VA Class:AP101

AHFS Class:

• Antimalarials 8:30.08

Generic Name(s):

• Primaquine Phosphate

Primaquine, an 8-aminoquinoline derivative, is an antimalarial agent.100,140

Malaria

Treatment of Malaria

Primaquine phosphate is used in conjunction with other appropriate antimalarial agents for the treatment of malaria caused by Plasmodium vivax 100,134,140,143,144 or P. ovale †.134,140,143,144 Primaquine is used to provide a radical cure to prevent relapse of P. vivax 100,140,143,144 or P. ovale malaria.140,143,144 Although primaquine eradicates hypnozoites that can remain dormant in the liver and cause delayed attacks and relapse after treatment with other antimalarials,140,143 it has low activity against asexual erythrocytic forms of Plasmodium .140 Therefore, a regimen that includes a blood schizonticidal agent (e.g., chloroquine [or hydroxychloroquine]; quinine sulfate with doxycycline or tetracycline; mefloquine; fixed combination of atovaquone and proguanil hydrochloride [atovaquone/proguanil], fixed combination of artemether and lumefantrine [artemether/lumefantrine]) is always used in conjunction with primaquine for the treatment of P. ovale or P. vivax malaria.143,144

The US Centers for Disease Control and Prevention (CDC) states that a regimen of chloroquine (or hydroxychloroquine) given in conjunction with primaquine remains an effective choice for treatment of uncomplicated P. vivax or P. ovale malaria, except for infections acquired in areas with a high prevalence of chloroquine-resistant P. vivax (Papua New Guinea, Indonesia).143 For treatment of uncomplicated malaria acquired in Papua New Guinea or Indonesia or known to be caused by chloroquine-resistant P. vivax , CDC recommends a regimen of quinine sulfate and doxycycline (or tetracycline) given in conjunction with primaquine, atovaquone/proguanil given in conjunction with primaquine, or mefloquine given in conjunction with primaquine.143,144

Assistance with diagnosis or treatment of malaria is available by contacting the CDC Malaria Hotline at 770-488-7788 or 855-856-4713 from 9:00 a.m. to 5:00 p.m. Eastern Standard Time or the CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays.143,144

Prevention of Malaria

Primaquine is used for presumptive antirelapse therapy (terminal prophylaxis) to prevent delayed primary attacks or relapse of P. vivax or P. ovale † malaria in travelers returning from areas where these Plasmodium are endemic.100,115,134 Since most malarious areas of the world (except the Caribbean) have at least one species of relapsing malaria, travelers to these areas have some risk of acquiring either P. vivax or P. ovale , although the actual risk for an individual traveler is difficult to define.115 CDC states that primaquine presumptive antirelapse therapy generally is indicated only for individuals who have had prolonged exposure to malaria-endemic areas (e.g., missionaries, military personnel, Peace Corps volunteers).115

Primaquine also can be used for primary prophylaxis of malaria†.115,133,134,135 Although other antimalarials usually are recommended for prevention of malaria in travelers to malarious areas (chloroquine [or hydroxychloroquine], atovaquone/proguanil, doxycycline, mefloquine), primaquine may be an option when the other drugs cannot be used and is a good choice when travelers will be in areas with a high incidence of P. vivax malaria.115,134 For short-term travelers, primaquine offers the advantages of a short once-daily regimen; for last-minute travelers, primaquine prophylaxis can be started 1-2 days prior to travel unlike some other antimalarials that must be started 1-2 weeks before travel (chloroquine, hydroxychloroquine, mefloquine).115 If primaquine is used for primary prophylaxis, primaquine presumptive antirelapse therapy is not needed.115

Information on the risk of malaria transmission in specific countries, information on mosquito avoidance measures, recommendations regarding whether chemoprophylaxis of malaria is indicated, and information on the choice of antimalarials for prevention of malaria are available from CDC at [Web] and [Web].115

Pneumocystis jirovecii Pneumonia

Treatment of Pneumocystis jirovecii Pneumonia

Primaquine is used in conjunction with clindamycin for the treatment of Pneumocystis jirovecii (formerly Pneumocystis carinii ) pneumonia† (PCP) in individuals with human immunodeficiency virus (HIV) infection.109,110,112,113,114,116,117,119,122,123,124,130,134,440,441 Primaquine is designated an orphan drug by FDA for use in conjunction with clindamycin for the treatment of PCP associated with acquired immunodeficiency syndrome (AIDS).132

