PRIMAQUINE PHOSPHATE

INDICATIONS AND USAGE Primaquine phosphate Tablets are indicated for the radical cure (prevention of relapse) of vivax malaria.

DOSAGE AND ADMINISTRATION Primaquine phosphate Tablets are recommended only for the radical cure of vivax malaria, the prevention of relapse in vivax malaria, or following the termination of chloroquine phosphate suppressive therapy in an area where vivax malaria is endemic. Patients suffering from an attack of vivax malaria or having parasitized red blood cells should receive a course of chloroquine phosphate, which quickly destroys the erythrocytic parasites and terminates the paroxysm. Primaquine phosphate Tablets should be administered concurrently to eradicate the exoerythrocytic parasites in adults at a dosage of 1 tablet (equivalent to 15 mg base) daily for 14 days. Primaquine phosphate Tablets can be taken with or without food. Administration of Primaquine phosphate Tablets with food may reduce the incidence of gastrointestinal symptoms.

CONTRAINDICATIONS Severe glucose-6-phosphate dehydrogenase (G6PD) deficiency (see WARNINGS ). Pregnant women (see WARNINGS , Usage in Pregnancy ). Primaquine phosphate is contraindicated in acutely ill patients suffering from systemic disease manifested by tendency to granulocytopenia, such as rheumatoid arthritis and lupus erythematosus. The drug is also contraindicated in patients receiving concurrently other potentially hemolytic drugs or depressants of myeloid elements of the bone marrow. Because quinacrine hydrochloride appears to potentiate the toxicity of antimalarial compounds which are structurally related to primaquine, the use of quinacrine in patients receiving primaquine is contraindicated. Similarly, primaquine should not be administered to patients who have received quinacrine recently, as toxicity is increased.

ADVERSE REACTIONS Gastrointestinal: Nausea, vomiting, epigastric distress, abdominal cramps. Hematologic: Leukopenia, hemolytic anemia, decreased hemoglobin, methemoglobinemia. Hemolytic anemia occurs commonly in patients with G6PD deficiency and may be severe or fatal in patients with severe G6PD deficiency (see WARNINGS ). Methemoglobin levels are usually <10%, but methemoglobinemia may be severe in nicotinamide adenine dinucleotide (NADH) methemoglobin reductase deficient individuals or in patients with other risk factors (see PRECAUTIONS ). Leukopenia was observed in patients with rheumatoid arthritis or lupus erythematosus (see PRECAUTIONS ). Cardiac: Cardiac arrhythmia and QT interval prolongation (see PRECAUTIONS , OVERDOSAGE ). Nervous System: Dizziness. Skin and Soft Tissue: Rash, pruritus.

