Krintafel Drug Information

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. Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with KRINTAFEL.

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. Administer KRINTAFEL with food to increase systemic absorption.

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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below reflect exposure to 4,129 subjects, of whom 810 received a 300-mg single dose of KRINTAFEL. In Trial 1, in patients with P. vivax malaria, the most common adverse reactions reported in ≥5% of patients treated with KRINTAFEL are listed in Table 1.

Table 1. Selected Adverse Reactions a Reported in ≥5% of Patients with P. vivax Malaria Receiving KRINTAFEL in a Randomized, Active-Controlled Trial (Trial 1) s Reported with KRINTAFEL Clinically significant adverse reactions with KRINTAFEL 300-mg single dose in clinical trials (n = 810) in ≤3% of subjects are listed below: Psychiatric Disorders: Anxiety, insomnia, abnormal dreams. Nervous System Disorders: Somnolence.

Laboratory Investigations: Increased blood creatinine, increased blood methemoglobin, increased alanine aminotransferase. Immune System Disorders: Hypersensitivity reactions (e.g., angioedema, urticaria). Eye Disorders: Vortex keratopathy, photophobia.

Effect of KRINTAFEL on Organic Cation Transporter-2 (OCT2) and Multidrug and Toxin Extrusion (MATE) Substrates The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates in humans is unknown. However, in vitro observations suggest the potential for increased concentrations of these substrates which may increase the risk of toxicity of these drugs. Avoid coadministration of KRINTAFEL with OCT2 and MATE substrates (e.g., dofetilide, metformin).

If coadministration cannot be avoided, monitor for drug-related toxicities and consider dosage reduction if needed based on approved product labeling of the coadministered drug.

Pregnancy Risk Summary The use of KRINTAFEL during pregnancy may cause hemolytic anemia in a fetus who is G6PD deficient. Treatment with KRINTAFEL during pregnancy is not recommended. Available data with use of KRINTAFEL 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 KRINTAFEL 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. 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 respectively. Clinical Considerations 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.

Data 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). 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.

Pediatric Use The safety and effectiveness of KRINTAFEL have been established in pediatric patients aged 16 years and older. Use of KRINTAFEL in these pediatric patients is supported by evidence from adequate and well-controlled studies of KRINTAFEL. Safety and effectiveness of KRINTAFEL in pediatric patients younger than 16 years have not been established.

• KRINTAFEL is contraindicated in:
• Patients with G6PD deficiency or unknown G6PD status due to the risk of hemolytic anemia.
• Breastfeeding by a lactating woman when the infant is found to be G6PD deficient or if the G6PD status of the infant is unknown.
• Patients with known hypersensitivity to tafenoquine, other 8-aminoquinolines, or any component of KRINTAFEL.
• G6PD deficiency or unknown G6PD status.
• Known hypersensitivity reactions to tafenoquine, other 8-aminoquinolines, or any component of KRINTAFEL.

Hemoglobin decline and methemoglobinemia may be encountered in an overdose with KRINTAFEL. Treatment of overdosage consists of institution of appropriate symptomatic and/or supportive therapy.