Co-trimoxazole is the drug of choice for the treatment of mild, moderate, or severe PCP, including PCP in HIV-infected adults, adolescents, and children.134,440,441 CDC, National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) state that a regimen of primaquine and clindamycin is an alternative for the treatment of mild, moderate, or severe PCP in HIV-infected adults and adolescents who have had an inadequate response to co-trimoxazole or when co-trimoxazole is contraindicated or cannot be used.440 Although data are not available regarding use in children, CDC, NIH, IDSA, and American Academy of Pediatrics (AAP) state that a regimen of primaquine and clindamycin also can be considered an alternative to co-trimoxazole for the treatment of PCP in HIV-infected children based on data in adults.441

Results of clinical studies indicate that oral primaquine (15 or 30 mg daily) in conjunction with clindamycin administered IV (1.8-3.6 g given in 3 or 4 divided doses daily) or orally (1.2-3.6 g in 3 or 4 divided doses daily [in some cases oral clindamycin was administered after initial IV administration]) for a total 21 days of therapy is effective for the treatment of PCP in HIV-infected adults.109,110,112,113,114,116,117,122,130 Most patients exhibit clinical improvement within 2-7 days,110,112,113 and the combination generally appears to be well tolerated.110,112,117,122,123

Prevention of Pneumocystis jirovecii Pneumonia

Co-trimoxazole is the drug of choice for prevention of initial episodes (primary prophylaxis) of PCP in HIV-infected adults, adolescents, and children.440,441 CDC, NIH, and IDSA state that a regimen of primaquine and clindamycin is not recommended for primary PCP prophylaxis because data are insufficient to determine efficacy of the regimen for such prophylaxis.440

Although a regimen of primaquine and clindamycin has been used as an alternative to co-trimoxazole for long-term suppressive or chronic maintenance therapy (secondary prophylaxis) of PCP† in a limited number of AIDS patients,114,123 this regimen is not included in CDC, NIH, IDSA, and AAP recommendations for secondary prophylaxis of PCP in HIV-infected adults, adolescents, or children.440,441 Co-trimoxazole is the drug of choice for secondary PCP prophylaxis in HIV-infected adults, adolescents, and children.440,441

Administration

Primaquine phosphate is administered orally.100 The drug usually is administered once daily as a single dose at the same time each day.115

Primaquine should be taken with food to decrease adverse GI effects (e.g., nausea, abdominal pain).115,134,161

Prior to initiation of primaquine, appropriate laboratory tests should be performed to rule out glucose-6-phosphate dehydrogenase (G6PD) deficiency.100,115,143,440 Primaquine is contraindicated in individuals with severe G6PD deficiency.100,115 A decision to use primaquine in individuals with mild to moderate G6PD deficiency or when G6PD status is unknown and G6PD testing is not available must be based on an assessment of the risks and benefits of the drug.100 (See Hemolytic Anemia and G6PD Deficiency under Cautions: Precautions and Contraindications.)

Dosage

Dosage of primaquine phosphate usually is expressed in terms of primaquine.100,134,144

Each 26.3-mg tablet of primaquine phosphate contains 15 mg of primaquine.100

Treatment of Malaria

Radical Cure of P. ovale or P. vivax Malaria

When primaquine is used in conjunction with other appropriate antimalarial agents for the treatment of malaria caused by Plasmodium vivax or P. ovale to provide a radical cure and prevent delayed attacks or relapse, the US Centers for Disease Control and Prevention (CDC) and other experts recommend that adults receive 30 mg of primaquine (52.6 mg of primaquine phosphate) once daily for 14 days115,134,144 and children receive 0.5 mg/kg (0.8 mg/kg of primaquine phosphate) once daily for 14 days.115,134,144 Pediatric dosage should not exceed the usual adult dosage.115,144 Although the manufacturer recommends 15 mg of primaquine (26.3 mg of primaquine phosphate) once daily for 14 days,100 this dosage may be inadequate if malaria is acquired in Southeast Asia (particularly Indonesia and Oceania).140

As an alternative to the daily primaquine regimen or if the drug is used to provide a radical cure and prevent delayed attacks or relapse of P. vivax or P. ovale malaria in patients with borderline G6PD deficiency, CDC recommends 45 mg of primaquine (79 mg of primaquine phosphate) once weekly for 8 weeks.144 However, consultation with an expert in infectious disease and/or tropical medicine is recommended if this alternative regimen is considered for individuals with borderline G6PD deficiency.144 (See Hemolytic Anemia and G6PD Deficiency under Cautions: Precautions and Contraindications.)

