Navy Medical Department Guide to Malaria Prevention and Control

Appendix 4: Antimalarial Medications

Department of the Navy
Bureau of Medicine and Surgery

Antimalarial drugs are divided into 4 classifications corresponding to their action on the different plasmodium life cycle stages in human hosts (see Table 5-1). The 4 classes are listed below:

1. Blood schizonticides attack plasmodia in red blood cells preventing or terminating the clinical attack.

2. Tissue schizonticides attack the exoerythrocytic forms in the liver. .

3. Gametocytocidal drugs attack the gametocyte stage in red blood cells.

4. Hypnozoiticidal drugs kill dormant P. vivax or P. ovale hypnozoites in liver cells.

All common drugs used worldwide for treatment of malaria are discussed in this chapter. As with treatment of tuberculosis, multi-drug treatment regimens are becoming necessary as drug-resistant strains emerge. The status, availability, effectiveness, dosage, and side effects of each are presented. Drugs are listed by generic name in alphabetical order and divided into three sections; 1) anti-malarial drugs availablethrough the military supply system; 2) Anti-malarial drugs available in the U.S., but not in the military supply system; and 3) Anti-malarial drugs under development or available in foreign countries. An important avenue of treatment is nasogastric administration of oral anti-malarial medications. If intravenous treatment in severe malaria patients is not possible, oral anti-malarial medications pulverized, mixed with water, and delivered via nasogastric tube are absorbed well and effectively. Dosage for nasogastric treatment is the same as the oral dose.

Table 5-1. Antimalarial Drugs classified by action on Plasmodia Life Cycle Stages

Section 1. Antimalarial Drugs Available in the Military Supply System

Chloroquine Phosphate
Status: FDA approved.
Availability: Currently available.
Product: A 4-aminoquinoline compound, chloroquine is a blood schizontocide active against P. vivax, P. malariae, and P. ovale. It has limited activity against most P. falciparum infections.
Description: 500 mg (300 mg base) tablets for oral administration.
Effectiveness: Chloroquine phosphate is indicated for suppressive treatment and for acute attacks of malaria due to Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It does not prevent relapse in patients with P. vivax and P. ovale infections, because it does not eliminate persistent liver stage parasites. Primaquine must be given to achieve radical cure (elimination of dormant hypnozoites in liver cells). Because of the increasing frequency of parasite resistance to chloroquine, its use as a prophylactic is limited to Mexico, Central America, and limited areas of the Middle East.
Dose & Administration: For prophylaxis: One 500 mg tablet weekly beginning 2 weeks prior to departure to endemic areas and continued for 4 additional weeks upon return.
For treatment: An initial dose of two 500 mg tablets followed by one 500 mg tablet in 6-8 hours, then a single 500 mg dose on each of two consecutive days for a total of five tablets (2,500 mg) in 3 days.
Side Effects: The most frequently observed side effects are gastrointestinal and include anorexia, nausea, vomiting, diarrhea, and abdominal cramps. Mild and transient headache, tinnitus, and deafness have been reported. Ocular reactions including blurred vision, and reversible interference with visual accommodation or focusing of vision may also occur. Long-term or high-dosage therapy may result in irreversible retinal damage.
Chloroquine may cause hemolysis when administered to patients with G-6-PD deficiency, but reactions are not as severe as those seen with primaquine. G-6-PD deficient service members taking chloroquine prophylaxis should be informed of side effects (see Chapter 6), and advised to seek medical evaluation if they occur. For severe reactions, an alternate prophylactic regimen should be provided.

