Primaquine (Monograph)

Drug class: Antimalarials
VA class: AP101
CAS number: 63-45-6

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Introduction

Antimalarial; 8-aminoquinoline derivative.^{100 140}

Uses for Primaquine

Malaria

Treatment of malaria caused by Plasmodium vivax^{100 134 140 143 144} or P. ovale^{† [off-label]}.^{134 140 143 144} Provides a radical cure to prevent relapse of malaria caused by these Plasmodium.^{100 140 143 144} Has only low activity against asexual erythrocytic forms of Plasmodium;¹⁴⁰ a regimen that includes a blood schizonticidal agent (e.g., chloroquine [or hydroxychloroquine]; quinine with doxycycline or tetracycline; mefloquine; fixed-combination of atovaquone and proguanil [atovaquone/proguanil]; fixed combination of artemether and lumefantrine [artemether/lumefantrine]) is always used in conjunction with primaquine for treatment of P. ovale or P. vivax malaria.^{143 144}

Presumptive antirelapse therapy (terminal prophylaxis) in travelers who received a suitable antimalarial for prevention of malaria but are returning from areas where P. vivax or P. ovale is endemic.^{100 115 134} If primaquine not used for terminal prophylaxis in individuals who may have been exposed to P. ovale or P. vivax malaria, delayed primary attacks or relapse caused by these Plasmodium can occur.¹¹⁵

Prevention of malaria^{† [off-label]} (primary prophylaxis).^{115 134} Primaquine may be an option when other recommended antimalarials (choroquine [or hydroxychloroquine], atovaquone/proguanil, doxycycline, mefloquine) cannot be used for primary prophylaxis and is a good choice when travelers will be in areas with high incidence of P. vivax malaria.^{115 134} If primaquine is used for primary prophylaxis, primaquine presumptive antirelapse therapy is not needed.¹¹⁵

Assistance with diagnosis or treatment of malaria is available from 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 CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays.^{143 144}

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

Pneumocystis jirovecii Pneumonia

Treatment of Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia^{† [off-label]} (PCP); used in conjunction with clindamycin.^{109 110 112 113 114 116 117 119 122 123 124 130 134 440 441} Designated an orphan drug by FDA for use in conjunction with clindamycin for treatment of PCP associated with AIDS.¹³²

Co-trimoxazole is drug of choice for treatment of mild, moderate, or severe PCP, including PCP in HIV-infected adults, adolescents, and children.^{134 440 441} CDC, NIH, and IDSA state that a regimen of primaquine and clindamycin is an alternative for 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 not tolerated.⁴⁴⁰ Although data not available regarding use in children, CDC, NIH, IDSA, and AAP state that a regimen of primaquine and clindamycin also can be considered an alternative to co-trimoxazole for treatment of PCP in HIV-infected children based on data in adults.⁴⁴¹

Not recommended for prevention of initial episodes (primary prophylaxis) of PCP in HIV-infected individuals because data insufficient to determine efficacy;^{440 441} not included in recommendations for long-term suppressive or chronic maintenance therapy (secondary prophylaxis) of PCP.^{440 441} Co-trimoxazole is drug of choice for primary and secondary prophylaxis of PCP in HIV-infected adults, adolescents, and children.^{440 441}

Primaquine Dosage and Administration

General

• Prior to use, perform appropriate laboratory tests to rule out glucose-6-phosphate dehydrogenase (G6PD) deficiency.^{100 115 143 440} (See Hemolytic Anemia and G6PD Deficiency under Cautions.)

Administration

Oral Administration

Administer orally;¹⁰⁰ usually as a single daily dose at the same time each day.¹¹⁵

Take with food to decrease adverse GI effects (e.g., nausea, abdominal pain).^{115 134 161}

Dosage

Available as primaquine phosphate;¹⁰⁰ dosage usually expressed in terms of primaquine.^{100 134 144}

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

Pediatric Patients

Malaria

Radical Cure of P. ovale or P. vivax Malaria

Oral

0.5 mg/kg (0.8 mg/kg of primaquine phosphate) once daily for 14 days.^{115 134 144}

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

Oral

0.5 mg/kg (0.8 mg/kg of primaquine phosphate) once daily for 14 days^{115 134} given after leaving malarious area.¹¹⁵