Prevention of Malaria

Presumptive Antirelapse Therapy (Terminal Prophylaxis) of P. ovale or P. vivax Malaria

When primaquine is indicated for presumptive antirelapse therapy (terminal prophylaxis) to prevent delayed primary attacks or relapse of P. ovale or P. vivax malaria in individuals exposed to malaria in areas where P. ovale or P. vivax is endemic, CDC and other experts recommend that adults receive 30 mg of primaquine (52.6 mg of primaquine phosphate) once daily for 14 days and children receive 0.5 mg/kg (0.8 mg/kg of primaquine phosphate) once daily for 14 days115,134 given after the traveler has left the malarious area.115 Although the manufacturer recommends 15 mg of primaquine (26.3 mg of primaquine phosphate) once daily for 14 days,100 this dosage may be inadequate in areas with P. vivax relatively resistant to primaquine (e.g., Oceania).140

When primaquine presumptive antirelapse therapy is indicated in individuals who received primary prophylaxis with chloroquine, hydroxychloroquine, doxycycline, or mefloquine, primaquine should be given during the final 2 weeks of primary prophylaxis or, if that is not feasible, it should be given for 14 days after primary prophylaxis is discontinued.115

When presumptive antirelapse therapy with primaquine is indicated in individuals who received primary prophylaxis with the fixed combination of atovaquone and proguanil hydrochloride (atovaquone/proguanil), primaquine may be given during the final 7 days of primary prophylaxis and then for an additional 7 days or, if that is not feasible, it should be given for 14 days after primary prophylaxis is discontinued.115

Primary Prophylaxis of Malaria (Including Chloroquine-resistant Malaria)

If primaquine is used for primary prophylaxis of malaria†, adults should receive 30 mg of primaquine (52.6 mg of primaquine phosphate) once daily and children should receive 0.5 mg/kg (0.8 mg/kg of primaquine phosphate) once daily.115,134 Pediatric dosage should not exceed the usual adult dosage.115

When used for primary prophylaxis, CDC recommends that primaquine be initiated 1-2 days prior to entering a malarious areas and continued during the stay and for 7 days after leaving the area.115

Pneumocystis jirovecii Pneumonia

If a regimen of primaquine and clindamycin is used as an alternative for the treatment of mild to moderate Pneumocystis jirovecii pneumonia† (PCP), CDC, National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) recommend that adults and adolescents receive oral primaquine in a dosage of 30 mg once daily for 21 days in conjunction with oral clindamycin (450 mg every 6 hours or 600 mg every 8 hours) given for 21 days.440

If a regimen of primaquine and clindamycin is used as an alternative for the treatment of moderate to severe PCP†, CDC, NIH, and IDSA recommend that adults and adolescents receive oral primaquine in a dosage of 30 mg once daily for 21 days in conjunction with IV clindamycin (600 mg every 6 hours or 900 mg every 8 hours) or oral clindamycin (450 mg every 6 hours or 600 mg every 8 hours) given for 21 days.440

Although data regarding use in children are not available, if a regimen of primaquine and clindamycin is used as an alternative for the treatment of PCP in pediatric patients, some clinicians recommend that oral primaquine be given in a dosage of 0.3 mg/kg once daily (up to 30 mg daily) for 21 days in conjunction with IV clindamycin (10 mg/kg [up to 600 mg] every 6 hours) or oral clindamycin (10 mg/kg [up to 300-450 mg] every 6 hours) given for 21 days.441

Hematologic Effects

Hemolytic reactions (moderate to severe) may occur if primaquine is administered to individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency100,115,140 or individuals with a family or personal history of favism.100 The severity of hemolytic anemia depends on the dose of the drug and specific genetic defect in the individual with G6PD deficiency.100,140 Hemolytic reactions can be fatal.115 (See Hemolytic Anemia and G6PD Deficiency under Cautions: Precautions and Contraindications.)