Doxycycline Hyclate
Availability: Currently available.
Product: A widely used antibiotic useful as an anti-malarial primarily for prevention of P. falciparum infections.
Description: Available as 100mg tablets for oral administration.
Effectiveness: Doxycycline is indicated for the prophylaxis of malaria due to P. falciparum; it is less effective against P. vivax infections. It is effective against asexual, erythrocytic forms of P. falciparum, but not gametocytes of the sexual stage. It is also indicated for treatment of resistant strains of falciparum malaria.
Dose & Administration: For prophylaxis: One 100 mg tablet daily beginning 1-2 days prior to departure to endemic areas, daily during stay in the area, and continued for 4 weeks after departure.
For treatment: Doxycycline (100 mg twice daily for 7 days) or tetracyline (250 mg four times daily for 7 days) given as part of a multi-drug regimen is effective in areas with drug resistant strains of falciparum malaria. Most often used with mefloquine.
Side Effects: Most frequently observed side effects include nausea and epigastric distress; less frequent are incidents of diarrhea and vomiting. Stomach and esophageal ulceration has been reported. The frequency and severity of gastrointestinal side effects may be reduced by taking doxycycline with meals. Absorption of this drug is impaired by antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate. Monilial vaginitis and increased sensitivity to sun exposure are also common side effects.

Halofantrine (Halfan7)
Status: FDA approved for treatment only.
Availability: Currently available in the UK, not yet marketed in the U.S.
Product: A phenanthrenemethanol discovered and developed by Walter Reed Army Institute of Research, and subsequently co-developed by SmithKline Beecham.
Description: 250 mg tablets, indicated for the treatment of mild to moderate malaria caused by P. falciparum and P. vivax in adults who can tolerate oral medication.
Effectiveness: Halofantrine is effective against chloroquine-sensitive and chloroquine-resistant P. falciparum. It is also effective against P. vivax and some multi-resistant strains of P. falciparum. There may be cross-resistance to mefloquine in certain endemic areas.
Dose & Administration for Treatment: 500 mg (250 mg tablets x 2) every 6 hours for three doses (total first course dose 1500 mg). Repeat this course of therapy in 7 days. Halofantrine should be taken on an empty stomach (no food 2 hours before or 2 hours after each dose).
Side Effects: Generally well tolerated. May cause gastro-intestinal symptoms, including diarrhea. In doses higher than normal or when taken with food containing fat, can cause prolongation of QT interval. Prior treatment with mefloquine increases the likelihood of QT interval prolongation. Can lead to torsade-de-pointes in individuals with congenital prolonged QT syndrome.

Mefloquine HCl (Lariam^R)
Status: FDA approved.
Availability: Currently available.
Product: An anti-malarial drug effective against P. falciparum and P. vivax infections.
Description: Available as 250 mg tablets.
Effectiveness: Mefloquine HCl provides improved prophylaxis against chloroquine-resistant strains of P. falciparum and P. vivax. However, P. falciparum strains resistant to mefloquine have been reported.
Dose & Administration: For prophylaxis: One 250 mg tablet weekly, beginning 2 weeks prior to departure to endemic areas, and continued for 4 additional weeks after departure.
For treatment: Five 250 mg tablets (15-25 mg/kg) given as a single oral dose. The drug should be taken with at least 8 ounces of water with meals or a snack.
Side Effects: The most frequently observed side effect is vomiting, (3% incidence). It has also been associated with the occurrence of neurologic and psychiatric events after both prophylactic and therapeutic use. Minor neurologic events include dizziness, vertigo, headache, decrease in sleep, visual, and auditory disturbances. Serious adverse events such as seizures, disorientation, and toxic encephalopathy have been reported after therapeutic doses in patients with predisposing medical history (epilepsy, alcohol and drug abuse, or psychiatric disorder). Neurologic side effects have an incidence of less than 1%.