Individuals who received primary prophylaxis with chloroquine, hydroxychloroquine, doxycycline, or mefloquine: Administer primaquine presumptive antirelapse therapy during final 2 weeks of primary prophylaxis or, if not feasible, administer for 14 days after primary prophylaxis discontinued.¹¹⁵

Individuals who received primary prophylaxis with atovaquone/proguanil: Administer primaquine presumptive antirelapse therapy during final 7 days of primary prophylaxis and then for an additional 7 days or, if not feasible, administer for 14 days after primary prophylaxis discontinued.¹¹⁵

Primary Prophylaxis of Malaria† [off-label]

Oral

0.5 mg/kg (0.8 mg/kg of primaquine phosphate) once daily.^{115 134}

Initiate prophylaxis 1–2 days prior to entering a malarious area and continue during stay and for 7 days after leaving the area.¹¹⁵

Pneumocystis jirovecii Pneumonia (PCP)† [off-label]

Treatment of PCP in HIV-infected Children†

Oral

0.3 mg/kg (up to 30 mg) once daily for 21 days;^{134 441} used in conjunction with clindamycin (10 mg/kg [up to 600 mg] IV every 6 hours or 10 mg/kg [up to 300–450 mg] orally every 6 hours) given for 21 days.⁴⁴¹

Treatment of Mild to Moderate PCP in HIV-infected Adolescents†

Oral

30 mg once daily for 21 days;⁴⁴⁰ used in conjunction with oral clindamycin (450 mg every 6 hours or 600 mg every 8 hours) given for 21 days.⁴⁴⁰

Treatment of Moderate to Severe PCP in HIV-infected Adolescents†

Oral

30 mg once daily for 21 days;⁴⁴⁰ used 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

Adults

Malaria

Radical Cure of P. ovale or P. vivax Malaria

Oral

30 mg of primaquine (52.6 mg of primaquine phosphate) once daily for 14 days recommended by CDC and others.^{115 134 144} Although 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 regimen or if used in patients with borderline G6PD deficiency, CDC recommends 45 mg of primaquine (79 mg of primaquine phosphate) once weekly for 8 weeks.^{143 144} Consultation with an expert in infectious disease and/or tropical medicine recommended if this regimen considered for individuals with borderline G6PD deficiency.^{143 144} (See Hemolytic Anemia and G6PD Deficiency under Cautions.)

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

Oral

30 mg of primaquine (52.6 mg of primaquine phosphate) once daily for 14 days given after leaving malarious areas recommended by CDC and others.^{115 134} Although 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 that are relatively resistant to primaquine (e.g., Oceania).¹⁴⁰

Individuals who received primary prophylaxis with chloroquine, hydroxychloroquine, doxycycline, or mefloquine: Administer primaquine presumptive antirelapse therapy during final 2 weeks of primary prophylaxis or, if not feasible, administer for 14 days after primary prophylaxis discontinued.¹¹⁵

Individuals who received primary prophylaxis with atovaquone/proguanil: Administer primaquine presumptive antirelapse therapy during final 7 days of primary prophylaxis and then for an additional 7 days or, if not feasible, administer for 14 days after primary prophylaxis discontinued.¹¹⁵

Primary Prophylaxis of Malaria†

Oral

30 mg of primaquine once daily.^{115 134}

Initiate prophylaxis 1–2 days prior to entering a malarious area and continue during stay and for 7 days after leaving the area.¹¹⁵

Pneumocystis jirovecii Pneumonia (PCP)†

Treatment of Mild to Moderate PCP†

Oral

30 mg once daily for 21 days;^{134 440} used in conjunction with oral clindamycin (450 mg every 6 hours or 600 mg every 8 hours) given for 21 days.⁴⁴⁰

Treatment of Moderate to Severe PCP†

Oral

30 mg once daily for 21 days;^{134 440} used 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

Prescribing Limits

Pediatric Patients

Malaria

Treatment or Prevention of Malaria

Oral

Do not exceed adult dosage.^{115 144}

Adults

Malaria

Treatment or Prevention of Malaria

Oral

Manufacturer states do not exceed 15 mg of primaquine (26.3 mg of primaquine phosphate) once daily for 14 days;¹⁰⁰ CDC and others recommend 30 mg of primaquine (52.6 mg of primaquine phosphate) once daily.^{115 134 144}

Special Populations

Hepatic Impairment

No specific dosage recommendations.¹⁰⁰

Renal Impairment

No specific dosage recommendations.¹⁰⁰

Geriatric Adults

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹⁰⁰

Cautions for Primaquine

Contraindications

• Severe G6PD deficiency.¹⁰⁰ (See Hemolytic Anemia and G6PD Deficiency under Cautions.)

