Primaquine

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.

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 treatment and after the end of treatment as follows: Advise sexually active females of childbearing potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using primaquine and after stopping treatment until 2 menses have elapsed). Advise treated males whose partners may become pregnant, to use a condom while on treatment and for 3 months after stopping treatment with primaquine. Nursing Mothers A breastfed infant with G6PD deficiency is at risk for hemolytic anemia from exposure to primaquine. Infant G6PD status should be checked before breastfeeding begins. Primaquine is contraindicated in breastfeeding women when the infant is found to be G6PD deficient or the G6PD status of the infant is unknown (see CONTRAINDICATIONS ). Advise the woman with a G6PD-deficient infant or if the G6PD status of the infant is unknown not to breastfeed. The presence of primaquine and its major metabolite in breast milk and infant plasma were evaluated in a published study of 21 G6PD-normal lactating women and their G6PD-normal infants aged 28 days or older. After repeat administration of a 0.5 mg/kg/day primaquine base dose for 14 days in the lactating women, low concentrations of primaquine and carboxyprimaquine were measured both in breast milk and in infant plasma. The estimated infant ingested dose was found to be less than 1% of a 0.5 mg/kg/day primaquine base dose determined from an observed milk to maternal plasma AUC ratio of 0.34 (range: 0.12 to 0.64) and assuming an infant milk consumption of 150 mL/kg/day. Infant primaquine concentrations in plasma were below measurement thresholds (2.28 ng/mL) in all but 1 infant capillary plasma sample (2.6 ng/mL), and carboxyprimaquine concentrations in plasma were likewise unmeasurable in the majority of infant samples (range, 4.88 ng/mL [measurement threshold] to maximum value 25.8 ng/mL). There is no information on the effects of primquine on the breastfed infant, or the effects on milk production.

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.

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 transporter. Therefore, there is a potential for increased concentrations of drugs that are P-gp substrates when co-administered with Primaquine phosphate Tablets. Increase monitoring for adverse reactions associated with P-gp substrate drugs where minimal concentration changes may lead to serious adverse reactions when concomitantly administered with Primaquine phosphate Tablets.

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.

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 phosphate Tablets are provided in TABLE 1. TABLE 1: Summary of Pharmacokinetic Parameters and Properties (Mean ± SD) in Patients with P. vivax malaria. PK Parameter a 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) b 1 0.48 ± 0.26 5.15 ± 1.01 AUC or AUC 0-24 (μg/mL*h) b 14 0.49 ± 0.19 7.24 ± 1.82 Primaquine Absorption Bioavailability c >70 % T max 2.3 ± 1.1 hours Effect of food on Primaquine Phosphate Tablet (relative to fasting) d 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) e 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 ) f 5.6 ± 1.0 hours % of dose excreted in urine g, h 64%, (including 3.6% of primaquine, the remnant being metabolites other than carboxyprimaquine) C max =maximum plasma concentration; AUC=area under the plasma concentration-time curve from time zero up to infinity; MAO-A = monoamine oxidase A a 15 mg once daily in adult patients (18 years of age and older) with P. vivax malaria, unless otherwise specified b AUC for primaquine, AUC 0-24 for carboxyprimaquine c Healthy participants d 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 e IV dose administration of [ 14 C]-primaquine in healthy participants f The mean terminal half-life of carboxyprimaquine is approximately 22 hours g Oral administration of [ 14 C]-primaquine in healthy participants; no data in feces h The main circulating metabolite, carboxyprimaquine is subjected to further metabolism and not eliminated through urine Specific Populations Gender and ethnicity No gender nor ethnicity effect has been evidenced in studies conducted to date. Elderly patients There are no pharmacokinetics studies in patients older than 52 years of age. Hepatic impairment Single dose pharmacokinetics study performed in patients with mild or moderate hepatic impairment indicate that only moderate hepatic dysfunction impacted significantly the PK of primaquine with a 3-fold lower primaquine C max in patients with moderate hepatic dysfunction as compared to healthy subjects. The primaquine AUC was not significantly modified. No data are available after repeated dosing in patients with hepatic impairment. It is not known whether in patients with hepatic impairment, accumulation of primaquine and its metabolites could occur or if there could be an impact on generation of metabolites contributing to pharmacological activity. Renal impairment Single dose pharmacokinetics studies performed in patients with chronic severe (eGFR 15 to 29 mL/min) or end-stage (< 15 mL/min) renal impairment indicate higher primaquine C max (up to 1.7-fold higher as compared to healthy subjects) but no evidence of major difference in AUC or t 1/2 . It is not known whether after repeated dosing there could be an accumulation of metabolites that are mainly excreted by renal route. Drug Interaction Studies Effect of other Drugs on the Pharmacokinetics of primaquine In vitro data suggest primaquine is not a substrate of either P-gp or BCRP membrane transporters. Effect of primaquine on the Pharmacokinetics of other drugs In vitro data suggest primaquine has the potential to inhibit CYP1A2 enzyme activity, but no or low potential to inhibit MAO-A, MAO-B, or CYP450 isoforms 2A6, 2C8, 2C9, 2C19, 2D6, 3A4 enzymes involved in drug biotransformation. In vitro data suggest primaquine has the potential to inhibit the P-gp membrane transporter. Pharmacogenomics Published clinical reports indicate that primaquine is a CYP2D6 substrate. Experiments in mice indicate primaquine activity likely depends on the formation of CYP2D6 metabolite(s). CYP2D6 has variants that affect CYP2D6 metabolic function. CYP2D6 poor metabolizers are individuals with two nonfunctional alleles (e.g., CYP2D6*5/*5 ), and as a result have no CYP2D6 activity. CYP2D6 intermediate metabolizers are individuals with a combination of nonfunctional, reduced, or normal function alleles, and as a result have reduced CYP2D6 activity (e.g., CYP2D6*1/*5 , CYP2D6*4/*10 ). 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 phosphate Tablets (see PRECAUTIONS ).