Primaquine Phosphate
Status: FDA approved.
Availability: Currently available.
Product: An anti-malarial drug for elimination of persistent P. vivax and P. ovale liver stage parasites (hypnozoites).
Description: Available as 26.3 mg (15 mg base) tablets for oral administration.
Effectiveness: Primaquine phosphate is indicated for cure and prevention of relapse of P. vivax and P. ovale malaria.
Dose & Administration: For treatment and terminal prophylaxis: One tablet daily for 14 days in individuals who are not G-6-PD deficient. The primaquine regimen must overlap at least one dose of chloroquine. Therefore, primaquine must be started no later than 1 week after the last dose of chloroquine.
Current Navy guidance directs that G-6-PD deficient service members are not to be given primaquine. Therefore, if, in the future, use of primaquine in G-6-PD deficient service members is authorized; give three tablets as a single dose once a week for 8 weeks in G-6-PDA- deficient individuals, or two tablets as a single dose once a week for 30 weeks in G-6-PD^Med deficient individuals.
Side Effects: The most frequently observed side effects include abdominal discomfort, nausea, headache, interference with visual accommodation, and pruritus. Methemoglobinemia is common, but rarely necessitates interruption of therapy. Leukopenia and agranulocytosis occur rarely. Do not use during pregnancy. If used for treatment in G-6-PD individuals, caution service members of possible side effects (see Chapter 6). If side effects occur, advise members to seek medical evaluation and treatment.

Quinidine Gluconate
Status: FDA approved for treatment of cardiac arrhythmias and intravenous treatment of severe malaria.
Availability: Currently available.
Manufacturer: Generic.
Product: Quinidine is a cinchona alkaloid, the dextrostereoisomer of quinine. Used to treat cardiac arrhythmia, it is now the drug of choice for intravenous treatment of chloroquine-resistant falciparum malaria as intravenous quinine is no longer available in the U.S.
Description: 80 mg/ml (55mg base /ml) intravenous solution available in 10 ml vials as quinidine gluconate.
Effectiveness: Very effective and safe for intravenous treatment of severe malaria. No reports of resistance in any strains of Plasmodia.
Dose & Administration: For prophylaxis: Not indicated.
For treatment: Loading dose of 10 mg/kg (6.2 mg base/kg) given over 1-2 hours, followed by continuous infusion of 1.2 mg/kg/hour (0.72 mg base/kg/hour) for 72 hours or until patient can swallow. Intravenous quinidine can safely be administered by monitoring EKG, blood pressure, and infusion speed; quinidine blood levels should be kept between 3-7 mg/L if monitored. Life-threatening arrhythmias are rare with proper doses, but infusion should be stopped temporarily if the EKG shows prolongation of the QRS interval by >50%, or if the QT interval is prolonged >50% of the preceding R-R interval. Hypotension may occur if infusion is too rapid. Loading dose is not indicated if patient started quinine, quinidine, or mefloquine treatment within the preceding 24 hours.
Side Effects: Quinidine is toxic to the heart if given too quickly or in too high a dose. EKG changes including prolonged QT intervals are common, but life threatening arrhythmias are rare if proper dosages are used. Most side effects are gastrointestinal in nature and include nausea, vomiting, abdominal pain, diarrhea, and rarely, esophagitis. Symptoms of mild to moderate cinchonism (ringing in the ears, headache, nausea, and impaired vision) may appear in sensitive patients after one dose of the drug. Less frequent side effects include urticaria, skin flushing with intense itching, and hypersensitivity reactions of angioedema, acute asthmatic episode, and liver toxicity.

Quinine (Quinamm^R)
Status: FDA approved.
Availability: Currently available in the U.S. in tablet form only.
Product: The first successful compound for treatment of malaria, it has been available for three centuries. With the introduction of chloroquine, the use of quinine fell dramatically, but the widespread emergence of chloroquine-resistant P. falciparum has increased its use. The intravenous form was last available in the U.S. in 1991.
Description: Available as 130, 200, 260, 300, and 325 mg capsules, and 260 and 325 mg tablets that have a very bitter taste. Indicated for treatment of all forms of malaria in patients able to swallow tablets.
Effectiveness: Acts rapidly against asexual erythrocytic stages of all four Plasmodium species that infect humans. There is resistance reported in the rural, northern mountainous area of Thailand and West Africa. Quinine should be used as part of a multi-drug regimen in those areas.
Dose & Administration: For prophylaxis: Not indicated.
For treatment: Adults: 600-650 mg 3 times a day for 7 days.
Children: 10 mg/kg 3 times a day for 7 days.
Side Effects: Quinine has the poorest therapeutic-to-toxic ratio of all of the anti-malarial drugs. Side effects are collectively known as cinchonism and include ringing in the ears, decreased hearing, headache, nausea, vomiting, and mild visual disturbances. These side effects are all dose related and reversible. Less common side effects include urticaria, angioedema of the face, itching, agranulocytosis, hepatitis, and hypoglycemia in patients with high P. falciparum parasitemia.