• Pregnant women.¹⁰⁰ (See Pregnancy under Cautions.)

• Acutely ill patients who have systemic disease manifested by a tendency to develop granulocytopenia (e.g., rheumatoid arthritis, lupus erythematosus).¹⁰⁰

• Patients receiving other potentially hemolytic drugs or agents capable of depressing the myeloid elements of bone marrow.¹⁰⁰

Warnings/Precautions

Warnings

Hemolytic Anemia and G6PD Deficiency

Hemolytic reactions (moderate to severe) may occur if used in individuals with G6PD deficiency^{100 115 140} or in individuals with family or personal history of favism.¹⁰⁰ Hemolytic reactions can be fatal.¹¹⁵

Perform appropriate laboratory testing to rule out G6PD deficiency before initiating primaquine.^{100 115 143}

Severe G6PD deficiency: Do not prescribe primaquine.¹⁰⁰

Mild to moderate G6PD deficiency: Base decision to prescribe primaquine on an assessment of risks and benefits.¹⁰⁰ If use of the drug is considered, evaluate baseline hematocrit and hemoglobin concentration before treatment and closely monitor hematologic parameters during treatment (e.g., at days 3 and 8).¹⁰⁰

G6PD status unknown and G6PD testing unavailable: Base decision to prescribe primaquine on an assessment of risks and benefits.¹⁰⁰ Assess risk factors for G6PD deficiency or favism.¹⁰⁰ If use of the drug is considered, evaluate baseline hematocrit and hemoglobin concentration before treatment and closely monitor hematologic parameters during treatment (e.g., at days 3 and 8).¹⁰⁰

Consider that residual risk of hemolysis exists despite G6PD testing because of limitations of the tests.¹⁰⁰ Routine hematologic monitoring (particularly CBCs and hemoglobin concentrations) is advisable during primaquine therapy, even in G6PD-normal individuals.¹⁰⁰

Do not exceed recommended dosage.¹⁰⁰

Monitor closely if used in individuals who have had a previous idiosyncratic reaction to primaquine (as manifested by hemolytic anemia, methemoglobinemia, or leukopenia) or in individuals with a personal or family history of hemolytic anemia or nicotinamide adenine dinucleotide (NADH) methemoglobin reductase deficiency.¹⁰⁰

Discontinue immediately if evidence of hemolytic anemia occurs (e.g., darkening of urine, marked fall in hemoglobin concentration or erythrocyte count) or if leukocyte count suddenly decreases.¹⁰⁰

Ensure that adequate medical support and follow-up to manage hemolytic risk are available for all patients receiving primaquine.¹⁰⁰

Cardiac Effects

Cardiac arrhythmia^{100 140} and prolonged QT interval¹⁰⁰ reported.

Because of potential for QT interval prolongation, monitor ECG if used in patients with cardiac disease, long QT syndrome, history of ventricular arrhythmias, uncorrected hypokalemia and/or hypomagnesemia, or bradycardia (<50 bpm) and whenever used concomitantly with drugs that prolong the QT interval.¹⁰⁰

Females and Males of Reproductive Potential

Sexually active females of reproductive potential: Perform pregnancy test prior to initiation of primaquine;¹⁰⁰ pregnancy must be avoided during and after treatment until an ongoing ovulatory cycle has been completed.¹⁰⁰ (See Pregnancy under Cautions.)

Sexually active males whose partners may become pregnant: Use condom during primaquine treatment and for 3 months after the drug discontinued.¹⁰⁰ (See Pregnancy under Cautions.)

