5 WARNINGS AND PRECAUTIONS

5.1 Hemolytic Anemia

Due to the risk of hemolytic anemia in patients with G6PD deficiency, G6PD testing must be performed before prescribing KRINTAFEL [see Dosage and Administration (2.1)]. 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 KRINTAFEL is contraindicated in patients with G6PD deficiency or unknown G6PD status [see Contraindications (4)]. Patients were excluded from clinical trials of KRINTAFEL if they had a G6PD enzyme activity level <70% of the site median value for G6PD normal activity [see Clinical Studies (14)]. In clinical trials, declines in hemoglobin levels were reported in some G6PD-normal patients [see Adverse Reactions (6.1)]. Monitor patients for clinical signs or symptoms of hemolysis. Advise patients to seek medical attention if signs of hemolysis occur.

5.2 G6PD Deficiency in Pregnancy or Lactation

Potential Harm to the Fetus

The use of KRINTAFEL 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 KRINTAFEL during pregnancy is not recommended and to avoid pregnancy or use effective contraception for 3 months after the dose of KRINTAFEL [see Use in Specific Populations (8.1, 8.3)].

Potential Harm to the Breastfeeding Infant

A G6PD-deficient infant may be at risk for hemolytic anemia from exposure to KRINTAFEL through breast milk. Infant G6PD status should be checked before breastfeeding begins. KRINTAFEL 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 (4)]. 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 KRINTAFEL [see Use in Specific Populations (8.2)].

5.3 Methemoglobinemia

Asymptomatic elevations in methemoglobin have been observed in the clinical trials of KRINTAFEL [see Adverse Reactions (6.1)]. 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.

5.4 Psychiatric Effects

Psychiatric adverse reactions including anxiety (<1%), abnormal dreams (<1%), and insomnia (3%) have been reported in clinical trials of KRINTAFEL [see Adverse Reactions (6.1)]. 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 KRINTAFEL have not been established at doses or regimens other than the approved regimen; use of KRINTAFEL at doses or regimens other than a 300-mg single dose is not approved by FDA.

The benefit of treatment with 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 KRINTAFEL (approximately 15 days), signs or symptoms of psychiatric adverse reactions that may occur could be delayed in onset and/or duration [see Clinical Pharmacology (12.3)].

5.5 Hypersensitivity Reactions

Serious hypersensitivity reactions (e.g., angioedema, urticaria) have been observed with administration of KRINTAFEL [see Adverse Reactions (6.1)]. Institute appropriate therapy if hypersensitivity reactions occur. Do not re- administer KRINTAFEL. KRINTAFEL is contraindicated in patients who develop hypersensitivity to tafenoquine or any component of KRINTAFEL or other 8-aminoquinolines [see Contraindications (4)].

Due to the long half-life of KRINTAFEL (approximately 15 days), signs or symptoms of hypersensitivity adverse reactions that may occur could be delayed in onset and/or duration [see Clinical Pharmacology (12.3)]. Advise patients to seek medical attention if signs of hypersensitivity occur.

5.6 Risk of P. vivax Malaria Recurrence

Lack of efficacy in reducing P. vivax malaria recurrence in patients treated with KRINTAFEL combined with an artemisinin-containing antimalarial was seen in a clinical trial (NCT02802501). In this double-blind, randomized, placebo- controlled trial in which all patients with P. vivax malaria were treated with dihydroartemisinin/piperaquine (not approved artemisinin-containing antimalarial) and were coadministered KRINTAFEL, primaquine, or placebo, lack of efficacy (recurrence rates at 6 months following treatment) was seen in patients treated with KRINTAFEL.

Concomitant administration of KRINTAFEL with antimalarials other than chloroquine is not recommended.

2 DOSAGE AND ADMINISTRATION

2.1 Tests to be Performed Prior to Treatment with KRINTAFEL

All patients must be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to prescribing KRINTAFEL [see Contraindications (4), Warnings and Precautions (5.1)].

Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with KRINTAFEL [see Use in Specific Populations (8.1, 8.3)].

2.2 Recommended Dosage and Administration

The recommended dose of KRINTAFEL in patients aged 16 years and older is a single dose of 300 mg administered as two 150-mg tablets taken together. Coadminister KRINTAFEL on the first or second day of chloroquine therapy for acute P. vivax malaria [see Clinical Studies (14)].

Administer KRINTAFEL with food to increase systemic absorption [see Clinical Pharmacology (12.3)].

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

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year oral carcinogenicity studies were conducted in rats and mice. Renal cell adenomas and carcinomas were increased in male rats at doses of 1 mg/kg/day and above (3 times the clinical exposure based on AUC comparisons). Tafenoquine was not carcinogenic in mice. Given the single-dose administration of KRINTAFEL, these findings may not represent a carcinogenicity risk to humans.

Mutagenesis

Tafenoquine did not cause mutations or chromosomal damage in 2 definitive in vitro tests (bacterial mutation assay and mouse lymphoma L5178Y cell assay) or in an in vivo oral rat micronucleus test.

Impairment of Fertility

In a rat fertility study, tafenoquine was given orally at 1.5, 5, and 15 mg/kg/day (up to about 0.5 times the human dose based on body surface area comparisons) to males for at least 67 days, including 29 days prior to mating, and to females from 15 days prior to mating through early pregnancy. Tafenoquine resulted in reduced number of viable fetuses, implantation sites, and corpora lutea at 15 mg/kg in the presence of maternal toxicity (mortality, piloerection, rough coat, and reduced body weight).

17 PATIENT COUNSELING INFORMATION

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

G6PD Testing and Hemolytic Anemia

Inform patients of the need for testing for G6PD deficiency before starting KRINTAFEL. 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 [see Warnings and Precautions (5.1)].

Important Administration Instructions

Advise patients to take KRINTAFEL with food to increase absorption [see Dosage and Administration (2)].

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

Potential Harm to the Fetus

Advise females of reproductive potential of the potential risk of KRINTAFEL to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.2), Use in Specific Populations 8.1)].

Advise females of reproductive potential to avoid pregnancy or use effective contraception for 3 months after the dose of KRINTAFEL [see Use in Specific Populations (8.3)].

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 KRINTAFEL [see Contraindications (4), Warnings and Precautions (5.2), Use in Specific Populations (8.2)].

Methemoglobinemia

Inform patients that methemoglobinemia has occurred with KRINTAFEL. Advise patients of the symptoms of methemoglobinemia and instruct them to seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.3)].

Psychiatric Symptoms

Advise patients with a history of psychiatric illness regarding the potential for new or worsening psychiatric symptoms with KRINTAFEL and instruct them to seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.4)].

Hypersensitivity Reactions

Inform patients that hypersensitivity reactions have occurred with KRINTAFEL. Advise patients of the symptoms of hypersensitivity reactions and instruct them to seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.5)].

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