Section 2. Antimalarial Drugs Available in the United States but not in the Military Supply System

Atovaquone
Status: Atovaquone is available as Mepron^R in the U.S., and is FDA approved for treatment of Pneumocystis carinii pneumonia. It is currently not FDA approved for treatment of malaria.
Availability: Atovaquone was recently introduced in the combination drug Malarone^R(atovaquone and proguanil) for treatment of malaria. Malarone^Ris distributed in partnership with WHO under close supervision only to patients resistant to conventional malaria treatment. Malarone^Ris not available in the U.S.
Product: An antiprotozoal agent that is a synthetic derivative of hydroxynaphthoquinone, and may exert its effect by selectively inhibiting electron transport in mitochondria.
Description: Mepron^R (250 mg; intravenous solution,750 mg/5ml), Malarone^R(atovaquone and proguanil).
Effectiveness: Atovaquone is indicated in the acute treatment of mild to moderately severe Pneumocystis carinii pneumonia in patients who cannot tolerate co-trimoxazole. Recent trials have shown that a 3 day course of 1000 mg of atovaquone and 400 mg of proguanil had a cure rate of 87% for chloroquine-resistant falciparum malaria.
Dose & Administration: For prophylaxis: Not indicated. For treatment: For malaria, 1000 mg per day for 3 days in daily combination with 400 mg of proguanil. Atovaquone should be administered with food.
Side Effects. Atovaquone is well tolerated. Common side effects listed in order of occurrence are rash, nausea, diarrhea, headache, fever, and vomiting.

Hydroxychloroquine Sulfate (Plaquenil^R)
Status: FDA approved for prophylaxis and treatment.
Availability: Currently available.
Product: Also a 4-aminoquinoline compound, hydroxychloroquine sulfate has the same actions, effectiveness, and indications as chloroquine phosphate.
Description: 200 mg (155 mg base) tablets.
Effectiveness: Like chloroquine, it is a blood schizontocide active against P. vivax, P. malariae, P. ovale, but with limited activity against most P. falciparum infections. It does not prevent relapse in patients with P. vivax and P. ovale infections, and must be followed with primaquine to effect radical cure of these diseases. As with chloroquine, because of increased parasite resistance, hydroxychloroquine sulfate is considered most useful for prophylaxis in Mexico, Central America, and limited areas of the Middle East.
Dose & Administration: For prophylaxis: Adults: 2 tablets (400 mg) each week beginning 2 weeks prior to exposure, and continued for 4 weeks after leaving endemic area. If unable to begin two weeks prior, an initial double (loading) dose of 4 tablets (800 mg) may be taken in 2 doses 6 hours apart. Children: Administration same as adults; dosage is 5 mg base/kg each week, not to exceed the adult dosage regardless of weight. If unable to begin prophylaxis 2 weeks before exposure, give an initial double (loading) dose of 10 mg base/kg in two doses 6 hours apart.
For treatment: Adults: Initial dose of 4 tablets (800 mg) followed by 2 tablets (400 mg) in 6-8 hours, then 2 tablets (400 mg) on the next 2 days for a total dose of 10 tablets (2000 mg). Children: Four doses as follows; dose 1: 10 mg base/kg; dose 2: 5 mg base/kg 6 hours after dose 1; dose 3: 5 mg base/kg 18 hours after dose 2; dose 4: 5 mg base/kg 24 hours after dose 3.
Side Effects: Usually well tolerated. Side effects reported include mild and transient headache, dizziness, and gastrointestinal complaints of diarrhea, loss of appetite, nausea, abdominal cramps, and rarely, vomiting.

