Arakoda (tafenoquine succinate)

It isessential 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.

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

*The recommended dosage of tafenoquine succinate (Arakoda(R)) is described in Table 1 below. Tafenoquine succinate may be administered for up to 6 months of continuous dosing.

Table 1: Recommended Dosage of Tafenoquine Succinate (Arakoda(R)) in Adults (>=18 Years of Age).

Regimen Name Timing Dosage Loading regimen For each of the 3 days 200 mg (2 of the 100 mg before travel to a tablets) once daily for malarious area 3 days Maintenance regimen While in the malarious 200 mg (2 of the 100 mg area tablets) once weekly; start 7 days after the last loading regimen dose Terminal prophylaxis In the week following 200 mg (2 of the 100 mg regimen exit from the malarious tablets) taken one time area 7 days after the last maintenance dose

*Complete the full course of tafenoquine succinate including the loading dose and the terminal dose.

*See full prescribing information for instructions on how to replace missed doses.

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There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Tafenoquine/Dofetilide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The active tubular secretion via organic cationic transporter 2 (OCT2) of dofetilide may be inhibited by tafenoquine.(1)

CLINICAL EFFECTS: The concurrent administration of dofetilide with tafenoquine may result in elevated levels and increased effects of dofetilide including torsades de pointes.(1)

PREDISPOSING FACTORS: Renal impairment may increase risk for excessive QTc prolongation as dofetilide is primarily renally eliminated. To prevent increased serum levels and risk for ventricular arrhythmias, dofetilide must be dose adjusted for creatinine clearance < or = to 60 mL/min.(1) The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of dofetilide states that the concurrent administration of dofetilide with known inhibitors of the renal cation transport system should not be used. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting tafenoquine.(1) The manufacturer of tafenoquine states the concurrent administration of tafenoquine with organic cationic transporter 2 (OCT2) substrates, such as dofetilide, should be avoided. If coadministration cannot be avoided, monitor for drug-related toxicities.(3)

DISCUSSION: Dofetilide is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. Tafenoquine is believed to inhibit the cation transport system (OCT2).(1,3)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Tafenoquine/Metformin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Metformin renal clearance is mediated by OCT2 and MATE1 transporters.(1) Tafenoquine inhibits elimination by these pathways.(2)

CLINICAL EFFECTS: Use of tafenoquine may increase levels of metformin, which may result in lactic acidosis.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment, sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population.

PATIENT MANAGEMENT: The US labeling for metformin recommends the dose of metformin be adjusted as needed.(1) The manufacturer of tafenoquine states the concurrent administration of tafenoquine with OCT2 and MATE1 substrates, such as metformin, should be avoided. If coadministration cannot be avoided, monitor for drug-related toxicities.(2) Evaluate patient's renal function and consider discontinuation in patients with renal impairment. Monitor for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: elevated blood lactate levels (greater than 5 mmol/L), low pH, an increased anion gap, and increased lactate to pyruvate ratio.

DISCUSSION: Metformin renal clearance is mediated by OCT2 and MATE1 transporters.(1) Tafenoquine is believed to inhibit the OCT2 and MATE1 pathways.(2)

Tafenoquine/Procainamide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The active tubular secretion of procainamide and N-acetylprocainamide via organic cation transporter 2 (OCT2) may be inhibited by tafenoquine.(1)

CLINICAL EFFECTS: The concurrent administration of procainamide with tafenoquine may result in elevated levels and increased toxicities of procainamide, including torsades de pointes.(1)

PREDISPOSING FACTORS: Renal impairment may increase risk for excessive QTc prolongation as procainamide is primarily renally eliminated. The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The manufacturer of tafenoquine states the concurrent administration of tafenoquine with organic cation transporter 2 (OCT2) substrates with a narrow therapeutic index, such as procainamide, should be avoided.(1,2) If concurrent use cannot be avoided, monitor patient for signs and symptoms of procainamide toxicity. Procainamide and N-acetylprocainamide levels should be checked. Elderly patients and those with impaired renal function are especially at risk.

DISCUSSION: Procainamide and its metabolite N-acetylprocainamide are primarily excreted in the urine by both glomerular filtration and active tubular secretion via the cation transport system. Tafenoquine is believed to inhibit the cation transport system (OCT2).(1-3) Signs and symptoms of procainamide toxicity include widening of the QRS complex, tachycardia, intraventricular conduction delay, hypotension, oliguria, lethargy, confusion, nausea and vomiting.

There are no moderate interactions for this drug.

*G6PD deficiency or unknown G6PD status.

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

*Patients with a history of psychotic disorders or current psychotic symptoms.

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

• Glucose-6-phosphate dehydrogenase (g6Pd) deficiency
• Hemoglobin H disease
• Lactation
• Psychotic disorder

There are no severe contraindications for this drug.

• NADH methemoglobin reductase deficiency

The most common adverse reactions (incidence >=1%) were: headache, dizziness, back pain, diarrhea, nausea, vomiting, increased alanine aminotransferase (ALT), motion sickness, insomnia, depression, abnormal dreams, anxiety.

More Frequent

• Anemia

Rare or Very Rare

• Angioedema
• Drug-induced psychosis
• Hemolytic anemia
• Hypersensitivity drug reaction
• Methemoglobinemia
• Urticaria

More Frequent

• Dizziness
• Headache disorder
• Nausea
• Vomiting

Less Frequent

• Drowsy
• Insomnia
• Photophobia

Rare or Very Rare

• Corneal verticillata
• Depression
• Dream disorder
• Symptoms of anxiety

No enhanced messaging available.

Safety and effectiveness of tafenoquine succinate (Arakoda(R)) in pediatric patients have not been established.

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. If a pregnancy is detected during tafenoquine succinate use, discontinue tafenoquine succinate as soon as possible and switch to an alternative prophylactic drug for malaria during pregnancy. 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 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 about 1.5 times 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 2% to 4% and 15% to 20%, respectively.

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.

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 (about 1.5 times 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.

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.

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.

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 during treatment with tafenoquine succinate and for 3 months after the final dose of tafenoquine succinate.

Clinical trials of tafenoquine succinate (Arakoda(R)) 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.