KRINTAFEL

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KRINTAFEL

Classes

Antimalarials

Administration
Oral Administration Oral Solid Formulations

Administer with food.
Swallow tablets whole. Do not break, crush, or chew the tablets.
 
For radical cure (prevention of relapse) single-dose therapy:
In the event of vomiting within 1 hour after dosing, repeat the dose. Do not attempt redosing more than once.
 
For multidose malaria prophylaxis therapy:
For 1 loading dose missed, replace 1 dose of 200 mg so that total of 3 daily loading doses have been taken. Begin maintenance dose 1 week after last loading dose.
For 2 loading doses missed, replace 2 doses of 200 mg on 2 consecutive days so that total of 3 daily loading doses have been taken. Begin maintenance dose 1 week after last loading dose.
For 1 or 2 weekly maintenance doses missed, replace 1 dose of 200 mg on any day up to the time of the next scheduled weekly dose.
For 3 or more weekly maintenance doses missed, replace 2 doses of 200 mg, taken as 200 mg once daily on 2 consecutive days up to the time of the next scheduled weekly dose.
For terminal prophylaxis dose missed, replace 1 dose of 200 mg as soon as remembered.

Adverse Reactions
Severe

angioedema / Rapid / 0-3.0
hemolytic anemia / Delayed / 0-1.0
night blindness / Delayed / 0-1.0
visual impairment / Early / 0-1.0
methemoglobinemia / Early / Incidence not known

Moderate

keratopathy / Delayed / 0-93.0
elevated hepatic enzymes / Delayed / 3.0-4.0
photophobia / Early / 0-3.0
thrombocytopenia / Delayed / 0-1.0
anemia / Delayed / 0-1.0
depression / Delayed / 0-1.0
psychosis / Early / 0-1.0
hyperesthesia / Delayed / 0-1.0
amnesia / Delayed / 0-1.0
hyperbilirubinemia / Delayed / 0-1.0
jaundice / Delayed / 0-1.0
cholestasis / Delayed / 0-1.0
blurred vision / Early / 0-1.0
hyperacusis / Delayed / 0-1.0

Mild

headache / Early / 5.0-32.0
diarrhea / Early / 5.0-18.0
back pain / Delayed / 14.0-14.0
dizziness / Early / 1.0-8.0
nausea / Early / 5.0-7.0
vomiting / Early / 2.0-6.0
vertigo / Early / 5.0-5.0
insomnia / Early / 1.0-3.0
urticaria / Rapid / 0-3.0
drowsiness / Early / 0-3.0
abnormal dreams / Early / 0-2.0
agitation / Early / 0-1.0
anxiety / Delayed / 0-1.0
syncope / Early / 0-1.0
tremor / Early / 0-1.0
hypoesthesia / Delayed / 0-1.0
somnambulism / Early / Incidence not known
nightmares / Early / Incidence not known

Common Brand Names

Arakoda, KRINTAFEL

Dea Class

Rx

Description

Oral antimalarial
Used for malaria prophylaxis in adults and for radical cure (prevention of relapse) of P. vivax malaria in patients aged 16 years and older who are receiving appropriate antimalarial therapy for acute P. vivax infection
Glucose-6-phosphate dehydrogenase (G6PD) deficiency screening required prior to use

Dosage And Indications
For the radical cure (prevention of relapse) of malaria due to P. vivax or P. ovale† in patients who are receiving appropriate antimalarial therapy for acute infection. Oral dosage (Krintafel) Adults

300 mg PO as a single dose on the first or second day of the appropriate antimalarial therapy.[63373] Guidelines recommend for chloroquine-susceptible P. vivax or P. ovale in combination with chloroquine or hydroxychloroquine. The FDA-approved labeling indicates tafenoquine only for use with chloroquine due to recurrence demonstrated in patients receiving artemisinin-based therapy.

Adolescents 16 to 17 years

300 mg PO as a single dose on the first or second day of the appropriate antimalarial therapy.[63373] Guidelines recommend for chloroquine-susceptible P. vivax or P. ovale in combination with chloroquine or hydroxychloroquine. The FDA-approved labeling indicates tafenoquine only for use with chloroquine due to recurrence demonstrated in patients receiving artemisinin-based therapy.

