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Tafenoquine (Krintafel)

Class: Antimalarials
Chemical Name: (4RS)-N4-{2,6-Dimethoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]quinolin-8-yl}pentane-1,4-diamine
Molecular Formula: C24H28F3N3O3C24H28F3N3O3•C4H6O4
CAS Number: 106635-80-7
Brands: Krintafel

Medically reviewed by Drugs.com. Last updated on Feb 4, 2019.

Introduction

Tafenoquine succinate is an antimalarial agent.

Uses for Tafenoquine (Krintafel)

Tafenoquine succinate has the following uses:

Tafenoquine succinate (Krintafel) is an antimalarial indicated for the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged 16 years and older who are receiving appropriate antimalarial therapy for acute P. vivax infection.1

Tafenoquine succinate has the following limitations of use:

Tafenoquine succinate (Krintafel) is NOT indicated for the treatment of acute P. vivax malaria.1

Tafenoquine (Krintafel) Dosage and Administration

General

Tafenoquine succinate (Krintafel) is available in the following dosage form(s) and strength(s):

Tablets: 150 mg of tafenoquine.1

Clinicians should be aware that there are 2 different oral formulations of tafenoquine succinate with different indications and dosage regimens.1 2 The 100-mg tablets (e.g., Arakoda) are labeled for use for prophylaxis of malaria in adults; the 150-mg tablets (e.g., Krintafel) are labeled for use for the radical cure (prevention of relapse) of Plasmodium vivax malaria in adults and pediatric patients 16 years of age and older.1 2 Exercise caution to ensure that the appropriate dosage is used for the specific indication.

All patients must be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to prescribing tafenoquine succinate.1

Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with tafenoquine succinate.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Administer tafenoquine succinate with food to increase systemic absorption.1

Swallow tablets whole. Do not break, crush, or chew the tablets.1

In the event of vomiting within 1 hour after dosing, a repeat dose should be given. Re-dosing should not be attempted more than once.1

Pediatric Patients

The recommended dose of tafenoquine succinate (Krintafel) in pediatric patients aged 16 years and older is a single dose of 300 mg administered as two 150-mg tablets taken together. Coadminister tafenoquine succinate on the first or second day of the appropriate antimalarial therapy (e.g. chloroquine) for acute P. vivax malaria.1

Adults

The recommended dose of tafenoquine succinate (Krintafel) in adults is a single dose of 300 mg administered as two 150-mg tablets taken together. Coadminister tafenoquine succinate on the first or second day of the appropriate antimalarial therapy (e.g., chloroquine) for acute P. vivax malaria.1

Cautions for Tafenoquine (Krintafel)

Contraindications

  • G6PD deficiency or unknown G6PD status.1

  • Breastfeeding by a lactating woman when the infant is found to be G6PD deficient or if G6PD status is unknown.1

  • Known hypersensitivity reactions to tafenoquine, other 8-aminoquinolines, or any component of the tafenoquine succinate formulation.1

Warnings/Precautions

Hemolytic Anemia

Due to the risk of hemolytic anemia in patients with G6PD deficiency, G6PD testing must be performed before prescribing tafenoquine succinate. 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. Treatment with tafenoquine succinate is contraindicated in patients with G6PD deficiency or unknown G6PD status. Patients were excluded from clinical trials of tafenoquine succinate (Krintafel) if they had a G6PD enzyme activity level <70% of the site median value for G6PD normal activity. In clinical trials, declines in hemoglobin levels were reported in some G6PD-normal patients. Monitor patients for clinical signs or symptoms of hemolysis. Advise patients to seek medical attention if signs of hemolysis occur.1

G6PD Deficiency in Pregnancy or Lactation

Potential Harm to the Fetus: The use of tafenoquine succinate 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. Advise females of reproductive potential that treatment with tafenoquine succinate during pregnancy is not recommended and to avoid pregnancy or use effective contraception for 3 months after the dose of tafenoquine succinate.1

Potential Harm to the Breastfeeding Infant: A G6PD-deficient infant may be at risk for hemolytic anemia from exposure to tafenoquine succinate through breast milk. Infant G6PD status should be checked before breastfeeding begins. Tafenoquine succinate is contraindicated in breastfeeding women when the infant is found to be G6PD deficient or the G6PD status of the infant is unknown. Advise the woman with a G6PD-deficient infant or if the G6PD status of the infant is unknown not to breastfeed for 3 months after the dose of tafenoquine succinate.1

