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Primaquine

Pronunciation

(PRIM a kween)

Index Terms

  • Primaquine Phosphate
  • Prymaccone

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as phosphate:

Generic: 26.3 mg

Pharmacologic Category

  • Aminoquinoline (Antimalarial)
  • Antimalarial Agent

Pharmacology

Primaquine is an antiprotozoal agent active against exoerythrocytic stages of Plasmodium ovale and P. vivax, also active against the primary exoerythrocytic stages of P. falciparum and gametocytes of Plasmodia; disrupts mitochondria and binds to DNA

Absorption

Well absorbed

Metabolism

Hepatic to carboxyprimaquine (active) via CYP1A2

Excretion

Urine (small amounts as unchanged drug)

Time to Peak

Serum: 1 to 3 hours

Half-Life Elimination

7 hours; reported range: 3.7 to 9.6 hours

Use: Labeled Indications

Malaria: Radical cure (prevention of relapse) of vivax malaria

Use: Unlabeled

Prevention of relapse of P. ovale malaria; prevention of malaria; treatment of uncomplicated P. vivax and P. ovale malaria; treatment of Pneumocystis jirovecii pneumonia (PCP)

Contraindications

Severe G6PD deficiency; pregnancy; use in acutely ill patients who have a tendency to develop granulocytopenia (eg, rheumatoid arthritis, systemic lupus erythematosus); concurrent use with other medications causing hemolytic anemia or myeloid bone marrow suppression; concurrent use with or recent use of quinacrine

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to primaquine or any component of the formulation

Documentation of allergenic cross-reactivity for aminoquinolines is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Note: Screen for G6PD deficiency prior to initiating treatment. Dosage expressed as mg of base (15 mg base = 26.3 mg primaquine phosphate).

Malaria: Oral:

Treatment or prevention of relapse of P. vivax malaria: 15 mg once daily in combination with chloroquine for 14 days (maximum dose: 15 mg/day)

Treatment of uncomplicated P. vivax and P. ovale malaria (off-label use): 30 mg once daily for 14 days with chloroquine or hydroxychloroquine; alternative regimen (for mild G6PD deficiency or as an alternative to daily regimen): 45 mg once weekly for 8 weeks (use only after consultation with an infectious disease/tropical medicine expert) (CDC 2013)

Chemoprophylaxis (off-label use): 30 mg once daily; start 1 to 2 days prior to travel and continue for 7 days after departure from malaria-endemic area (CDC Yellow Book 2014)

Presumptive antirelapse therapy for P. vivax and P. ovale malaria (off-label use): 30 mg once daily for 14 days after departure from malaria-endemic area (CDC Yellow Book 2014)

Pneumocystis pneumonia (PCP) treatment in HIV-infected patients (alternative to preferred therapy) (off-label use): Oral: 30 mg once daily for 21 days (in combination with clindamycin) (HHS [OI adult 2015])

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Screen for G6PD deficiency prior to initiating treatment. Dosage expressed as mg of base (15 mg base = 26.3 mg primaquine phosphate).

Malaria: Oral:

Treatment of uncomplicated P. vivax and P. ovale malaria (off-label use): 0.5 mg/kg (maximum: 30 mg/day) daily for 14 days with chloroquine or hydroxychloroquine (CDC 2013)

Chemoprophylaxis (off-label use): 0.5 mg/kg once daily (maximum dose: 30 mg/day); start 1 to 2 days prior to travel and continue for 7 days after departure from malaria-endemic area (CDC Yellow Book 2014)

Presumptive antirelapse therapy for P. vivax and P. ovale malaria (off-label use): 0.5 mg/kg (maximum dose: 30 mg/day) once daily for 14 days after departure from malaria-endemic area (CDC Yellow Book 2014)

Pneumocystis pneumonia (PCP) treatment in HIV-infected patients (alternative to preferred therapy) (off-label use) (alternative to preferred therapy):

Children: 0.3 mg/kg once daily for 21 days (in combination with clindamycin) (HHS [OI pediatric 2013])

Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Extemporaneously Prepared

A 6 mg base/5 mL oral suspension may be made using tablets. Crush ten 15 mg base tablets and reduce to a fine powder. In small amounts, add a total of 10 mL Carboxymethylcellulose 1.5% and mix to a uniform paste; mix while adding Simple Syrup, NF to almost 125 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 125 mL. Label "shake well" and "refrigerate". Stable 7 days.

Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Administration

Administer with meals to decrease adverse GI effects. If patient vomits within 30 minutes of taking a dose, then they should repeat the dose (CDC 2013).

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Agomelatine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Agomelatine. Avoid combination

Anthelmintics: Aminoquinolines (Antimalarial) may decrease the serum concentration of Anthelmintics. Monitor therapy

Antipsychotic Agents (Phenothiazines): Antimalarial Agents may increase the serum concentration of Antipsychotic Agents (Phenothiazines). Monitor therapy

Artemether: May enhance the adverse/toxic effect of Antimalarial Agents. Management: Artemether/Lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. Avoid combination

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

Bendamustine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Bendamustine. Concentrations of the active metabolites of bendamustine may be decreased. Monitor therapy

Beta-Blockers: Aminoquinolines (Antimalarial) may decrease the metabolism of Beta-Blockers. Exceptions: Atenolol; Carteolol (Ophthalmic); Levobunolol; Metipranolol; Nadolol; Sotalol. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Cardiac Glycosides: Aminoquinolines (Antimalarial) may increase the serum concentration of Cardiac Glycosides. Monitor therapy

CloZAPine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Management: Reduce the dose of clozapine to one-third of the original dose when adding a strong CYP1A2 inhibitor, and monitor patient response closely. Return to the original clozapine dose when the strong CYP1A2 inhibitor is removed. Consider therapy modification

Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

CYP1A2 Substrates: CYP1A2 Inhibitors (Strong) may decrease the metabolism of CYP1A2 Substrates. Consider therapy modification

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapsone (Systemic): May enhance the adverse/toxic effect of Antimalarial Agents. Specifically, concomitant use of dapsone with antimalarial agents may increase the risk for hemolytic reactions. Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Systemic). Specifically, concomitant use of antimalarial agents with dapsone may increase the risk of hemolytic reactions. Management: Closely monitor patients for signs/symptoms of hemolytic reactions with concomitant use of dapsone and antimalarial agents, particularly in patients deficient in glucose-6-phosphate dehydrogenase (G6PD), methemoglobin reductase, or with hemoglobin M. Consider therapy modification

Dapsone (Topical): Antimalarial Agents may enhance the adverse/toxic effect of Dapsone (Topical). Specifically, the risk of hemolytic reactions may be increased. Management: Closely monitor for signs/symptoms of hemolytic reactions with concomitant use of topical dapsone and antimalarial agents. Patients with glucose-6-phosphate dehydrogenase deficiency may be at particularly high risk for adverse hematologic effects. Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

DULoxetine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of DULoxetine. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Imatinib: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Ivabradine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Lumefantrine: Antimalarial Agents may enhance the adverse/toxic effect of Lumefantrine. Management: Artemether/Lumefantrine (combination product) should not be used with other antimalarials unless there is no other treatment option. Avoid combination

Mefloquine: Aminoquinolines (Antimalarial) may enhance the adverse/toxic effect of Mefloquine. Specifically, the risk for QTc-prolongation and the risk for convulsions may be increased. Mefloquine may increase the serum concentration of Aminoquinolines (Antimalarial). Management: Avoid concurrent use, and delay administration of mefloquine until at least 12 hours after the last dose of an aminoquinoline antimalarial when possible. Avoid combination

MiFEPRIStone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Nitric Oxide: May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when nitric oxide is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine. Monitor therapy

Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Pentoxifylline: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Pentoxifylline. Monitor therapy

Perhexiline: CYP2D6 Substrates may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Pirfenidone: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Pirfenidone. Management: See full monograph for specific recommendations. Canadian product labeling specifically lists the use of pirfenidone with fluvoxamine as contraindicated. Consider therapy modification

Pomalidomide: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Pomalidomide. Management: Avoid when possible. Monitor toxicity closely when combined. In patients also receiving a P-gp inhibitor and strong CYP3A4 inhibitor, reduce pomalidomide dose by 50% (Canadian labeling says to reduce dose with any use of a strong CYP1A2 inhibitor). Avoid combination

Prilocaine: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Prilocaine. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Management: Monitor patients for signs of methemoglobinemia (e.g., hypoxia, cyanosis) when prilocaine is used in combination with other agents associated with development of methemoglobinemia. Avoid lidocaine/prilocaine in infants receiving such agents. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Rasagiline: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Rasagiline. Management: Limit rasagiline dose to 0.5 mg once daily in patients taking strong CYP1A2 inhibitors. Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Nitrite: Methemoglobinemia Associated Agents may enhance the adverse/toxic effect of Sodium Nitrite. Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Tasimelteon: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Tasimelteon. Avoid combination

Tetracaine (Topical): May enhance the adverse/toxic effect of Methemoglobinemia Associated Agents. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of TiZANidine. Management: Tizanidine use with ciprofloxacin or fluvoxamine is contraindicated. If use with another strong inhibitor cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on response. Monitor closely. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Adverse Reactions

Frequency not defined.

