Proguanil (Systemic)
VA CLASSIFICATION
Primary: AP101
Commonly used brand name(s): Paludrine.
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.
Category:
Antimalarial—
Indications
General considerations
Malaria transmission occurs in large areas of Central and South America, Hispaniola, sub-Saharan Africa, the Indian subcontinent, Southeast Asia, the Middle East, and Oceania {01}. The estimated risk of a traveler acquiring malaria varies markedly from area to area {01}. Country-specific information on malaria risk can be obtained from the Centers for Disease Control and Prevention (CDC) or from the CDC's web site at http://www.cdc.gov/travel/yellowbk {01} {02} {03}.
Travelers to malarious areas should be advised to use an appropriate drug regimen and personal protection measures to prevent malaria {01}. Because of the nocturnal feeding habits of Anopheles mosquitoes, malaria transmission occurs primarily between dusk and dawn {01} {02}. Therefore, travelers should take protective measures to reduce contact with mosquitoes especially during these hours (see Patient Consultation ) {01}. However, travelers should be informed that regardless of methods employed, malaria still may be contracted {01}.
Asplenic travelers are at increased risk for severe malaria and should take extra precautions to avoid contracting the disease {04}. These precautions should involve careful use of antimosquito measures, strict compliance with appropriate chemoprophylaxis, and avoidance of unnecessary visits to malarious areas {04}.
Drug resistance to chloroquine has been confirmed or is probable in all countries with Plasmodium falciparum malaria except the Dominican Republic, Haiti, countries in Central America west of the Panama Canal Zone, Egypt, and most countries in the Middle East {01} {05}. In addition, resistance to both chloroquine and the sulfadoxine and pyrimethamine combination is widespread in Thailand, Myanmar, Cambodia, and the Amazon basin area of South America, and resistance has been reported sporadically in sub-Saharan Africa {01}.
The appropriate chemoprophylactic regimen is determined by the traveler's risk of acquiring malaria in the area to be visited and by the risk of exposure to chloroquine-resistant P. falciparum {01} {06}. Indications for prophylaxis for children are identical to those for adults {01} {06}. Chemoprophylaxis should begin 1 to 2 weeks before arrival in the endemic area, allowing time for development of an adequate blood concentration of the chemoprophylactic agent and evaluation of any adverse reactions (see General Dosing Information ) {01} {06}.
Accepted
Malaria (prophylaxis)—Proguanil is indicated for the causal prevention and suppression of malaria caused by susceptible strains of P. falciparum and other species of Plasmodium found in some geographical areas of the world {07}.
Note: A high degree of resistance appears to develop in all species of Plasmodium and in some geographical areas this has limited the usefulness of proguanil {07}. Proguanil should not be used alone if resistance to other antimalarials has been confirmed {07}. Cross-resistance occurs with other antimalarials {07}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Source—
Synthetic biguanide derivative of pyrimidine {18}.
Molecular weight—
Proguanil: 253.7 {18}
Proguanil hydrochloride: 290.2
Mechanism of action/Effect:
Proguanil is a slow-acting blood schizonticidal (suppresses intraerythrocytic schizogony) {07} {18}. Proguanil acts through its active metabolite, cycloguanil. The mechanism of action probably is due to interference of cycloguanil with the folic-folinic system of the parasite through inhibition of the plasmodial enzyme, dihydrofolate reductase. This inhibition results in the depletion of folate, an essential cofactor in the biosynthesis of nucleic acids, thus resulting in interference with the synthesis of protozoal nucleic acids and protein production {10} {14} {15}.
Proguanil may also have some sporonticidal activity, rendering the gametocyte noninfective to the mosquito vector {07}.
Absorption:
Rapidly and well absorbed in humans following oral doses ranging from 50 to 500 mg {07}.
Protein binding:
High (approximately 75%) {07}.
