Get your patient on Primaquine Phosphate - Primaquine Phosphate tablet (Primaquine Phosphate)
Primaquine Phosphate - Primaquine Phosphate tablet prescribing information
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
Known hypersensitivity reactions to primaquine phosphate, other 8-aminoquinolones, or to any component in Primaquine phosphate Tablets.
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 phosphate Tablets is contraindicated. Similarly, Primaquine phosphate Tablets 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 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.
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: Microcrystalline Cellulose, Pregelatinized Starch, Lactose Monohydrate, Magnesium Stearate, Purified Water, Hypromellose, Opadry Purple, Titanium Dioxide, Macrogol/PEG, FD&C Red #40 and FD&C Blue #2.
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.
| 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 ).
CLINICAL STUDIES
Persons with acute attacks of vivax malaria, provoked by the release of erythrocytic forms of the parasite, respond readily to therapy, particularly to chloroquine phosphate. Primaquine eliminates tissue (exoerythrocytic) infection and prevents relapses in experimentally induced vivax malaria in human volunteers and in persons with naturally occurring infections and is a valuable adjunct to conventional therapy in vivax malaria.
To report SUSPECTED ADVERSE REACTIONS, contact Unichem Pharmaceuticals (USA) Inc. at 1-866-562-4616 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
HOW SUPPLIED
Primaquine phosphate Tablets USP are solid oral formulation round purple tablet debossed "BY4" available in 26.3 mg (=15 mg base) and 100 count.
Available in bottles of 100 tablets. (NDC 76385-102-01)
Store at 25° C (77° F); excursions permitted to 15° - 30° C (59° - 86° F) [see USP Controlled Room Temperature].
Dispense in tight, light-resistant container as defined in the USP/NF.
