PRIMAQUINE PHOSPHATE TABLETS, USP

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.

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.

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).

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.

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.

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).

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.

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 mutations¹, chromosomal damage and DNA strand breaks². 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).

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 study⁶, 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 cesarean section, embryo resorption, a decrease in fetal survival rate and body size, internal abnormalities (including hydrocephalia, heterotaxia), and an increase in skeletal variations were observed at the mid dose-level. There were no fetal abnormalities at the low dose level providing a potential safety margin of at least 7 times the recommended clinical dose.

For the second reproductive toxicity study⁷, 6 to10 animals per group were used. Dose levels of 0.57, 5.7, 11.4 and 34 mg/kg/day of primaquine (as base) (representing approximatively 0.4, 4, 7 and 22 times the HD on a body surface area comparison) were administered orally to Sprague Dawley rats between GD8 and GD16, or of 57 mg/kg only once on GD13 (representing more than 37 times the HD on a body surface area comparison). A total of 1/7 and 4/6 pregnant females at 34 mg/kg/day and at 57 mg/kg, respectively, died. Primaquine-associated teratogenic malformations (including cleft palate and small chin) were observed in 4/54 fetuses in the 57 mg/kg single-dose group.

Safety and effectiveness in pediatric patients have not been established.

Primaquine phosphate Tablets are contraindicated in breastfeeding women when the infant is found to be G6PD deficient or the G6PD status of the infant is unknown (see CONTRAINDICATIONS and WARNINGS, Nursing Mothers).

Clinical studies of Primaquine phosphate Tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Efficacy and safety of Primaquine phosphate Tablets after repeated dosing have not been assessed in patients with hepatic impairment. Primaquine is metabolized in the liver to generate active metabolites, and it is not known if efficacy could be affected in patients with hepatic impairment. Because of limited data, there is no specific dosing adjustment. If Primaquine phosphate Tablets are administered to such patients, monitoring of efficacy and for primaquine-related adverse reactions is needed, in particular in patients with severe hepatic impairment (see CLINICAL PHARMACOLOGY).

The efficacy and safety of Primaquine phosphate Tablets after repeated dosing have not been assessed in patients with renal impairment. Because of limited data, there is no specific dosing adjustment. If Primaquine phosphate Tablets are administered to such patients, monitoring of efficacy and for primaquine-related adverse reactions is needed, in particular in patients with severe renal impairment (see CLINICAL PHARMACOLOGY).

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.

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.

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.