Primaquine

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

CLINICAL PHARMACOLOGY Microbiology 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. Antimicrobial Activity Primaquine phosphate is active against the dormant liver forms of P.vivax , namely hypnozoites, as well as exoerythrocytic stages of the parasite. Thereby, it prevents the development of the blood (erythrocytic) forms of the parasite which are responsible for relapses in vivax malaria. Primaquine phosphate is also active against gametocytes of Plasmodium falciparum . Resistance Development of resistance to primaquine phosphate in Plasmodium species has not been well studied. Pharmacokinetics Following single oral dosing, the C max and AUC of primaquine increase approximately dose-proportionally over a primaquine base dose range of 15 mg to 45 mg (3 times the approved dose). The pharmacokinetic parameters and properties of primaquine and carboxyprimaquine (main circulating metabolite not expected to be active) in patients with P. vivax malaria following Oral Administration of primaquine are provided in TABLE 1. TABLE 1: Summary of Pharmacokinetic Parameters and Properties (Mean ± SD) in Patients with P. vivax malaria. PK Parameter 15 mg once daily in adult patients (18 years of age and older) with P. vivax malaria, unless otherwise specified Day Primaquine Carboxyprimaquine C max (ng/mL) 1 50.7 ± 21.2 291 ± 52 C max (ng/mL) 14 49.7 ± 14.4 432 ±112 AUC or AUC 0-24 (μg/mL*h) AUC for primaquine, AUC 0-24 for carboxyprimaquine 1 0.48 ± 0.26 5.15 ± 1.01 AUC or AUC 0-24 (μg/mL*h) † 14 0.49 ± 0.19 7.24 ± 1.82 Primaquine Absorption Bioavailability Healthy participants >70 % T max 2.3 ± 1.1 hours Effect of food on primaquine (relative to fasting) Values refer to increase in mean systemic exposure with bread and butter: 82% fat, ~28g fat after single dose of 30 mg primaquine in healthy participants Geometric mean [95% confidence interval] ↑ 14% [3, 27] (AUC); ↑ 26% [12, 40] (C max ) Distribution % Bound to human plasma proteins 74% (mainly to alpha 1 acid glycoprotein) Volume of distribution (V) IV dose administration of [ 14 C]-primaquine in healthy participants 243 ± 69 L Metabolism Metabolic pathways -Oxidative deamination, MAO-A -Hydroxylation of the quinoline ring, CYP2D6 -Direct conjugations Elimination Major route of elimination Metabolism Apparent Clearance (CL/F) 37.6 ± 14.7 L/hr Mean terminal half-life (t 1/2 ) The mean terminal half-life of carboxyprimaquine is approximately 22 hours 5.6 ± 1.0 hours % of dose excreted in urine The main circulating metabolite, carboxyprimaquine is subjected to further metabolism and not eliminated through urine , Oral administr

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.

ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, please call Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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.

WARNINGS Hemolytic Anemia Hemolytic reactions (moderate to severe) may occur in individuals with G6PD deficiency and in individuals with a family or personal history of favism. Areas of high prevalence of G6PD deficiency are Africa, Southern Europe, Mediterranean region, Middle East, South-East Asia, and Oceania. People from these regions have a greater tendency to develop hemolytic anemia due to a congenital deficiency of erythrocytic G6PD while receiving primaquine and related drugs. Due to the risk of hemolytic anemia in patients with G6PD deficiency, G6PD testing must be performed before using primaquine. Before initiating treatment, obtain baseline hemoglobin and hematocrit. In case of severe anemia, postpone the G6PD test and decision on treatment with primaquine until recovery. Due to the limitations of G6PD tests, physicians need to be aware of residual risk of hemolysis and adequate medical support and follow-up to manage hemolytic risk should be available. This is of particular importance in individuals with a personal or family history of hemolytic anemia. Patients with G6PD Deficiency Primaquine is contraindicated in patients with severe G6PD deficiency (see CONTRAINDICATIONS ). In case of mild to moderate G6PD deficiency, a decision to prescribe primaquine must be based on an assessment of the risks and benefits of using primaquine. If primaquine administration is considered, baseline hematocrit and hemoglobin must be checked before treatment and close hematological monitoring (e.g., at day 3 and 8) is required. Adequate medical support to manage hemolytic risk should be available. Patients with Unknown G6PD Status When the G6PD status is unknown and G6PD testing is not available, a decision to prescribe primaquine must be based on an assessment of the risks and benefits of using primaquine. Risk factors for G6PD deficiency or favism must be assessed. Baseline hematocrit and hemoglobin must be checked before treatment and close hematological monitoring (e.g., at day 3 and 8) is required. Adequate medical support to manage hemolytic risk should be available. Patients without G6PD Deficiency In G6PD normal patients it is also advisable to perform routine blood examinations (particularly blood cell counts and hemoglobin determinations) during therapy. Risk of Hemolysis with Other Drugs Avoid the concurrent administration of hemolytic agents in all patients (see CLINICAL PHARMACOLOGY, Drug Interactions ). Warn patients to discontinue the use of primaquine promptly if signs suggestive of hemolytic anemia occur (such as darkening of the urine, pale skin, shortness of breath, dizziness, and fatigue) and to contact their healthcare professional immediately. Pregnancy Safe usage of primaquine in pregnancy has not been established. Primaquine is contraindicated in pregnant women. The use of primaquine during pregnancy may cause hemolytic anemia in a G6PD-deficient fetus. Even if a pregnant woman has normal levels of G6PD, the fetus could be G6PD-deficient (see CONTRAINDICATIONS ). Animal data show toxicity to reproduction and embryofetal development. (See PRECAUTIONS, Animal Pharmacology and/or Animal Toxicology ). Nonclinical data from studies conducted in bacteria and in animals treated with primaquine show evidence of gene mutations and chromosomal/DNA damage, teratogenicity, and injury to embryos and developing fetuses when primaquine is administered to pregnant animals. Inform patients of the potential for adverse genetic and reproductive effects associated with primaquine treatment (see PRECAUTIONS, Carcinogenesis, Mutagenesis, and Impairment of Fertility , and Animal Pharmacology and/or Animal Toxicology ). Use in Females and Males of Reproductive Potential Pregnancy Testing Sexually active females of reproductive potential should have a pregnancy test prior to starting treatment with primaquine. Contraception Patients should avoid pregnancy during treatment. The use of effective contraception is recommended during t

CONTRAINDICATIONS Known hypersensitivity reactions to primaquine phosphate, other 8-­aminoquinolones, or to any component in primaquine. Severe glucose-6-phosphate dehydrogenase (G6PD) deficiency (see WARNINGS, Hemolytic Anemia ). Pregnant women (see WARNINGS, Pregnancy ). Breastfeeding by a lactating woman when the infant is found to be G6PD deficient or if G6PD status is unknown (see WARNINGS, Nursing Mothers ). 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.

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.