Biotransformation:
Variably metabolized {12} {17} in the liver by cytochrome P450 isoenzymes to the active triazine metabolite, cycloguanil {13} {14}. This variable metabolism of proguanil may have profound clinical importance in poor metabolizers such as the Asian and African populations at risk for malaria infection. Prophylaxis with proguanil may not be effective in these persons because they may not achieve adequate therapeutic levels of the active compound, cycloguanil, even after multiple doses {12}.
Half-life:
Approximately 20 hours {10} {17}.
Time to peak concentration:
Following an oral 200-mg dose:
Proguanil: Approximately 3 to 4 hours {17}.
Cycloguanil: Approximately 1 hour {10}.
Peak plasma concentration
Following an oral 200-mg dose:
Proguanil: Approximately 140 nanograms per mL {10}.
Cycloguanil: Approximately 75 nanograms per mL {10}.
Elimination:
Renal—40 to 60% of the proguanil is excreted in the urine {07} {13}, of which 60% is unchanged drug and 30% is the active metabolite cycloguanil {07}.
Fecal—About 10% {13}.
Precautions to Consider
Pregnancy/Reproduction
Pregnancy—
Note: Malaria in pregnant women results in a higher mortality rate and greater morbidity than in other adults {06} {09}. Therefore, pregnant women should avoid traveling to areas where chloroquine-resistant Plasmodium falciparum malaria is endemic {03}. However, because the risks of malaria in pregnancy may far outweigh any harmful effects of chemoprophylaxis {09}, an appropriate antimalarial regimen may be considered for prophylactic use in women who are pregnant or likely to become pregnant when exposure to chloroquine-resistant P. falciparum is unavoidable {09}.
Problems in humans have not been documented {07}. Proguanil has been widely used for more than 30 years and has been shown to be safe for use in pregnancy {11} {16}. Folate supplements, however, are recommended with use of proguanil during pregnancy because proguanil, as a folate antagonist, tends to deplete folate and may cause or accentuate anemia in pregnancy {11}.
Breast-feeding
Proguanil is distributed into breast milk. However, problems in humans have not been documented. The amount of proguanil distributed is insufficient to provide any prophylactic benefit to the infant against malaria. Therefore, a separate chemoprophylaxis may be required for the nursing infant {10} {14}.
Pediatrics
Note: Children of any age can contract malaria {01}. Consequently, the indications for prophylaxis are identical to those described for adults {01}. Mefloquine may be considered for use in children when travel to areas with chloroquine-resistant P. falciparum is unavoidable {01}.
Children who cannot take mefloquine or doxycycline can be given chloroquine for prophylaxis in chloroquine-sensitive areas {06} {08}. The combination of chloroquine and proguanil for sub-Saharan Africa has lower efficacy {08}. Children should avoid travel to areas with chloroquine-resistant P. falciparum malaria unless they can take a highly effective antimalarial agent, such as mefloquine, doxcycline, or primaquine {06} {08}. Primaquine is safe and highly effective in children provided that their glucose-6-phosphate dehydrogensae (G6PD) level is normal {08}.
Appropriate studies on the relationship of age to the effects of proguanil have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date.
Geriatrics
Note: There are no special dosage recommendations for the elderly; however, it may be advisable to monitor elderly patients so that optimum dosage can be individually determined {07}.
Appropriate studies on the relationship of age to the effects of proguanil 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
Hypersensitivity to proguanil{07}
» Renal failure, severe (impaired elimination may result in accumulation of proguanil and an increased incidence of side effects {11}; use when renal failure is present has been associated with blood dyscrasias such as pancytopenia and megaloblastic anemia {07} {11})
Side/Adverse Effects
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 rare
Hypersensitivity (skin rash or itching)
{07}{10}{14}
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Anorexia (lack of appetite)
gastric intolerance, mild (diarrhea; nausea; vomiting)—usually subsides as treatment continues{10}{14}
headache{15}
stomatitis (mouth sores or ulcers{10}{14})
Those not indicating need for medical attention
Incidence less frequent or rare
Alopecia, reversible {10}{14}(temporary hair loss)
Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).
Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
Epigastric discomfort (abdominal or stomach pain)
hematuria {07}(blood in urine; lower back pain; pain or burning while urinating)
renal irritation (pain or burning while urinating){10}{16}
vomiting {07}
Treatment of overdose
Because there is no specific antidote for proguanil overdose, treatment should include the following {10}:
Specific treatment:
Symptomatic treatment may be given.
Supportive care:
Supportive measures necessary for maintaining the vital functions of the patient may be administered. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Proguanil (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Hypersensitivity to proguanil
Pregnancy—Folate supplements should be taken by pregnant women receiving proguanil
Breast-feeding—Proguanil is distributed into breast milk
Other medical problems, especially severe renal failure
Proper use of this medication
Taking medication with water after meals to minimize adverse effects
Crushing the tablet and mixing it with milk, honey, or jam when giving to young children
» Taking the medication at least 24 hours before arrival in a malarious area, then daily while staying in the malarious area; continuing to take medication daily for 6 weeks after leaving the malarious area
» Compliance with full course of therapy
» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses; intermittent dosing may result in less adequate protection
» Proper storage
Precautions while using this medication
Personal protection measures to prevent malaria such as
Remaining in air-conditioned or well-screened rooms to reduce human-mosquito contact
Sleeping under mosquito netting; preferably impregnated with pyrethrum-containing insecticide
Wearing suitable clothing (long-sleeved shirt and long trousers) to protect arms and legs when mosquitoes are out
Applying mosquito repellents containing N,N–diethyl- m-toluamide [DEET]) to uncovered areas of skin when mosquitoes are out
Using a pyrethrum-containing flying insect spray to kill mosquitoes
» Checking with physician if fever or “flu-like” symptoms develop during travel or within a year (particularly within the first 2 months) after leaving the malarious area
Side/adverse effects
Signs of potential side effects, especially hypersensitivity
General Dosing Information
Proguanil should be taken with water after meals at the same time each day {07}. For young children, proguanil tablets should be crushed and mixed with milk, honey, or jam {07}. Nonimmune persons entering a malarious region should begin treatment 24 hours before arrival {07}. A daily dose of proguanil should be taken continuously for 6 weeks after leaving the area {07}.
Antimalarial chemoprophylaxis should be recommended depending on the estimated risk of infection {02}. Chloroquine alone should be used only in areas with chloroquine-sensitive Plasmodium falciparum malaria {02}. For travel to areas of risk where chloroquine-resistant P. falciparum exists, mefloquine alone should be used {01}.
Persons who travel to areas where drug-resistant P. falciparum is endemic and for whom mefloquine is not recommended should use an alternative regimen, as follows: • Doxycycline alone taken daily is an alternative regimen for travelers who cannot tolerate mefloquine or for whom mefloquine is not recommended {01} {04}. Doxycycline is as effective as mefloquine for travel to most malarious areas {01}. It is the only available effective prophylactic agent for travelers to malaria-endemic areas of Thailand bordering Myanmar and Cambodia {01}.
• Chloroquine alone taken weekly is recommended only for those travelers to areas with drug-resistant P. falciparum who cannot use mefloquine or doxcycycline {01}. Chloroquine with daily proguanil may be more effective than chloroquine alone {01}. However, the combination of chloroquine and proguanil for sub-Saharan Africa has lower efficacy {08}. Travelers should avoid areas with chloroquine-resistant P. falciparum malaria unless they can take a highly effective antimalarial agent, such as mefloquine, doxycycline, or primaquine {06} {08}.
Primaquine in an adult dose of 30 mg per day (two tablets daily) has been shown to provide excellent protection against P. falciparum and Plasmodium vivax malaria in Indonesia, Kenya, and Colombia {08}. If primaquine is considered for treatment, glucose-6-phosphate dehydrogenase (G6PD) level should be determined prior to primaquine administration {08}.
