Introduction

Tafenoquine succinate is an antimalarial agent.

Uses for Tafenoquine (Arakoda)

Tafenoquine succinate has the following uses:

Tafenoquine succinate (Arakoda) is an antimalarial indicated for the prophylaxis of malaria in patients aged 18 years and older.

Tafenoquine (Arakoda) Dosage and Administration

General

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

Tablets: 100 mg of tafenoquine.

Clinicians should be aware that there are 2 different oral formulations of tafenoquine succinate with different indications and dosage regimens. 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. 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.

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

Dosage

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

Adults

Dosage and Administration

• Administer tafenoquine succinate with food.

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

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

• 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.

Contraindications

• 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.

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 with 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. 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 discontinue tafenoquine succinate and seek medical attention if signs of hemolysis occur.

G6PD Deficiency in Pregnancy and 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 during treatment and for 3 months after the last dose of tafenoquine succinate. 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.

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

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 discontinue tafenoquine succinate and seek medical attention if signs of methemoglobinemia occur.

Psychiatric Effects

In patients receiving tafenoquine succinate (Arakoda) in clinical trials, psychiatric adverse reactions included sleep disturbances (2.5%), depression/depressed mood (0.3%), and anxiety (0.2%). Tafenoquine succinate was discontinued in a subject with an adverse reaction of suicide attempt (0.1%). Subjects with a history of psychiatric disorders were excluded from three of five tafenoquine succinate trials in which mefloquine was included as a comparator.

Psychosis was reported in three patients with a history of psychosis or schizophrenia who received tafenoquine doses (350 mg to 500 mg single dose, or 400 mg daily for 3 days) different from the approved tafenoquine succinate regimen. Safety and effectiveness of tafenoquine succinate have not been established at doses or regimens other than the approved regimen; use of tafenoquine succinate (Arakoda) at doses or regimens other than a 200-mg weekly dose is not approved by FDA.

Tafenoquine succinate (Arakoda) is contraindicated in patients with a history of psychotic disorders or current psychotic symptoms. If psychotic symptoms (hallucinations, delusions, or grossly disorganized thinking or behavior) occur, consider discontinuation of tafenoquine succinate and prompt evaluation by a mental health professional as soon as possible. Other psychiatric symptoms, such as changes in mood, anxiety, insomnia, and nightmares, should be promptly evaluated by a medical professional if they are moderate and last more than three days or are severe.

Hypersensitivity Reactions

Serious hypersensitivity reactions (e.g., angioedema and urticaria) have been observed with administration of tafenoquine. Hypersensitivity reactions have been reported in clinical trials of tafenoquine succinate. Discontinue prophylaxis with tafenoquine succinate and institute appropriate therapy if hypersensitivity reactions occur. Tafenoquine succinate is contraindicated in patients who develop hypersensitivity to tafenoquine or any component of the tafenoquine succinate formulation or other 8-aminoquinolines.

Delayed Adverse Reactions

Adverse reactions including hemolytic anemia, methemoglobinemia, psychiatric effects, and hypersensitivity reactions were reported with the use of tafenoquine succinate or tafenoquine in clinical trials. Due to the long half-life of tafenoquine succinate (approximately 17 days), psychiatric effects, hemolytic anemia, methemoglobinemia, and signs or symptoms of hypersensitivity reactions that may occur could be delayed in onset and/or duration. Advise patients to seek medical attention if signs of hypersensitivity occur.

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. 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.

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.

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.

Females and Males of Reproductive Potential

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

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 final dose of tafenoquine succinate.

Pediatric Use

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

Geriatric Use

Clinical trials of tafenoquine succinate (Arakoda) 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.

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.

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.

Common Adverse Effects

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.

General

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

Tablets: 100 mg of tafenoquine.

Clinicians should be aware that there are 2 different oral formulations of tafenoquine succinate with different indications and dosage regimens. 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. 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.

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

Dosage

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

Adults

Dosage and Administration

• Administer tafenoquine succinate with food.

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

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

• 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.

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.