Areas with high prevalence of G6PD deficiency include Africa, Southern Europe, Mediterranean region, Middle East, Southeast Asia, and Oceania.100 Individuals from these regions have a greater tendency to develop hemolytic anemia while receiving primaquine due to congenital G6PD deficiency.100

Methemoglobinemia has been reported when primaquine was used in individuals with nicotinamide adenine dinucleotide (NADH) methemoglobin reductase deficiency.100

Mild anemia and leukopenia100 have been reported with primaquine, and agranulocytosis has been reported rarely.

GI Effects

Nausea,100 vomiting,100 epigastric distress,100 and abdominal cramps100 have been reported in patients receiving primaquine.100 The incidence and severity of adverse GI effects appear to be dose related.140 Administration with food may decrease adverse GI effects.115,134,140

Cardiac Effects

Cardiac arrhythmia100,140 and prolonged QT interval100 have been reported in patients receiving primaquine.

Other Adverse Effects

Rash100 and pruritus100,140 have been reported in patients receiving primaquine.

Dizziness,100 headache,140 and visual disturbances140 have been reported with primaquine.

Precautions and Contraindications

Primaquine is contraindicated in individuals with severe G6PD deficiency.100 (See Hemolytic Anemia and G6PD Deficiency under Cautions: Precautions and Contraindications.)

Primaquine is contraindicated in pregnant women.100 (See Pregnancy under Cautions: Pregnancy and Lactation.)

Primaquine is contraindicated in acutely ill patients who have systemic disease manifested by a tendency to develop granulocytopenia (e.g., rheumatoid arthritis, lupus erythematosus).100 Primaquine also is contraindicated in patients receiving other potentially hemolytic drugs or agents capable of depressing the myeloid elements of bone marrow.100

Hemolytic Anemia and G6PD Deficiency

Because of the risk of potentially fatal hemolysis if primaquine is used in patients with G6PD deficiency, appropriate laboratory testing should be performed to rule out G6PD deficiency before primaquine is initiated.100,115,143

Primaquine should not be prescribed for individuals with severe G6PD deficiency.100

In individuals with mild to moderate G6PD deficiency, a decision to prescribe primaquine must be based on an assessment of the risks and benefits of the drug.100 If primaquine is considered for such individuals, baseline hematocrit and hemoglobin concentration must be evaluated before treatment and hematologic parameters must be closely monitored during treatment (e.g., at days 3 and 8).100

If G6PD status is unknown and G6PD testing is unavailable, a decision to prescribe primaquine must be based on an assessment of the risks and benefits of the drug.100 Risk factors for G6PD deficiency or favism must be assessed.100 If primaquine is considered for individuals with unknown G6PD status, baseline hematocrit and hemoglobin concentration must be evaluated before treatment and hematologic parameters must be closely monitored during treatment (e.g., at days 3 and 8).100

Because of limitations of currently available G6PD testing, clinicians should be aware that a residual risk of hemolysis exists despite such testing.100 Routine hematologic monitoring (particularly blood cell counts and hemoglobin concentrations) is advisable during primaquine therapy, even in G6PD-normal individuals.100

Because adverse hematologic effects, including anemia, methemoglobinemia, and leukopenia, have occurred following administration of large doses of primaquine, the usual dosage of the drug should not be exceeded.100

If primaquine is administered to individuals who have shown a previous idiosyncratic reaction to primaquine (as manifested by hemolytic anemia, methemoglobinemia, or leukopenia) or to individuals with a personal or family history of hemolytic anemia or NADH methemoglobin reductase deficiency, the individual should be monitored closely for tolerance to the drug.100

Primaquine should be discontinued immediately if signs suggesting hemolytic anemia occur (e.g., darkening of the urine, marked decrease in hemoglobin concentrations or erythrocyte count) or if a sudden decrease in leukocyte count occurs.100

Adequate medical support and follow-up to manage hemolytic risk should be available for all patients receiving primaquine.100

Prolongation of QT Interval

Because of the potential for QT interval prolongation, ECG should be monitored if primaquine is used in patients with cardiac disease, long QT syndrome, history of ventricular arrhythmias, uncorrected hypokalemia and/or hypomagnesemia, or bradycardia (less than 50 beats per minute) and whenever primaquine is used concomitantly with drugs that prolong the QT interval.100

Females and Males of Reproductive Potential

Sexually active females of reproductive potential should be tested for pregnancy prior to initiation of primaquine and warned to avoid pregnancy during and after treatment with the drug until an ongoing ovulatory cycle has been completed.100 (See Pregnancy under Cautions: Pregnancy and Lactation.)