Oral Dosage Forms
PROGUANIL HYDROCHLORIDE TABLETS
Usual adult and adolescent dose
Malaria (prophylaxis)
Oral, 100 mg a day {07}. In highly endemic areas this dose may be safely increased to 200 mg a day {07}.
Note: For all countries with chloroquine-resistant malaria the dose of proguanil should be increased to 200 mg a day given with 300 mg chloroquine base (approximately equivalent to 500 mg chloroquine phosphate) once a week {07}.
Usual pediatric dose
Malaria (prophylaxis)
Infants and children up to 1 year of age: Oral, 25 mg a day {07}.
Children 1 to 4 years of age: Oral, 50 mg a day {07}.
Children 5 to 8 years of age: Oral, 75 mg a day {07}.
Children 9 to 12 years of age: Oral, 100 mg a day {07}.
Children 12 years of age and over: See Usual adult and adolescent dose {07}.
Strength(s) usually available
U.S.—
Not commercially available.
Canada—
100 mg (Rx) [Paludrine]{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, unless otherwise specified by manufacturer. Protect from light {07}.
Auxiliary labeling:
• Take with food {07}.
• Continue medication for full time of treatment {07}.
Revised: 08/18/2000
References
- Centers for Disease Control and Prevention (CDC). Malaria. In: CDC, Health information for international travel 1996-7. Atlanta: U.S. Department of Health and Human Services; 1997. p. 128-37.
- Lobel HO, Kozarsky PE. Update on prevention of malaria for travelers. JAMA 1997; 278(21): 1767-71.
- Pannel comment, 2/99.
- Bradly DJ, Warhurst DC. Malaria prophylaxis: guidelines for travelers from Britain. BMJ 1995; 310: 709-11.
- Weiss WR, Oloo AJ, Johnson A, et al. Daily primaquine is effective for prophylaxis against falciparum malaria in Kenya: comparison with mefloquine, doxycycline, and chloroquine plus proguanil. J Infect Dis 1995; 171: 1569-75.
- American Academy of Pediatrics. Malaria. In: Peter G, editor. 1997 Red book: report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics; 1997. p. 335-42.
- Paludrine (Wyeth-Ayerst). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association; 1998. p. 1262-3.
- Pannel comment, 2/99.
- Smoak BL, Writer JV, Keep LW, et al. The effects of inadvertent exposure of mefloquine chemoprophylaxis on pregnancy outcomes and infants of US army servicewomen. J Infect Dis 1997; 176: 831-3.
- Walker G, editor. ABPI Data sheet compendium. London: Datapharm Publications Ltd; 1993-94. p. 657.
- Kenyon J, editor. Minimizing the adverse effects of antimalarials. Drugs and Therapy Perspectives 1993; 2(5): 14-6.
- Helsby NA, Edwards G, Breckenridge AM, et al. The multiple dose pharmacokinetics of proguanil. Br J Clin Pharmacol 1993; 35: 653-6.
- White NJ. Clinical pharmacokinetics of antimalarial drugs. Clin Pharm 1985; 10: 187-215.
- Keystone JS. Prevention of malaria. Drugs 1990; 39(3): 337-54.
- Nevill CG, Watkins WM, Carter JY, et al. Comparison of mosquito nets, proguanil hydrochloride, and placebo to prevent malaria. Br Med J 1988; 297(6645): 401-3.
- McLarty DG, Webber RH, Jaatinen M, et al. Chemoprophylaxis of malaria in non-immune residents in Dar es Salaam, Tanzania. Lancet 1984; 2(8404): 656-9.
- Watkins WM, Mberu EK, Neville CG, et al. Variability in the metabolism of proguanil to the active metabolite cycloguanil in healthy Kenyan adults. Trans R Soc Trop Med Hyg 1990; 84(4): 492-5.
- Dollery C, editor. Therapeutic drugs. Edinburgh: Churchill Livingstone; 1991. p. 247-51.
