Clinical Pharmacology Corner: FDA Approves KRINTAFEL (tafenoquine)

FDA Approves KRINTAFEL (tafenoquine) for Radical Cure of Plasmodium Vivax malaria in Patients Aged 16 Years and OIder who are Receiving Appropriate Antimalarial Therapy for Acute P. Vivax Infection

On July 20, 2018, the U.S. Food and Drug Administration (FDA) approved KRINTAFEL (tafenoquine) 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. KRINTAFEL is not indicated for the treatment of acute P. vivax malaria. The approved recommended dosage of KRINTAFEL is a single 300 mg dose administered as two 150 mg tablets taken together with food. Coadminister KRINTAFEL on the first or second day of the appropriate antimalarial therapy for the acuteP. vivax malaria.

Due to the risk of hemolytic anemia, KRINTAFEL is contraindicated in patients with G6PD deficiency or unknown G6PD status and when breastfeeding by a lactating woman when the infant is found to be G6PD deficient or if the G6PD status of the infant is unknown. Test all patients for G6PD deficiency prior to prescribing KRINTAFEL, monitor for clinical signs and symptoms of hemolysis, and perform a pregnancy test for females of reproductive potential prior to initiating treatment.

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD) 

• MOA: Tafenoquine is an 8-aminoquinoline antimalarial drug that is active against the liver stages including the hypnozoite (dormant stage) of P. vivax. The molecular target of tafenoquine is not known.
• Absorption: Maximum plasma concentrations were generally observed 12 to 15 hours following oral administration. Plasma tafenoquine AUC increased by 41% and C_max increased by 31% when administered as an investigational capsule formulation with a high-calorie, high-fat meal (approximately 1,000 calories with 15% protein, 25% carbohydrate, and 60% fat) compared with the fasted state.
• Distribution: Protein binding of tafenoquine is > 99.5%. The apparent oral volume of distribution is approximately 1,600 L. Following single- and multiple-oral-dose administration, tafenoquine whole blood concentrations were on average 67% higher than corresponding plasma values.
• Elimination: The apparent oral clearance of tafenoquine is approximately 3 L/h. The average terminal half-life is approximately 15 days.
• Metabolism: Tafenoquine undergoes slow metabolism. Unchanged tafenoquine represented the only notable drug-related component in human plasma after a single oral dose of tafenoquine.
• Excretion: The full excretion profile of tafenoquine in humans is unknown. Over a 6-day collection period, renal elimination of unchanged tafenoquine was low.
• PD: A saturable relationship between tafenoquine AUC and clinical response (recurrence free rate at 6 months) was identified. Tafenoquine AUCs achieved with the 300 mg or higher than the approved recommended dosage were on the plateau of the exposure-response curve.

Drug Interactions

Avoid coadministration of KRINTAFEL with organic cation transporter-2 (OCT2) and multidrug and toxin extrusion (MATE) substrates (e.g., dofetilide, metformin). If coadministration cannot be avoided, monitor for drug-related toxicities of OCT2 and MATE substrates and consider dosage reduction if needed based on approved product labeling of these drugs. In vitro observations of coadministration with tafenoquine suggest the potential for increased concentrations of OCT2 and MATE substrates which may increase the risk of toxicity of these drugs. 

Use in Specific Populations

The pharmacokinetics of tafenoquine were not significantly impacted by age, sex, ethnicity, or body weight. The effect of renal or hepatic impairment on tafenoquine pharmacokinetics is unknown.

Efficacy and Safety

Efficacy of KRINTAFEL was demonstrated in a multi-regional, randomized, double-blind, controlled clinical trial and in a dose-ranging trial of similar design in adults positive for P. vivax. The primary efficacy endpoint in both studies was recurrence-free efficacy rates at 6 months. Additional information regarding efficacy trials can be found in the full prescribing information linked below.

 

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

Full prescribing information is available at https://go.usa.gov/xUP6x. 

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online athttp://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.