Cardiovascular: Cardiac arrhythmia, dizziness, prolonged Q-T interval on ECG

Dermatologic: Pruritus, skin rash

Gastrointestinal: Abdominal cramps, epigastric distress, nausea, vomiting

Hematologic & oncologic: Anemia, hemolytic anemia (in patients with G6PD deficiency), leukopenia, methemoglobinemia (in NADH-methemoglobin reductase-deficient individuals)

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: May cause QT prolongation; monitor ECG in patients with cardiac disease, long QT syndrome, a history of ventricular arrhythmias, uncorrected hypokalemia and/or hypomagnesemia, or bradycardia (<50 beats per minute), and during concomitant administration with QT interval prolonging agents.

• Hematologic effects: Anemia, methemoglobinemia, and leukopenia have been associated with primaquine use; monitor during treatment; do not exceed recommended dosage and duration. Closely monitor patients who have a family or personal history of hemolytic anemia or who have had a prior hematologic adverse reaction attributed to primaquine. Immediately discontinue if marked darkening of the urine or sudden decrease in hemoglobin concentration or leukocyte count occurs.

• Hemolytic anemia: Promptly discontinue with signs of hemolytic anemia (darkening of urine, marked fall in hemoglobin or erythrocyte count). Moderate to severe hemolytic reactions may occur in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency and personal or familial history of favism. Geographic regions with a high prevalence of G6PD deficiency (eg, Africa, southern Europe, Mediterranean region, Middle East, southeast Asia, Oceania) are associated with a higher incidence of hemolytic anemia.

Disease-related concerns:

• G6PD deficiency: Screen for G6PD deficiency prior to therapy initiation. Use is contraindicated in patients with severe G6PD deficiency. Assess benefits/risks of treatment when considering use in patients with mild to moderate G6PD deficiency or those patients whose G6PD status is unknown and testing is not available. Also assess risk factors for G6PD deficiency or favism in patients with unknown G6PD status. If a decision is made to administer primaquine to a patient with mild to moderate G6PD deficiency or unknown G6PD status (when testing is not available), perform baseline hematocrit and hemoglobin testing and closely monitor hematological parameters (eg, at day 3 and 8). Immediately discontinue treatment if signs of hemolytic anemia occur.

• NADH methemoglobin reductase deficiency: Use with caution in patients with a personal or family history of NADH methemoglobin reductase deficiency; methemoglobinemia may occur.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.

Monitoring Parameters

Periodic CBC (in G6PD normal patients), visual color check of urine, glucose, electrolytes; if hemolysis suspected, monitor CBC, haptoglobin, peripheral smear, urinalysis dipstick for occult blood, G6PD deficiency screening (prior to initiating treatment); baseline hematocrit and hemoglobin testing and periodic CBC (eg, at day 3 and 8) in patients with mild to moderate G6PD deficiency or unknown G6PD status (when testing is not available); ECG (in patients at risk for QT prolongation)

Pregnancy Considerations

Primaquine is contraindicated in pregnant women.

Malaria infection in pregnant women may be more severe than in nonpregnant women and has a high risk of maternal and perinatal morbidity and mortality. Therefore, pregnant women and women who are likely to become pregnant are advised to avoid travel to malaria-risk areas. When treatment is needed, other agents are preferred (CDC Yellow Book 2016). Consult current CDC guidelines for the treatment of malaria during pregnancy.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal cramps, abdominal pain, vomiting, or nausea. Have patient report immediately to prescriber signs of methemoglobinemia (blue or gray color of the lips, nails, or skin; arrhythmia; seizures; severe dizziness or passing out; severe headache; fatigue; loss of strength and energy; or shortness of breath), dark urine, chills, jaundice, dizziness, passing out, tachycardia, abnormal heartbeat, or severe loss of strength and energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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