Primaquine Phosphate 15 mg Tablet, 100-count — NDC 76385-102-01 (Billing 76385-0102-01)

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 phosphate Tablets are 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 phosphate Tablets 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 phosphate Tablets in pregnancy has not been established. Primaquine is contraindicated in pregnant women.

The use of Primaquine phosphate Tablets 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… [Excerpted — this section continues on DailyMed.]

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 membr… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS Methemoglobinemia Primaquine may cause a transient increase in methemoglobin levels up to 10% in patients without risk factors (see ADVERSE REACTIONS ). Methemoglobinemia may be severe in patients who are deficient in nicotinamide adenine dinucleotide (NADH), methemoglobin reductase or treated with methemoglobinemia-inducing drugs such as dapsone or sulfonamide, (see PRECAUTIONS , Drug Interactions ). Monitor methemoglobin levels closely in these cases.

Advise all patients to seek immediate medical attention if signs of methemoglobinemia occur such as bluish lips or nails. Leukopenia Primaquine may cause leukopenia in patients with established granulocytopenia, such as rheumatoid arthritis and lupus erythematosus. Avoid concurrent administration of bone-marrow depressants.

Discontinue the use of primaquine promptly if there is a sudden decrease in leukocyte count. Potential Prolongation of QT Interval Due to potential for QT interval prolongation, monitor ECG when using primaquine in patients with cardiac disease, long QT syndrome, a history of ventricular arrhythmias, uncorrected hypokalemia and/or hypomagnesemia, or bradycardia (<50 bpm), and during concomitant administration with QT interval prolonging agents (see PRECAUTIONS , Drug Interactions , ADVERSE REACTIONS , and OVERDOSAGE ).

Strong CYP2D6 Inhibitors, CYP2D6 Poor or Intermediate Metabolizers, and Treatment Failure Based on published non-clinical reports, primaquine activity likely depends on the formation of CYP2D6 metabolite(s). Therefore, CYP2D6 genetic variation or drugs that impact CYP2D6 activity may be associated with variability in clinical response to Primaquine phosphate Tablets. Limited published clinical data reported higher treatment failure rates in patients who were CYP2D6 poor or intermediate metabolizers than in patients who were CYP2D6 normal metabolizers (see CLINICAL PHARMACOLOGY ).

When possible, consider alternative medications that are not strong CYP2D6 inhibitors. Increase monitoring for possible relapse in patients with concurrent strong CYP2D6 inhibitor usage or in patients who are CYP2D6 poor or intermediate metabolizers (see PRECAUTIONS , Drug Interactions ). In case of treatment failure, after checking patient's compliance to treatment, reassess use of CYP2D6 inhibitors and assess the patient's CYP2D6 metabolizer status, if feasible.

For patients who are CYP2D6 poor or intermediate metabolizers, alternative treatment should be considered. Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with primaquine. No fertility studies have been conducted with primaquine.

Primaquine is reported in the literature to be a weak genotoxic agent which elicits both gene mutations 1 , chromosomal damage and DNA strand breaks 2 . The publications reported positive results in the in vitro reverse gene mutation assays using bacteria (Ames test) 3,4 and in the in vivo studies using rodents (mouse bone marrow cell sister chromatid exchange, mouse bone marrow cell chromosome abnormality, and rat DNA strand breaks in multiple organs) 2, 5 . The genotoxicity data obtained in vitro and in rodent models are suggestive of a human risk for genotoxicity with primaquine administration (see WARNINGS , Usage in Pregnancy ).

Animal Pharmacology and/or Animal Toxicology Literature data on reproductive toxicology identified embryo-fetal development toxicity. In studies in rats, teratogenic effects on fetus were observed (see WARNINGS , Usage in Pregnancy ). In the first reproductive toxicity study 6 , primaquine was administered orally to rats between gestation day (GD) 6 and GD15 at dose levels of 10.3, 30.8 and 61.5 mg/kg/day (as base) (representing approximatively 7, 20 and 40 times the human dose [HD] on a body surface area comparison) when considering a human body weight of 60 kg).

High dose levels induced death of pregnant females in almost all cases, while lower dose levels caused maternal toxicity. At ces… [Excerpted — this section continues on DailyMed.]