General Precautions

GI Effects

Nausea,¹⁰⁰ vomiting,¹⁰⁰ epigastric distress,¹⁰⁰ and abdominal cramps¹⁰⁰ reported; incidence and severity appear to be dose related.¹⁴⁰

Adverse GI effects may be decreased by administration with food.^{115 134 140}

Specific Populations

Pregnancy

Contraindicated during pregnancy.^{100 115 134 143} Safe use during pregnancy not established.¹⁰⁰ In addition, transplacental transfer of the drug to a G6PD-deficient fetus potentially could cause hemolytic anemia in utero.¹¹⁵

In animals, has been associated with teratogenicity and injury to embryos and developing fetuses.¹⁰⁰ Inform patients of potential for adverse genetic and reproductive effects.¹⁰⁰

Test all sexually active females of reproductive potential for pregnancy prior to initiation of primaquine.¹⁰⁰ Advise such women to use effective contraception (i.e., methods with pregnancy rates <1%) during and after primaquine therapy until an ongoing ovulatory cycle has been completed (up to next menses).¹⁰⁰ Advise sexually active males whose partners may become pregnant to use a condom during and for 3 months after primaquine therapy.¹⁰⁰

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

Lactation

Distributed into milk in low concentrations.¹⁴⁰

Manufacturer states discontinue nursing or the drug, taking into account importance of the drug to the mother.¹⁰⁰

CDC states do not use in nursing women unless the woman and breast-fed infant have been determined not to have G6PD deficiency.¹¹⁵

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹⁰⁰

Select dosage with caution (starting at the low end of dosage range) because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.¹⁰⁰

Common Adverse Effects

Hematologic effects (hemolytic anemia, leukocytosis, leukopenia); GI effects (nausea, vomiting, epigastric distress, abdominal cramps).¹⁰⁰

Drug Interactions

Specific Drugs

Primaquine Pharmacokinetics

Absorption

Bioavailability

Rapidly and well absorbed from GI tract.¹⁴⁰ Peak plasma concentrations generally attained within 2–4 hours.¹⁴⁰

Pharmacokinetics are altered during malaria infection; peak plasma concentrations may be higher in adults with malaria compared with healthy adults.¹⁴⁰

Food

In healthy adults, administration with food (approximately 28 g of fat) resulted in 1.23-fold increase in peak plasma concentration and 1.12-fold increase in AUC compared with administration in fasting state.¹⁴⁰

Distribution

Extent

Widely distributed following oral administration.¹⁰¹

Low concentrations distributed into milk.¹⁴⁰

Elimination

Metabolism

Extensively and rapidly metabolized in the liver.^{101 140} The principal metabolite is carboxyprimaquine; plasma concentrations of the metabolite greatly exceed those of unchanged primaquine.^{101 140}

Elimination Route

Only small amounts excreted unchanged in urine.¹⁰¹

Half-life

4–7 hours.^{115 140}

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C);¹⁰⁰ store in tight, light-resistant container.¹⁰⁰

Actions and Spectrum

• Antimalarial.^{100 140}

• Tissue schizonticidal agent active against the preerythrocytic and exoerythrocytic forms of Plasmodium falciparum, P. malariae, P. ovale, and P. vivax.¹⁴⁰ Also gametocytocidal against P. falciparum and other Plasmodium.¹⁴⁰

• Has only low activity against the erythrocytic forms of Plasmodium.¹⁴⁰

• Primaquine-resistant and primaquine-tolerant P. vivax reported.¹⁴⁰

• Exact mechanism of antimalarial activity unknown;^{140 161} appears to cause morphologic and physiologic changes in plasmodial mitochondria.¹⁴⁰ In the treatment of malaria caused by P. 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

• Mechanism of action against P. jirovecii unknown.¹⁴⁰

• Necessity of taking protective measures to reduce contact with mosquitoes (protective clothing, insect repellents, mosquito nets, remaining in air-conditioned or well-screened areas).^{115 134}

• Possibility of contracting malaria during travel, regardless of prophylactic regimen used.^{115 134}

• Importance of seeking medical attention as soon as possible if febrile illness develops during or after return from a malaria-endemic area and of informing clinician of possible malaria exposure.^{115 134}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.¹⁰⁰

• Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.^{100 115 143}

• Advise sexually active females and males of the importance of taking precautions to avoid pregnancy during and after primaquine therapy.¹⁰⁰ (See Pregnancy under Cautions.)

• Importance of advising patients of other important precautionary information.¹⁰⁰ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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