from arsenic, with severe side effects, and hence is used only for the treatment of the second stage of African trypanosomiasis with involvement of the central nervous system. Melarsoprol kills the parasites that cause sleeping sickness.

African trypanosomiasis is caused by microscopic parasites of the species Trypanosoma brucei. Two subspecies of the parasite cause disease in humans, one that progresses slowly, caused by T. b. gambiense found in western and central Africa, and a more acute infection caused by T. b. rhodesiense found in eastern and southern Africa. The Trypanosoma parasites live in the gut of the Glossina species of tsetse fly found in sub-Saharan Africa, and are transmitted when the tsetse fly bites humans for a blood meal.

Once the trypanosomes enter the skin tissue from the tsetse fly saliva, they get into the lymphatic system and bloodstream and start multiplying during the first stage of infection. In the second stage, the parasites enter the cerebrospinal fluid and affect the brain and central nervous system. Melarsoprol crosses the blood-brain and is used to treat only the second stage of the disease with CNS involvement because of its high toxicity.

Melarsoprol is a prodrug that is metabolized into its active form melarsen oxide, which inhibits the synthesis of adenosine triphosphate (ATP), the energy that the parasites require to survive. Melarsoprol is toxic to humans because it cannot distinguish between human and parasite ATP. Melarsen oxide also reacts with trypanothione, the antioxidant found in trypanosomes and inhibits the enzyme trypanothione reductase, which results in the accumulation of free radicals and oxidative damage in the parasitic cells, and death of the trypanosomes.

Currently, melarsoprol is the only treatment available for second stage of disease caused by T. b. rhodesiense, although other less toxic drugs are available for treatment of both stages of T. b. gambiense infection and first stage of T. b. rhodesiense infection. Melarsoprol is not approved by the FDA and is not commercially available in the US. It is available for the treatment of patients with African trypanosomiasis through the Centers for Disease Control (CDC) Drug Service to be used under an Investigational New Drug (IND) protocol.

• Do not use melarsoprol to treat patients with:
  • Hypersensitivity to any of its components
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a genetic disorder that causes red blood cells to break down with certain medications or infections.
• Avoid use during pregnancy, depending on the mother’s condition.
• Use with caution in patients with liver or kidney disease, cardiovascular conditions or neurological disorders.
• Exercise care to avoid leakage of medication from the vein (extravasation), it can damage the tissue around.
• Melarsoprol treatment can cause reactive encephalopathy, a brain disease that may be fatal sometimes. Fever and headache are early symptoms, progressing later to abnormal behavior, cerebral edema, seizures, coma, and other neurological disorders. Monitor the patient closely and discontinue melarsoprol immediately if such symptoms appear, and treat appropriately with corticosteroids.
• Melarsoprol contains propylene glycol which can be toxic in large amounts.

Common side effects of melarsoprol include:

• High blood pressure (hypertension)
• Cardiac insufficiency
• Heart muscle (myocardial) damage
• Headache
• High temperature (hyperthermia)
• Brain disease (encephalopathy)
• Peripheral nerve disease (neuropathy)
• Nausea
• Vomiting
• Diarrhea
• Bloody stools
• Colic
• Rash
• Hives (urticaria)
• Liver insufficiency
• Kidney insufficiency
• Albumin excretion in urine (albuminuria)
• Hypersensitivity reactions
• Severely low count of granulocyte immune cells (agranulocytosis)
• Jarisch-Herxheimer reaction, a transient inflammatory reaction to the toxins released by the protozoal death

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

African Trypanosomiasis (Sleeping Sickness)

Adult:

• 2-3.6 mg/kg/day intravenous (IV) for 3 days  
• After 1 week: 3.6 mg/kg/day IV for 3 days
• Repeat again after 10-21 days: 3.6 mg/kg/day

Pediatric:

• 18-25 mg/kg total over 1 month  
• Initial 0.36 mg/kg IV
• Increase gradually to 3.6 mg/kg IV at intervals of 1-5 days for total of 9-10 doses

Investigational drug

Not commercially available in US; however, available as treatment IND from CDC; 800-CDC-INFO (800-232-4636)

Overdose

• Melarsoprol is a highly toxic medication that is administered only under clinical supervision and overdose is unlikely.
• Overdose can damage multiple organ systems including the heart and nervous system, and cause death.
• Approximately 1-5% of patients die during treatment even with recommended doses.
• Treatment of melarsoprol toxicity includes immediate discontinuation of the drug and supportive and symptomatic treatment as required.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Melarsoprol has no known severe, serious, moderate, or mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider about all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or healthcare provider if you have any questions about the medication.

• There are no studies on the safety of melarsoprol use in pregnant women.
• Currently, melarsoprol is not recommended for use during pregnancy. Other less toxic agents are preferred.
• The World Health Organization (WHO) suggests deferring melarsoprol treatment until pregnancy is over, depending on the condition of the mother.
• There is no information on the use of melarsoprol in breastfeeding women.

• Notify your physician immediately if you develop:
  • Hypersensitivity reactions following administration of melarsoprol
  • Headache, fever, and/or seizure after initiation of treatment