Sexually active males receiving primaquine whose partners may become pregnant should be warned to use a condom during treatment with the drug and for 3 months after the drug is discontinued.100 (See Pregnancy under Cautions: Pregnancy and Lactation.)

Geriatric Precautions

Clinical studies of primaquine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.100 While other clinical experience has not revealed age-related differences in response, dosage for geriatric patients should be selected cautiously, usually initiating therapy at the low end of the dosage range.100 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.100

Mutagenicity and Carcinogenicity

Data from in vitro and animal studies indicate that primaquine is a weak genotoxic agent that can elicit gene mutations, chromosomal damage, and DNA strand breaks.100 Positive results were obtained when primaquine was tested in vitro (reverse gene mutation bacterial assays [Ames test]) and in vivo in rodents (mouse bone marrow cell sister chromatid exchange, mouse bone marrow cell chromosome abnormality, rat DNA strand breaks in multiple organs).100 These data suggest a human risk for genotoxicity with primaquine.100

The carcinogenic potential of primaquine has not been evaluated.100

Pregnancy and Lactation

Pregnancy

Primaquine is contraindicated in pregnant women.100,115,134,143 Safe use of the drug during pregnancy has not been established.100 In addition, transplacental transfer of the drug to a G6PD-deficient fetus potentially could cause hemolytic anemia in utero.115

In animal reproduction studies, primaquine was associated with teratogenicity and injury to embryos and developing fetuses.100 When oral primaquine was administered to rats on gestation days 6-15 at dosages of 10.3, 30.8, and 61.5 mg/kg daily (approximately 7, 20, and 40 times the human dosage based on body surface area comparison), the high dosage resulted in death of pregnant females in almost all cases and lower dosages were associated with maternal toxicity.100 At cesarean section, embryo resorption, decreased fetal survival rate and body size, internal abnormalities (e.g., hydrocephalia, heterotaxia), and increased skeletal variations were observed with the middle dosa 100 there were no fetal abnormalities at the lower dosage level.100 In a study in Sprague Dawley rats, oral primaquine was given at dosages of 0.57, 5.7, 11.4, and 34 mg/kg daily (approximately 0.4, 4, 7, and 22 times the human dosage based on body surface area comparison) on gestation days 8-16 or 57 mg/kg (more than 37 times the human dosage based on body surface area comparison) was administered once on gestation day 13.100 Fatalities occurred in 1 of 7 pregnant rats that received the dosage of 34 mg/kg daily and 4 of 6 pregnant rats that received a single dose of 57 mg/kg.100 Primaquine-associated teratogenic malformations (including cleft palate and small chin) were observed in 4 of 54 fetuses in the rats that received a single dose of 57 mg/kg.100

Patients must be informed of the potential for adverse genetic and reproductive effects associated with primaquine.100

Sexually active females of reproductive potential should undergo pregnancy testing prior to initiation of primaquine treatment.100 Such women should be advised to use effective contraception (i.e., methods with pregnancy rates less than 1%) during primaquine therapy and to continue to use effective contraception after the drug is discontinued until an ongoing ovulatory cycle has been completed (up to next menses).100 Sexually active males whose partners may become pregnant should be advised to use a condom during primaquine treatment and for 3 months after the drug is discontinued.100

If a pregnant woman requires treatment of Plasmodium vivax or P. ovale malaria, CDC recommends that oral chloroquine (300 mg once weekly) be given for prophylaxis for the duration of the pregnancy and that use of primaquine (to provide a radical cure) be deferred until after delivery and after the women has been tested and determined not to have G6PD deficiency.143,144

Lactation

Primaquine is distributed into milk in low concentrations.140 Because of the potential for serious adverse reactions in nursing infants from primaquine, the manufacturer states that a decision should be made to discontinue nursing or the drug, taking into account the importance of the drug to the mother.100