Drug Interactions Pharmacodynamics Interactions Quinacrine Concurrent use of quinacrine (mepacrine) and Primaquine phosphate Tablets are contraindicated. Increased toxicity was seen when quinacrine was used with pamaquine, another 8-aminoquinoline (see CONTRAINDICATIONS ). Hemolytic Agents and Methemoglobinemia-Inducing Drugs The concurrent administration of hemolytic agents or methemoglobinemia-inducing drugs and primaquine should be avoided (see PRECAUTIONS ). If the concurrent administration cannot be avoided, close blood monitoring is required. QT Interval Prolonging Drugs The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between Primaquine phosphate Tablets and other drugs that effect cardiac conduction is unknown. If Primaquine phosphate Tablets are used concomitantly with other drugs that prolong the QT interval, close and frequent electrocardiogram monitoring is advised (see PRECAUTIONS , ADVERSE REACTIONS , and OVERDOSAGE ). Effects of Other Drugs on the Pharmacokinetics of Primaquine Strong CYP2D6 Inhibitors Published clinical and non-clinical reports indicate reduced CYP2D6 activity may decrease the formation of active metabolites of primaquine, which may reduce antimalarial efficacy of Primaquine phosphate Tablets (see CLINICAL PHARMACOLOGY, Pharmacogenomics ). Where possible, consider alternative medications that are not strong CYP2D6 inhibitors. If concurrent use with Primaquine phosphate Tablets is necessary, increase monitoring for possible relapse. Concomitant use of an MAO-A inhibitor in patients with reduced or absent CYP2D6 activity (e.g., strong CYP2D6 inhibitor, CYP2D6 intermediate or poor metabolizer) is expected to increase primaquine exposure which may increase the risk of adverse reactions (see CLINICAL PHARMACOLOGY, Pharmacogenomics ). Defer initiation of MAO-A inhibitor therapy or consider alternative drug therapy in patients with reduced or absent CYP2D6 activity until primaquine treatment is completed. If concurrent use with Primaquine phosphate Tablets is necessary, increase patient monitoring for potential adverse reactions (see PRECAUTIONS ). Effects of Primaquine on the Pharmacokinetics of Other Drugs CYP1A2 Substrates Published clinical and non-clinical reports indicate primaquine inhibits CYP1A2 enzyme activity and thus may lead to increased exposure of CYP1A2 substrate drugs (e.g., duloxetine, alosetron, theophylline and tizanidine) when co-administered with Primaquine phosphate Tablets. Since data are limited, no predictions can be made regarding the extent of the impact on CYP1A2 substrate drug exposures. Increase monitoring for adverse reactions associated with the CYP1A2 substrate drug when concurrently administered with Primaquine phosphate tablets. CYP3A4 Substrates Refer to the Prescribing Information for a CYP3A substrate where minimal concentration changes may lead to serious adverse reactions (e.g. rivaroxaban, calcineurin inhibitors, ergot derivatives, tyrosine kinase inhibitors) for the recommended dosage modification and/or monitoring. Published clinical reports indicate primaquine may inhibit CYP3A4 enzyme activity and thus may lead to increased exposure of oral CYP3A4 substrate drugs when co-administered with Primaquine phosphate Tablets. Since data are limited, no predictions can be made regarding the extent of the impact on oral CYP3A4 substrate drug exposures. Increase monitoring for adverse reactions associated with CYP3A4 substrate drugs that prolong the QT interval (e.g., pimozide) or where minimal concentration changes may lead to serious adverse reactions when concurrently administered with Primaquine phosphate Tablets. P-gp Substrates Refer to the Prescribing Information for a P-gp substrate where minimal concentration changes may lead to serious adverse reactions (e.g., digoxin and dabigatran) for the recommended dosage modification and/or monitoring. In vitro observations suggest that primaquine inhibits the P-gp membrane …

Mechanism of Action Primaquine phosphate is an 8-aminoquinoline antimalarial drug. The mechanism of action has not been fully established. The major assumptions are an inhibition of the mitochondrial system of dormant parasites, and an oxidative stress generated through reactive metabolites in infected cells. In humans, primaquine phosphate activity is probably related to hydroxylated metabolites generated intrahepatically by CYP2D6.

DESCRIPTION Primaquine phosphate is 8-[(4-amino-1-methylbutyl) amino]-6-methoxyquinoline phosphate, a synthetic compound with potent antimalarial activity. The molecular formula of Primaquine phosphate is C 15 H 21 N 3 O∙2H 3 PO 4 and its molecular weight is 455.34. The structural formula of Primaquine phosphate is: Figure 1: Primaquine phosphate structure. Each Primaquine phosphate tablet contains 26.3 mg of primaquine phosphate (equivalent to 15 mg of primaquine base). The dosage is customarily expressed in terms of the base. Inactive Ingredients: Carnauba Wax, Hydroxypropyl Methylcellulose, Lactose, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol 400, Polysorbate 80, Pregelatinized Starch, Red Ferric Oxide, Talc, Titanium Dioxide. Chemical Structure

OVERDOSAGE Signs and symptoms Symptoms of overdosage of primaquine phosphate include abdominal cramps, vomiting, burning epigastric distress, central nervous system disturbances including headache, insomnia, and cardiovascular disturbances, including cardiac arrhythmia and QT interval prolongation, methemoglobinemia (indicated by cyanosis), moderate leukocytosis or leukopenia, granulocytopenia, and anemia. Acute hemolysis may occur with particular severity in G6PD deficient patients. Management Treatment of overdosage consists of institution of appropriate symptomatic and/or supportive therapy. Consider contacting a poison center or a medical toxicologist for overdosage management recommendations.

HOW SUPPLIED Primaquine Phosphate Tablets, USP are supplied as orange colored, round, biconvex, film-coated tablets of 26.3 mg (= 15 mg base), debossed with a "059" on one side and plain on the other side. Available in bottles of 100 (NDC 42291-510-01) Store at 25° C (77° F); excursions permitted to 15° C – 30° C (59° F – 86° F) [see USP Controlled Room Temperature] Dispense in tight, light-resistant container as defined in the USP/NF.