Pyrimethamine/Sulfadoxine (Fansidar^R)
Status: FDA approved for treatment only.
Availability: Currently available.
Product: A combination drug containing the DNA synthesis inhibitors pyrimethamine and sulfadoxine. Each blocks a different enzyme in the synthesis of DNA from guanosine triphosphate.
Description: A tablet containing 25 mg pyrimethamine and 500 mg sulfadoxine.
Effectiveness: Fansidar^R is useful as an alternative treatment of chloroquine-resistant falciparum malaria. It is also often used to treat suspected malaria cases in areas where persons developing malaria symptoms cannot obtain prompt medical evaluation. It once was used as a weekly prophylaxis, but caused frequent, severe allergic reactions. In 1984, American travelers who took Fansidar^R in Kenya were as likely to die from Fansidar^R toxicity as from malaria.
Dose & Administration: For prophylaxis: Not indicated. For treatment: Adults: 3 tablets in a single dose. Children: _ tab in those < 1 year old, _ tab in children 1-3 years old, 1 tab in children 4-8 years old, 2 tabs in adolescents 9-14 years old, 3 tabs in those >14 years old. All treatments, adult and children, are single dose.
Side Effects: Fatalities have occurred due to severe reactions, including Stevens-Johnson syndrome and toxic epidermal necrosis in persons using Fansidar^R as a prophylaxis. No fatal reactions have been reported when it has been used for treatment (3 tablets in a single dose). Adverse reactions, rare when Fansidar^R is used for treatment, include urticaria, serum sickness, itching, conjunctival or scleral injection, nausea, vomiting, headache, and drug fever.

Section 3. Antimalarial Drugs under development or Available in Foreign Countries

Artemisinin
Status: Under investigation.
Availability: Currently used in China and the Far East, not available in the U.S.
Product: A sesquiterpene lactone derived from the Chinese wormwood plant Artemesia annua, artemisinin has long been used to treat febrile illnesses in China. There it is known as "qinghaosu."
Description: Artemisinin compounds can be administered enterally, intravenously, or intramuscularly. In China, the drug has been used in the following forms:
Artemisinin suppositories represent a major advantage in treating severe malaria in patients unable to tolerate oral medications in situations where injections cannot be given. They have proved effective in cerebral and other severe falciparum infections. Sodium artesunate is a powder that is reconstituted just before intravenous injection. Artesunate is the tablet form, and has been efficacious in treatment of uncomplicated falciparum malaria. Artemether is the form used for intramuscular injection, and is given in an initial loading dose of 200 mg, followed on the subsequent 6 days with a dose of 100 mg.
Effectiveness: Artemisinin compounds are blood schizonticides effective against parasites resistant to chloroquine and quinine. In a trial in Thailand, artensuate tablets (100 mg initial dose, followed by 50 mg q 12 hrs for 5 days) combined with mefloquine (750 mg initial dose followed by 500 mg after 6 hrs), proved effective in curing adults with uncomplicated falciparum malaria and were more effective than artensuate or mefloquine given alone.
Dose & Administration: For prophylaxis: Not indicated. For treatment: Expected to be effective against all forms of human malaria, particularly severe and complicated falciparum malaria where rapid effects on parasites are needed. Dosage of each is under investigation.
Side Effects: No severe adverse effects have been reported in clinical trials by over 4,000 patients. Mild adverse effects include transient first-degree heart block, mild decreases in reticulocyte and neutrophil counts, elevated liver transaminases, abdominal pain, diarrhea, and drug fever.