CDC recommends that primaquine not be used in nursing women unless the woman and breast-fed infant have been determined not to have G6PD deficiency.115

Drugs that Prolong QT Interval

If primaquine is used concomitantly with other drugs that prolong the QT interval, caution is advised and ECG should be monitored.100

Quinacrine

Because quinacrine (not commercially available in the US) appears to potentiate the toxicity of antimalarial agents that are structurally related to primaquine, concomitant use of quinacrine and primaquine is contraindicated and primaquine should not be administered to patients who have recently received quinacrine.100

Acute Toxicity

Symptoms of overdosage of primaquine include abdominal cramps, vomiting, burning epigastric distress, CNS disturbances, cardiovascular disturbances (e.g., cardiac arrhythmia, QT interval prolongation), cyanosis, methemoglobinemia, moderate leukocytosis or leukopenia, and anemia.100 The most striking symptoms are granulocytopenia and acute hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency.100 Acute hemolysis occurs, but patients recover completely if the drug is discontinued.100

Mechanism of Action

The exact mechanism of antimalarial activity of primaquine has not been determined,140 but the drug appears to cause morphologic and physiologic changes in plasmodial mitochondria.140 In the treatment of malaria caused by Plasmodium vivax , primaquine eliminates tissue (exoerythrocytic) infection thereby preventing development of blood (erythrocytic) forms of the parasite that are responsible for relapse of P. vivax malaria.100

The mechanism of action of primaquine against Pneumocystis jirovecii (formerly Pneumocystis carinii ) is unknown.140

Spectrum

Primaquine is a tissue schizonticidal agent and is active against the preerythrocytic and exoerythrocytic forms of Plasmodium falciparum , P. malariae , P. ovale , and P. vivax .140 Primaquine also is gametocytocidal against the gametocytes of P. falciparum 100,140 and other Plasmodium .140

Primaquine has only low activity against erythrocytic forms of Plasmodium .140

Resistance

Primaquine-resistant and primaquine-tolerant Plasmodium vivax have been reported.140

Pharmacokinetics

Absorption

Primaquine is rapidly and well absorbed from the GI tract.140 Following oral administration, peak plasma concentrations of the drug generally are attained within 2-4 hours.140 In healthy adults, mean peak plasma concentrations of primaquine were 53, 104, or 176 ng/mL after a single dose of 15, 30, or 45 mg, respectively.140

The pharmacokinetics of primaquine are altered during malaria infection and peak plasma concentrations may be higher in adults with malaria compared with healthy adults.140

In healthy adults, administration of primaquine with food (approximately 28 g of fat) resulted in a 1.23-fold increase in peak plasma concentrations and a 1.12-fold increase in the area under the plasma concentration-time curve (AUC) of the drug compared with administration in the fasting state.140

Distribution

Although specific information on the distribution of primaquine into body tissues and fluids is not available, the drug appears to be widely distributed in the body following oral administration.101 Primaquine has an apparent volume of distribution of about 150-250 L in healthy adults.101

Low concentrations of primaquine are distributed into milk.140

Elimination

Primaquine has a plasma half-life of 4-7 hours.115,140

Primaquine is rapidly metabolized in the liver and only a small amount of the drug is excreted unchanged in urine.101,140 The principal metabolite of primaquine is carboxyprimaquine, and plasma concentrations of the metabolite greatly exceed those of unchanged primaquine.101,140

Chemistry and Stability

Chemistry

Primaquine is a synthetic antimalarial agent that is an 8-aminoquinoline derivative.100,140 Primaquine is commercially available as the phosphate salt.100 Primaquine phosphate occurs as an orange-red, odorless, crystalline powder with a bitter taste and is soluble in water.