For malaria prophylaxis. For primary malaria prophylaxis. Oral dosage (Arakoda) Adults

200 mg PO once daily for 3 days prior to entry into endemic area, then 200 mg PO once weekly starting 7 days after the last loading dose and continuing during travel to malarious area as maintenance regimen, then 200 mg PO once at 7 days after the last maintenance dose in the week after leaving the area as terminal prophylaxis regimen. Tafenoquine may be administered for up to 6 months of continuous dosing. Recommended for travel to all areas.

Adolescents† 16 to 17 years

200 mg PO once daily for 3 days prior to entry into endemic area, then 200 mg PO once weekly starting 7 days after the last loading dose and continuing during travel to malarious area as maintenance regimen, then 200 mg PO once at 7 days after the last maintenance dose in the week after leaving the area as terminal prophylaxis regimen. Tafenoquine may be administered for up to 6 months of continuous dosing. Recommended for travel to all areas.

For presumptive antirelapse malaria prophylaxis† of either P. vivax or P. ovale malaria. Oral dosage (Arakoda or Krintafel) Adults

300 mg PO as a single dose with the last dose of primary prophylaxis, or alternately, after primary prophylaxis has been completed.

Adolescents 16 to 17 years

300 mg PO as a single dose with the last dose of primary prophylaxis, or alternately, after primary prophylaxis has been completed.

Dosing Considerations
Hepatic Impairment

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. 