Methemoglobinemia

Asymptomatic elevations in methemoglobin have been observed in the clinical trials of tafenoquine succinate. Institute appropriate therapy if signs or symptoms of methemoglobinemia occur. Carefully monitor individuals with nicotinamide adenine dinucleotide (NADH)-dependent methemoglobin reductase deficiency. Advise patients to seek medical attention if signs of methemoglobinemia occur.1

Psychiatric Effects

Psychiatric adverse reactions including anxiety (<1%), abnormal dreams (<1%), and insomnia (3%) have been reported in clinical trials of tafenoquine succinate (Krintafel). Two cases of depression and 2 cases of psychosis have occurred primarily in patients with a history of psychiatric disorders following receipt of single doses of tafenoquine that were higher than the approved 300-mg dose (350 mg to 600 mg). Safety and effectiveness of tafenoquine succinate have not been established at doses or regimens other than the approved regimen; use of tafenoquine succinate (Krintafel) at doses or regimens other than a 300-mg single dose is not approved by FDA.1

The benefit of treatment with tafenoquine succinate (Krintafel) must be weighed against the potential risk for psychiatric adverse reactions in patients with a history of psychiatric illness. Due to the long half-life of tafenoquine succinate (approximately 15 days), signs or symptoms of psychiatric adverse reactions that may occur could be delayed in onset and/or duration.1

Hypersensitivity Reactions

Serious hypersensitivity reactions (e.g., angioedema, urticaria) have been observed with administration of tafenoquine succinate. Institute appropriate therapy if hypersensitivity reactions occur. Do not re-administer tafenoquine succinate. Tafenoquine succinate is contraindicated in patients who develop hypersensitivity to tafenoquine or any component of the tafenoquine succinate formulation or other 8-aminoquinolines.1

Due to the long half-life of tafenoquine succinate (approximately 15 days), signs or symptoms of hypersensitivity adverse reactions that may occur could be delayed in onset and/or duration. Advise patients to seek medical attention if signs of hypersensitivity occur.1

Specific Populations

Pregnancy

Risk Summary: The use of tafenoquine succinate during pregnancy may cause hemolytic anemia in a fetus who is G6PD deficient. Treatment with tafenoquine succinate during pregnancy is not recommended. Available data with use of tafenoquine succinate in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, there were increased abortions, with and without maternal toxicity, when tafenoquine succinate was given orally to pregnant rabbits at and above doses equivalent to about 0.4 times the clinical exposure based on body surface area comparisons. No fetotoxicity was observed at doses equivalent to the clinical exposure (based on body surface area comparisons) in a similar study in rats.1

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.1

Disease-Associated Maternal and/or Embryo/Fetal Risk: Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth.1

Animal Data: Tafenoquine resulted in dose-related abortions when given orally to pregnant rabbits during organogenesis (Gestation Days 6 to 18) at doses of 7 mg/kg (about 0.4 times the clinical exposure based on body surface area comparisons) and above. Doses higher than 7 mg/kg were also associated with maternal toxicity (mortality and reduced body weight gain). In a similar study in rats, doses of 3, 10, or 30 mg/kg/day resulted in maternal toxicity (enlarged spleen, reduced body weight, and reduced food intake) but no fetotoxicity at the high dose (equivalent to the clinical exposure based on body surface area comparisons). There was no evidence of malformations in either species. In a pre- and postnatal development study in rats, tafenoquine administered throughout pregnancy and lactation produced maternal toxicity and a reversible decrease in offspring body weight gain and decrease in motor activity at 18 mg/kg/day, which is equivalent to about 0.6 times the clinical dose based on body surface area comparisons.1

Lactation

Risk Summary: A breastfed infant with G6PD deficiency is at risk for hemolytic anemia from exposure to tafenoquine succinate. Infant G6PD status should be checked before breastfeeding begins. Tafenoquine succinate is contraindicated in breastfeeding women when the infant is found to be G6PD deficient or the G6PD status of the infant is unknown.1

There is no information regarding the presence of tafenoquine succinate in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. In a breastfed infant with normal G6PD, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tafenoquine succinate and any potential effects on the breastfed infant from tafenoquine succinate or from the underlying maternal condition.1

Clinical Considerations: Check the infant’s G6PD status before maternal breastfeeding commences. If an infant is G6PD deficient, exposure to tafenoquine succinate during breastfeeding may result in hemolytic anemia in the infant; therefore, advise the woman with an infant who has G6PD deficiency or whose G6PD status is unknown, not to breastfeed for 3 months after the dose of tafenoquine succinate.1

Females And Males of Reproductive Potential

Verify the pregnancy status in females of reproductive potential prior to initiating treatment with tafenoquine succinate.1