Stability

Primaquine phosphate tablets should be stored in tight, light-resistant containers at 25°C, but may be exposed to 15-30°C.100

100. Sanofi-Aventis. Primaquine phosphate tablets, film-coated prescribing information. Bridgewater, NJ; 2017 Jul.

101. White NJ. Clinical pharmacokinetics of antimalarial drugs. Clin Pharmacokinet . 1985; 10:187-215. [PubMed 3893840]

109. Ruf B, Pohle HD. Clindamycin/primaquine for Pneumocystis carinii pneumonia. Lancet . 1989; 2:626-7. [PubMed 2570324]

110. Toma E, Fournier D, Poisson M et al. Clindamycin with primaquine for Pneumocystis carinii pneumonia. Lancet . 1989; 1:1046-8. [PubMed 2566001]

112. Black JR, Feinberg J, Murphy RL et al. Clindamycin and primaquine as primary treatment for mild and moderately severe Pneumocystis carinii pneumonia in patients with AIDS. Eur J Clin Microbiol Infect Dis . 1991; 10:204-7. [PubMed 2060532]

113. Joseph P, Marzouk J, Phelps R. Oral clindamycin plus primaquine for Pneumocystis carinii pneumonia. Sixth International Conference on AIDS. 1990:373. Abstract No. 2078.

114. Kay R, DuBois RE. Clindamycin/primaquine therapy and secondary prophylaxis against Pneumocystis carinii pneumonia in patients with AIDS. South Med J . 1990; 83:403-4. [PubMed 2321069]

115. Centers for Disease Control and Prevention. CDC health information for international travel, 2018. Atlanta, GA: US Department of Health and Human Services. Updates may be available at CDC website. [Web]

116. Ruf B, Rohde I, Pohle HD. Efficacy of clindamycin/primaquine versus trimethoprim/sulfamethoxazole in primary treatment of Pneumocystis carinii pneumonia . Eur J Clin Microbiol Infect Dis . 1991; 10:207-10. [PubMed 2060533]

117. Toma E. Clindamycin/primaquine for treatment of Pneumocystis carinii pneumonia in AIDS. Eur J Clin Microbiol Infect Dis . 1991; 10:210-3. [PubMed 2060534]

119. Reviewers' comments (personal observations).

122. Vildé JL, Remington JS. Role of clindamycin with or without another agent for the treatment of pneumocystosis in patients with AIDS. J Infect Dis . 1992; 166:694-5. [PubMed 1500762]

123. Smith D, Gazzard B. Treatment and prophylaxis of Pneumocystis carinii pneumonia. Drugs . 1991; 42:628-39. [PubMed 1723365]

124. Noskin GA, Murphy RL, Black JR et al. Salvage therapy with clindamycin/primaquine for Pneumocystis carinii pneumonia. Clin Infect Dis . 1992; 14:183-8. [PubMed 1571426]

128. Wyler DJ. Malaria: overview and update. Clin Infect Dis . 1993; 16:449-58. [PubMed 8513046]

130. Lane HC, Laughon BE, Falloon J et al. Recent advances in the management of AIDS-related opportunistic infections. Ann Intern Med . 1994; 120:945-55. [PubMed 7909657]

132. Food and Drug Administration. List of orphan designations and approvals. From FDA web site. [Web]

133. Fryauff DJ, Baird JK, Basri H et al. Randomised placebo-controlled trial of primaquine for prophylaxis of falciparum and vivax malaria. Lancet . 1995; 346:1190-3. [PubMed 7475658]

134. . Drugs for parasitic infections. Treat Guidel Med Lett . 2013; 11:e1-31.

135. 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. [PubMed 7769294]

140. Edstein MD, Shanks GD. Primaquine. In: Grayson ML, ed. Kucers' the use of antibiotics: a clinical review of antibacterial, antifungal, antiparasitic, and antiviral drugs. 7th ed. Boca Raton, FL: CRC Press; 2018: 3097-3109.

143. Centers for Disease Control and Prevention. CDC treatment guidelines: Treatment of malaria (guidelines for clinicians). 2013 Jul. From the CDC website. Accessed 2018 Mar 9. [Web]

144. Centers for Disease Control and Prevention. Guidelines for treatment of malaria in the United States (based on drugs currently available for use in the United States-updated July 1, 2013). From the CDC website. Accessed 2018 Mar 9. [Web]

440. Panel on Opportunistic Infection in HIV-infected Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Accessed March 8, 2018. Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]

441. Panel on Opportunistic Infection in HIV-exposed and HIV-infected children, US Department of Health and Human Services (HHS). Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children: recommendations from the National Institutes of Health, Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. Accessed March 8, 2018. Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]

161. World Health Organization (WHO). Guidelines for the treatment of malaria. 2nd edition. Geneva, Switzerland: World Health Organization; 2010. Updates may be available at WHO website. [Web]