Drug Interactions

Alogliptin; Metformin: (Moderate) Consider the benefits and risks of coadministration of tafenoquine and metformin due to the potential for increased metformin concentrations and lactic acidosis. If coadministration cannot be avoided, monitor for metformin-related toxicities, and consider metformin dosage reduction, if needed. The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like metformin, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Tafenoquine may interfere with these common renal tubular transport systems involved in the renal elimination of metformin.
Canagliflozin; Metformin: (Moderate) Consider the benefits and risks of coadministration of tafenoquine and metformin due to the potential for increased metformin concentrations and lactic acidosis. If coadministration cannot be avoided, monitor for metformin-related toxicities, and consider metformin dosage reduction, if needed. The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like metformin, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Tafenoquine may interfere with these common renal tubular transport systems involved in the renal elimination of metformin.
Dapagliflozin; Metformin: (Moderate) Consider the benefits and risks of coadministration of tafenoquine and metformin due to the potential for increased metformin concentrations and lactic acidosis. If coadministration cannot be avoided, monitor for metformin-related toxicities, and consider metformin dosage reduction, if needed. The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like metformin, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Tafenoquine may interfere with these common renal tubular transport systems involved in the renal elimination of metformin.
Dofetilide: (Contraindicated) Coadministration of dofetilide and tafenoquine is contraindicated due to the potential for increased dofetilide concentrations and arrhythmias (QT prolongation and torsade de pointes). The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like dofetilide, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Dofetilide is eliminated by cationic renal secretion, and tafenoquine may interfere with the renal elimination of dofetilide.
Empagliflozin; Linagliptin; Metformin: (Moderate) Consider the benefits and risks of coadministration of tafenoquine and metformin due to the potential for increased metformin concentrations and lactic acidosis. If coadministration cannot be avoided, monitor for metformin-related toxicities, and consider metformin dosage reduction, if needed. The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like metformin, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Tafenoquine may interfere with these common renal tubular transport systems involved in the renal elimination of metformin.
Empagliflozin; Metformin: (Moderate) Consider the benefits and risks of coadministration of tafenoquine and metformin due to the potential for increased metformin concentrations and lactic acidosis. If coadministration cannot be avoided, monitor for metformin-related toxicities, and consider metformin dosage reduction, if needed. The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like metformin, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Tafenoquine may interfere with these common renal tubular transport systems involved in the renal elimination of metformin.
Ertugliflozin; Metformin: (Moderate) Consider the benefits and risks of coadministration of tafenoquine and metformin due to the potential for increased metformin concentrations and lactic acidosis. If coadministration cannot be avoided, monitor for metformin-related toxicities, and consider metformin dosage reduction, if needed. The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like metformin, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Tafenoquine may interfere with these common renal tubular transport systems involved in the renal elimination of metformin.
Glipizide; Metformin: (Moderate) Consider the benefits and risks of coadministration of tafenoquine and metformin due to the potential for increased metformin concentrations and lactic acidosis. If coadministration cannot be avoided, monitor for metformin-related toxicities, and consider metformin dosage reduction, if needed. The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like metformin, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Tafenoquine may interfere with these common renal tubular transport systems involved in the renal elimination of metformin.
Glyburide; Metformin: (Moderate) Consider the benefits and risks of coadministration of tafenoquine and metformin due to the potential for increased metformin concentrations and lactic acidosis. If coadministration cannot be avoided, monitor for metformin-related toxicities, and consider metformin dosage reduction, if needed. The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like metformin, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Tafenoquine may interfere with these common renal tubular transport systems involved in the renal elimination of metformin.
Linagliptin; Metformin: (Moderate) Consider the benefits and risks of coadministration of tafenoquine and metformin due to the potential for increased metformin concentrations and lactic acidosis. If coadministration cannot be avoided, monitor for metformin-related toxicities, and consider metformin dosage reduction, if needed. The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like metformin, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Tafenoquine may interfere with these common renal tubular transport systems involved in the renal elimination of metformin.
Metformin: (Moderate) Consider the benefits and risks of coadministration of tafenoquine and metformin due to the potential for increased metformin concentrations and lactic acidosis. If coadministration cannot be avoided, monitor for metformin-related toxicities, and consider metformin dosage reduction, if needed. The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like metformin, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Tafenoquine may interfere with these common renal tubular transport systems involved in the renal elimination of metformin.
Metformin; Repaglinide: (Moderate) Consider the benefits and risks of coadministration of tafenoquine and metformin due to the potential for increased metformin concentrations and lactic acidosis. If coadministration cannot be avoided, monitor for metformin-related toxicities, and consider metformin dosage reduction, if needed. The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like metformin, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Tafenoquine may interfere with these common renal tubular transport systems involved in the renal elimination of metformin.
Metformin; Rosiglitazone: (Moderate) Consider the benefits and risks of coadministration of tafenoquine and metformin due to the potential for increased metformin concentrations and lactic acidosis. If coadministration cannot be avoided, monitor for metformin-related toxicities, and consider metformin dosage reduction, if needed. The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like metformin, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Tafenoquine may interfere with these common renal tubular transport systems involved in the renal elimination of metformin.
Metformin; Saxagliptin: (Moderate) Consider the benefits and risks of coadministration of tafenoquine and metformin due to the potential for increased metformin concentrations and lactic acidosis. If coadministration cannot be avoided, monitor for metformin-related toxicities, and consider metformin dosage reduction, if needed. The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like metformin, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Tafenoquine may interfere with these common renal tubular transport systems involved in the renal elimination of metformin.
Metformin; Sitagliptin: (Moderate) Consider the benefits and risks of coadministration of tafenoquine and metformin due to the potential for increased metformin concentrations and lactic acidosis. If coadministration cannot be avoided, monitor for metformin-related toxicities, and consider metformin dosage reduction, if needed. The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like metformin, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Tafenoquine may interfere with these common renal tubular transport systems involved in the renal elimination of metformin.
Penicillamine: (Major) Do not use penicillamine concurrently with antimalarials due to an increased risk of severe hematologic and renal adverse reactions.
Pioglitazone; Metformin: (Moderate) Consider the benefits and risks of coadministration of tafenoquine and metformin due to the potential for increased metformin concentrations and lactic acidosis. If coadministration cannot be avoided, monitor for metformin-related toxicities, and consider metformin dosage reduction, if needed. The effect of coadministration of tafenoquine on the pharmacokinetics of OCT2 and MATE substrates, like metformin, in humans is unknown; however, in vitro observations suggest the potential for increased concentrations of OCT2 and MATE substrates. Tafenoquine may interfere with these common renal tubular transport systems involved in the renal elimination of metformin.
Rabies Vaccine: (Major) If administered concurrently, antimalarials can impair the immunologic response to the rabies vaccine, thereby, decreasing its protective effect. If possible, administration of antimalarials should be avoided during use of the rabies vaccine for postexposure prophylaxis. When antimalarials must be administered to persons also receiving the rabies vaccine for postexposure prophylaxis, a serum rabies antibody titer should be obtained on day 14 (day of the 4th vaccination) to ensure an acceptable antibody response has been induced.