Tafenoquine succinate may cause hemolytic anemia in a G6PD-deficient fetus. Advise females of reproductive potential that treatment with tafenoquine succinate during pregnancy is not recommended and to avoid pregnancy or use effective contraception for 3 months after the dose of tafenoquine succinate.1

Pediatric Use

The safety and effectiveness of tafenoquine succinate (Krintafel) have been established in pediatric patients aged 16 years and older. Use of tafenoquine succinate in these pediatric patients is supported by evidence from adequate and well-controlled studies of tafenoquine succinate.1

Safety and effectiveness of tafenoquine succinate in pediatric patients younger than 16 years have not been established.1

Geriatric Use

Clinical trials of tafenoquine succinate (Krintafel) did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.1

Renal Impairment

The pharmacokinetics of tafenoquine succinate have not been studied in patients with renal impairment. If tafenoquine succinate is administered to such patients, monitoring for adverse reactions associated with tafenoquine succinate is needed.1

Hepatic Impairment

The pharmacokinetics of tafenoquine succinate have not been studied in patients with hepatic impairment. If tafenoquine succinate is administered to such patients, monitoring for adverse reactions associated with tafenoquine succinate is needed.1

Common Adverse Effects

Common adverse reactions (≥5%) were dizziness, nausea, vomiting, headache, and decreased hemoglobin.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Avoid coadministration with drugs that are substrates of organic cation transporter-2 (OCT2) or multidrug and toxin extrusion (MATE) transporters.1

Actions and Spectrum

Mechanism of Action

Tafenoquine, an 8-aminoquinoline antimalarial, is active against the liver stages including the hypnozoite (dormant stage) of P. vivax. In addition to its effect on the parasite, tafenoquine causes red blood cell shrinkage in vitro. The molecular target of tafenoquine is not known.1

Spectrum

Tafenoquine is active against pre-erythrocytic (liver) and erythrocytic (asexual) forms as well as gametocytes of P. vivax. The activity of tafenoquine against the pre-erythrocytic liver stages of the parasite prevents the development of the erythrocytic forms of the parasite, which are responsible for relapses in P. vivax malaria.1

Resistance

A potential for development of resistance of Plasmodium species to tafenoquine was not evaluated.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

G6PD Testing and Hemolytic Anemia: Inform patients of the need for testing for G6PD deficiency before starting tafenoquine succinate. Advise patients of the symptoms of hemolytic anemia and instruct them to seek medical advice promptly if such symptoms occur. Patients should contact their healthcare provider if they develop dark lips or urine as these may be signs of hemolysis or methemoglobinemia.1

Important Administration Instructions: Advise patients to take tafenoquine succinate with food to increase absorption.1

Advise patients to swallow the tablet whole and not to break, crush, or chew it.1

Potential Harm to the Fetus: Advise females of reproductive potential of the potential risk of tafenoquine succinate to a fetus and to inform their healthcare provider of a known or suspected pregnancy.1

Advise females of reproductive potential to avoid pregnancy or use effective contraception for 3 months after the dose of tafenoquine succinate (Krintafel).1

Lactation: Advise women with a G6PD-deficient infant, or if they do not know the G6PD status of their infant, not to breastfeed for 3 months after the dose of tafenoquine succinate (Krintafel).1

Methemoglobinemia: Inform patients that methemoglobinemia has occurred with tafenoquine succinate. Advise patients of the symptoms of methemoglobinemia and instruct them to seek medical advice promptly if such symptoms occur.1

Psychiatric Symptoms: Advise patients with a history of psychiatric illness regarding the potential for new or worsening psychiatric symptoms with tafenoquine succinate and instruct them to seek medical advice promptly if such symptoms occur.1

Hypersensitivity Reactions: Inform patients that hypersensitivity reactions have occurred with tafenoquine succinate. Advise patients of the symptoms of hypersensitivity reactions and instruct them to seek medical advice promptly if such symptoms occur.1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Tafenoquine Succinate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, Film Coated

150 mg (of tafenoquine)

Krintafel

GlaxoSmithKline LLC

AHFS Drug Information. © Copyright 2021, Selected Revisions February 4, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. GlaxoSmithKline LLC. Krintafel (tafenoquine succinate) ORAL prescribing information. 2018 Jul. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5cf989d5-36f5-4561-a30b-9fcb9deb6b6a

2. 60 Degrees Pharmaceuticals, LLC. Arakoda (tafenoquine) ORAL prescribing information. 2018 Aug. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=299e49d8-470f-4779-a010-4a1ee0e0c6cd

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