Primaquine (primaquine phosphate)

Dosage of primaquine phosphate usually is expressed in terms of primaquine.

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

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

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

Prior to initiation of primaquine, appropriate laboratory tests should be performed to rule out glucose-6-phosphate dehydrogenase (G6PD) deficiency. Primaquine is contraindicated in individuals with severe G6PD deficiency. 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. (See Hemolytic Anemia and G6PD Deficiency under Cautions: Precautions and Contraindications.)

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antimalarial Agents/Penicillamine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use may result in additive or synergistic effects on the blood and kidneys(1) or increased penicillamine levels.(2)

CLINICAL EFFECTS: Concurrent use of penicillamine with antimalarials may result in serious hematologic or renal toxicity(1,2) or elevated levels of penicillamine.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of penicillamine states that penicillamine should not be used in patients receiving concurrent therapy with antimalarial agents.(1)

DISCUSSION: In patients with rheumatoid arthritis, concurrent chloroquine increased penicillamine plasma concentrations by 34% when compared to penicillamine alone.(2) In a 2-year controlled, double-blind trial of penicillamine, hydroxychloroquine, or combination therapy, patients on combination therapy did not do as well as patients receiving penicillamine alone.(3) Because antimalarial agents are associated with hematologic and renal toxicity, the manufacturer of penicillamine states that penicillamine should not be used in patients receiving concurrent antimalarials.(1)

Antimalarials/Artemether; Lumefantrine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Halofantrine and quinine may inhibit the metabolism of lumefantrine by CYP2D6.(1) The combination of artemether-lumefantrine and antimalarials may result in additive effects on the QT interval.(1)

CLINICAL EFFECTS: Concurrent use may result in toxicity and/or prolongation of the QT interval, which may result in life-threatening arrhythmias.(1,2)

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)

PATIENT MANAGEMENT: The UK manufacturer of artemether-lumefantrine states that the concurrent use of artemether-lumefantrine with other antimalarials is contraindicated.(1) The US manufacturer of artemether-lumefantrine states that artemether-lumefantrine should not be given concurrently with antimalarials.(2) If a patient deteriorates during artemether-lumefantrine therapy and requires another antimalarial agent, it may be started immediately, but the UK manufacturer of artemether-lumefantrine recommends ECG and potassium monitoring.(1) In patients who have previously received halofantrine, both the UK and US manufacturers of artemether-lumefantrine recommends that one month elapse between the last dose of halofantrine and the initiation of artemether-lumefantrine.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in 14 healthy subjects, administration of a single intravenous dose of quinine (10 mg/kg) 2 hours after the sixth dose of artemether-lumefantrine had no effect on lumefantrine or dihydroartemisinin levels. Artemether levels were decreased; however, this was not believed to be clinically significant.(1,2) Concurrent quinine and artemether-lumefantrine produced a slight, but significant increase on the QTc interval.(1)

Primaquine/Quinacrine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use of quinacrine with primaquine may potentiate the toxic effects of primaquine.(1)

CLINICAL EFFECTS: Concurrent use of primaquine with quinacrine may result in increased primaquine toxicity, including hemolytic anemia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of primaquine states that concurrent use of quinacrine and primaquine is contraindicated. Primaquine should not be administered to patient who have received quinacrine recently.(1)

DISCUSSION: Because quinacrine appears to potentiate the toxicity of antimalarial compounds which are structurally related to primaquine, the use of quinacrine in patients receiving primaquine is contraindicated. In addition, primaquine should not be administered to patient who have received quinacrine recently.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Primaquine/Maois

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Primaquine is metabolized by CYP2D6 and monoamine oxidase A (MAO-A). MAO-A inhibitors may inhibit the metabolism of primaquine.(1)

CLINICAL EFFECTS: Concurrent use of MAO-A inhibitors and primaquine may result in increased levels and toxicities of primaquine, including hemolytic anemia.(1)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients who are CYP2D6 poor metabolizers, CYP2D6 intermediate metabolizers and who receive concomitant treatment with a strong CYP2D6 inhibitor.(1)

PATIENT MANAGEMENT: The manufacturer of primaquine recommends deferring initiation of MAO-A inhibitor therapy or considering alternative drug therapy in patients with reduced or absent CYP2D6 activity (e.g., concurrent use of a strong CYP2D6 inhibitor or CYP2D6 intermediate or poor metabolizers) until primaquine treatment is completed. If concurrent use with primaquine is necessary, increase patient monitoring for potential adverse reactions.(1)

DISCUSSION: Primaquine is metabolized by CYP2D6 and MAO-A. Both metabolic pathways may be inhibited in patients who are taking concurrent MAO-A inhibitors and also taking strong CYP2D6 inhibitors or who are CYP2D6 intermediate or poor metabolizers. Individuals who are CYP2D6 intermediate or poor metabolizers exhibit a prolonged primaquine half-life and increased primaquine plasma concentrations when compared to individuals who are CYP2D6 normal metabolizers. CYP2D6 metabolizer status may be associated with variability in clinical response to primaquine.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Primaquine/Strong Cyp2d6 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong inhibitors of CYP2D6 may inhibit the metabolism of primaquine to its active metabolite.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP2D6 inhibitors may result in reduced antimalarial effect of primaquine due to decreased formation of the active primaquine metabolite.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When possible, consider alternative medications that are not strong CYP2D6 inhibitors. If concurrent therapy is warranted, monitor patients closely for possible relapse.

DISCUSSION: Published clinical reports indicate that primaquine is a CYP2D6 substrate. Reduced CYP2D6 activity may decrease the formation of the active metabolite of primaquine.(1) Strong CYP2D6 inhibitors linked to this monograph include bupropion, dacomitinib, fluoxetine, paroxetine, quinidine, and terbinafine.(2,3)

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• Bone marrow depression
• Glucose-6-phosphate dehydrogenase (g6Pd) deficiency
• Hemoglobin H disease
• Hemolytic anemia from pyruvate kinase and g6PD deficiencies
• Lactation
• Pregnancy

• Hemolytic anemia
• Neutropenic disorder

• Bradycardia
• Congenital long QT syndrome
• Hypokalemia
• Hypomagnesemia
• NADH methemoglobin reductase deficiency
• Prolonged QT interval
• Ventricular arrhythmias

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More Frequent

• Hemolytic anemia

Less Frequent

• Methemoglobinemia

Rare or Very Rare

• Cardiac arrhythmia
• Leukopenia

More Frequent

• Abdominal pain with cramps
• Nausea
• Vomiting

Rare or Very Rare

• Dizziness
• Pruritus of skin
• Skin rash

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

In animal reproduction studies, primaquine was associated with teratogenicity and injury to embryos and developing fetuses. 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. 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 dosage; there were no fetal abnormalities at the lower dosage level. 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. 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. 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.

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

Sexually active females of reproductive potential should undergo pregnancy testing prior to initiation of primaquine treatment. 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). 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.

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.

Primaquine is distributed into milk in low concentrations. 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.

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.

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