How Supplied

Arakoda/KRINTAFEL Oral Tab: 100mg, 150mg

Maximum Dosage
Adults

300 mg PO as single dose for radical cure (prevention of relapse) of P.vivax malaria; 200 mg/day PO for 3 days, then 200 mg/week PO for malaria prophylaxis.

Geriatric

300 mg PO as single dose for radical cure (prevention of relapse) of P.vivax malaria; 200 mg/day PO for 3 days, then 200 mg/week PO for malaria prophylaxis.

Adolescents

16 to 17 years: 300 mg PO as single dose for radical cure (prevention of relapse) of P.vivax malaria; safety and efficacy have not been established for malaria prophylaxis.
13 to 15 years: Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Mechanism Of Action

Tafenoquine is an 8-aminoquinoline antimalarial drug that is active against all stages of Plasmodium species that include the hypnozoite (dormant stage) in the liver. Tafenoquine is active against the pre-erythrocytic (liver) and erythrocytic (asexual) forms as well as gametocytes of P. falciparum and P. vivax. The activity against the pre-erythrocytic liver stages of the parasite prevents the development of the erythrocytic forms, which are responsible for malaria relapse. In vitro studies with the erythrocytic forms of P. falciparum suggest that tafenoquine may exert its effect by inhibiting hematin polymerization and inducing apoptotic-like death of the parasite. The molecular target of tafenoquine is not known. In addition to its effect on the parasite, tafenoquine causes red blood cell shrinkage in vitro.
 
Studies with the erythrocytic forms of P. falciparum suggest a potential for cross-resistance with primaquine, an 8-aminoquinoline; however, the clinical relevance of this finding is unknown.

Pharmacokinetics

Tafenoquine is administered orally. Protein binding of tafenoquine is more than 99.5%, and the apparent volume of distribution is approximately 1,600 to 2,470 L.
 
Tafenoquine undergoes slow, negligible metabolism. Unchanged tafenoquine represented the only notable drug-related component in human plasma after a single oral dose or once daily dosing for 3 days. The full excretion profile of tafenoquine is unknown. Over a 6-day collection period, renal elimination of unchanged tafenoquine was low. The apparent oral clearance of tafenoquine is approximately 3 to 4.2 L/hour, and the average terminal half-life is approximately 15 to 16.5 days.
 
Affected cytochrome P450 isoenzymes and drug transporters: OCT2, MATE-1, MATE2-K
Tafenoquine has been shown to be a human organic cation transporter-2 (OCT2) and multidrug and toxin extrusion transporter (MATE-1, MATE2-K) inhibitor in vitro; however, clinical drug interaction studies with tafenoquine and OCT2 and MATE substrates have not been conducted.

Oral Route

Maximum tafenoquine plasma concentrations were generally observed 12 to 15 hours after oral administration. After single- and multiple-oral doses, tafenoquine whole blood concentrations were on average 67% higher than corresponding plasma values. After a single 200 mg dose, the mean Cmax was 147 ng/mL and the mean AUC was 70 hour x mcg/mL. Plasma tafenoquine AUC increased by 41% and Cmax increased by 31% when a single tafenoquine dose was administered with a high-calorie, high-fat meal compared to the fasted state.

Pregnancy And Lactation
Pregnancy

Tafenoquine use during pregnancy is not recommended. Advise females of reproductive potential to avoid pregnancy during treatment with tafenoquine. If pregnancy occurs during prophylactic tafenoquine use, discontinue tafenoquine as soon as possible and switch to an alternative prophylactic drug for malaria during pregnancy. Use of tafenoquine during pregnancy may cause hemolytic anemia in a glucose-6-phosphate dehydrogenase (G6PD)-deficient fetus. Even if a pregnant woman is G6PD-normal, the fetus could be G6PD-deficient. Available data with tafenoquine use 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, increased abortions were observed 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. 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. Malaria during pregnancy increases the risk for adverse pregnancy outcomes, including maternal anemia, prematurity, spontaneous abortion, and stillbirth.

Tafenoquine is associated with reproductive risk. Verify pregnancy status in females of reproductive potential with pregnancy testing prior to tafenoquine use. Discuss contraception requirements with the patient. Advise females of reproductive potential to avoid pregnancy or use effective contraception for 3 months after the last tafenoquine dose.