Proguanil (Paludrine)
Status: Not approved by the FDA for use.
Availability: Available outside the U.S.
Product: Proguanil is an antifolate agent, and was the first agent found to inhibit dihydrofolate reductase (an enzyme important in DNA synthesis) in plasmodia. It was also recently released as part of the combination drug Malarone^R (Atovaquone and Proguanil).
Description: 100 mg tablets.
Effectiveness: It is useful as a prophylactic agent against P. falciparum and P. vivax. It acts too slowly to be used alone for treatment of acute malaria, but has been used successfully as part of multi-drug regimens for treatment of uncomplicated malaria. See description of atovaquone for further information.
Dose & Administration: For prophylaxis: 200 mg daily, alone or in combination with chloroquine.
For treatment: Useful in multi-drug regimens. Malarone^R (atovaquone and proguanil) given for 3 to 7 days has had success in treatment of P. ovale, P. malariae, and multi-drug resistant P. falciparum.
Side Effects: Very safe at daily dosage levels. Side effects of nausea, vomiting, abdominal pain, and diarrhea have been experienced at higher dosages.

Pyrimethamine/dapsone (Maloprim^R or Deltaprim^R)
Status: Not released in the U.S.
Availability: The combination drugs Maloprim^R and Deltaprim^R are available in the UK. Pyrimethamine and dapsone are available as individual products in the U.S., but not as combined formulations.
Product: A combination drug containing pyrimethamine and dapsone.
Description: 25 mg pyrimethamine and 100 mg dapsone used as malaria prophylaxis.
Effectiveness: Often prescribed in the UK for suppressive treatment of malaria due to P. vivax, P. malariae, P. ovale, and P. falciparum. Though toxicity is very uncommon, hemolysis and methemoglobinemia limit the use of this drug.
Dose & Administration: For prophylaxis: 1 tablet weekly. For treatment: Not indicated.
Side Effects: Hemolytic anemia, methemoglobinemia, Heinz body formation, and bone marrow suppression. Contraindicated in persons with G-6-PD deficiency.

Intravenous Quinine
Status: FDA approved.
Availability: Not available in the U.S. CDC stopped supplying intravenous quinine in 1991.
Product: See description in section 1.
Description: Intravenous concentrations vary, check when formulating intravenous solution for treatment.
Effectiveness: Acts rapidly against asexual erythrocytic stages of all four Plasmodium species that infect humans.
Dose & Administration: For prophylaxis: Not indicated.
For treatment: Adults: Loading dose of 20 mg salt/kg given over 4 hours, then followed in 8-12 hours by 10 mg salt/kg given over 4 hours every 8-12 hours until patient can swallow and tolerate oral medication.
Children: Loading dose of 15 mg salt/kg given over 2 hours, then followed in 8-12 hours by 10 mg salt/kg given over 2 hours every 12 hours until patient can swallow and tolerate oral medication.
Side Effects: Hypoglycemia is the most common severe side effect of quinine during treatment of malaria. When quinine is being given intravenously, blood glucose levels should be monitored. If there is any change in mental status, hypoglycemia should be suspected. See section 1 for description of other side effects.

WR 238605
Status: Under investigation.
Availability: Clinical trials only.
Product: This is a new 8-aminoquinoline developed by Walter Reed Army Institute of Research now undergoing clinical trials.
Description: Not applicable.
Effectiveness: Similar in structure to primaquine, in initial tests it appears to be 10 times more active than that drug. It is a tissue schizontocide and has shown some blood schizontocide activity.
Dose & Administration: Pending. It is being developed as a less toxic alternative to primaquine to be used for radical cure of P. vivax and P. ovale malaria. It is under consideration for potential use for malaria prophylaxis.
Side Effects: There is currently no data on the relative toxicity of this drug compared to primaquine in G-6-PD deficiency.

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Operational Medicine 2001

Health Care in Military Settings

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