Arakoda Drug Information
Generic name: TAFENOQUINE
Uses of Arakoda
ARAKODA is indicated for the prophylaxis of malaria in patients aged 18 years and older.
Dosage & Administration of Arakoda
Tests to be Performed Prior to ARAKODA Dose Initiation
All patients must be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to prescribing ARAKODA. Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with ARAKODA.
Recommended Dosage and Administration Instructions
The recommended dosage of ARAKODA is described in Table 1 below. ARAKODA can be administered for up to 6 months of continuous dosing. Table 1: Recommended Dosage of ARAKODA in Patients (18 Years of Age and Older) • Administer ARAKODA with food. • Swallow the tablet whole.
Do not break, crush or chew the tablets. • Complete the full course of ARAKODA including the loading dose and the terminal dose. Table 2: How to Replace Missed Doses of ARAKODA
| Regimen Name | Timing | Dosage |
|---|---|---|
| Loading regimen | For each of the 3 days before travel to a malarious area | 200 mg (2 of the 100 mg tablets) once daily for 3 days |
| Maintenance regimen | While in the malarious area | 200 mg (2 of the 100 mg tablets) once weekly – start 7 days after the last loading regimen dose |
| Terminal prophylaxis regimen | In the week following exit from the malarious area | 200 mg (2 of the 100 mg tablets) one-time 7 days after the last maintenance dose |
| Regimen Name | Timing | Dosage |
|---|---|---|
| Loading regimen | For each of the 3 days before travel to a malarious area | 200 mg (2 of the 100 mg tablets) once daily for 3 days |
| Maintenance regimen | While in the malarious area | 200 mg (2 of the 100 mg tablets) once weekly – start 7 days after the last loading regimen dose |
| Terminal prophylaxis regimen | In the week following exit from the malarious area | 200 mg (2 of the 100 mg tablets) taken one time, 7 days after the last maintenance dose |
| Dose(s) Missed | How to Replace Missed Dose(s): |
|---|---|
| 1 Loading dose | 1 dose of 200 mg (2 of the 100 mg tablets) so that a total of 3 daily loading doses have been taken. Begin maintenance dose 1 week after the last loading dose. |
| 2 Loading doses | 2 doses of 200 mg (2 of the 100 mg tablets) on 2 consecutive days so that a total of 3 daily loading doses have been taken. Begin maintenance dose 1 week after the last loading dose. |
| 1 Maintenance (weekly) dose | 1 dose of 200 mg (2 of the 100 mg tablets) on any day up to the time of the next scheduled weekly dose. |
| 2 Maintenance (weekly) doses | 1 dose of 200 mg (2 of the 100 mg tablets) on any day up to the time of the next scheduled weekly dose. |
| 3 or more Maintenance (weekly) doses | 2 doses of 200 mg (2 of the 100 mg tablets), taken as 200 mg (2 of the 100 mg tablets) once daily for 2 days up to the time of the next weekly dose. |
| Terminal prophylaxis dose | 1 dose of 200 mg (2 of the 100 mg tablets) as soon as remembered. |
Side Effects of Arakoda
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 of tafenoquine was studied in clinical trials at various doses and regimens in 3,184 subjects. The mean duration of exposure to ARAKODA in these five clinical trials was 21 weeks (range 10-29 weeks).
Trial 3, an active comparator (mefloquine) controlled trial was conducted in healthy soldiers deployed in East Timor (Timor Leste). A placebo-controlled Trial 5 was conducted in healthy volunteers in the United States and United Kingdom. Adverse Reactions Reported with ARAKODA in Trial 3 and Pooled Trials Adverse reactions occurring in ≥1% of subjects in the ARAKODA group in the placebo-controlled pooled Trials are presented in Table 3.
The keratopathy did not result in any apparent functional visual changes and resolved within one year after drug cessation in all patients. Retinal abnormalities were noted in less than 1% of subjects receiving ARAKODA. A total of 7 serious ocular adverse reactions (SARs) were reported in ARAKODA-treated subjects in the trials which included ophthalmic evaluations: 5 reports of keratopathy and two reports of retinal disorders.
Laboratory Abnormalities Methemoglobinemia: Asymptomatic methemoglobin elevations were observed in 13% of subjects receiving ARAKODA. Hemoglobin decrease: Hemoglobin decreases of ≥ 3 g/dL were observed in 2.3% of subjects receiving ARAKODA. Blood and lymphatic system disorders: hemolytic anemia, anemia, thrombocytopenia Ear and labyrinth disorders: hyperacusis, Meniere’s disease Eye disorders: night blindness, photophobia, blurred vision, visual acuity reduced, visual impairment, vitreous floaters Hepatobiliary disorders: hyperbilirubinemia, jaundice cholestatic Immune system disorders: hypersensitivity Investigations: blood bilirubin increased, blood creatinine increased, glomerular filtration rate decreased Nervous system disorders: amnesia, coordination abnormal, hyperesthesia, hypoesthesia, somnolence, syncope, tremor, visual field defect Psychiatric disorders: agitation, neurosis Skin and subcutaneous tissue disorders: urticaria.
| Adverse Reaction | ARAKODA 1 (n=333) % | Placebo (n=295) % | Mefloquine 2 (n=147) % |
|---|---|---|---|
| 1 ARAKODA was administered as 200 mg daily for 3 days, then 200 mg weekly 2 Mefloquine was administered as 250 mg daily for 3 days, then 250 mg weekly 3 Includes headache, sinus headache, migraine and tension headache. 4 Includes dizziness and dizziness postural 5 Includes abnormal dreams, insomnia, nightmares, sleep disorder, and somnambulism. | |||
| Nervous system Disorders | 35 | 34 | 47 |
| Headache 3 | 32 | 32 | 44 |
| Dizziness 4 | 5 | 3 | 10 |
| Musculoskeletal and connective tissue disorders | 27 | 26 | 37 |
| Back pain | 14 | 9 | 11 |
| Gastrointestinal disorders | 31 | 33 | 46 |
| Diarrhea | 5 | 3 | 1 |
| Nausea | 5 | 2 | 2 |
| Vomiting | 2 | 2 | 1 |
| Investigations | 8 | 7 | 11 |
| Alanine Aminotransferase (ALT) increased/abnormal | 4 | 2 | 3 |
| Psychiatric disorders | 2 | 1 | 2 |
| Any sleep symptom 5 | 1 | 1 | 0 |
| Insomnia | 1 | 1 | 0 |
| Depression/depressed mood | 1 | 0 | 0 |
Warnings & Cautions for Arakoda
Hemolytic Anemia Due to the risk of hemolytic anemia in patients with G6PD deficiency, G6PD testing must be performed before prescribing ARAKODA. 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 ARAKODA 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 ARAKODA and seek medical attention if signs of hemolysis occur.
G6PD Deficiency in Pregnancy and Lactation Potential Harm to the Fetus The use of ARAKODA 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 ARAKODA during pregnancy is not recommended and to avoid pregnancy or use effective contraception during treatment and for 3 months after the last dose of ARAKODA.
If a pregnancy is detected during ARAKODA use, discontinue ARAKODA 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 ARAKODA through breast milk. Infant G6PD status should be checked before breastfeeding begins.
ARAKODA 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 ARAKODA and for 3 months after the final dose.
Methemoglobinemia
Asymptomatic elevations in methemoglobin have been observed in the clinical trials of ARAKODA. Institute appropriate therapy if signs or symptoms of methemoglobinemia occur. Carefully monitor individuals with nicotinamide adenine dinucleotide (NADH)-dependent methemoglobin reductase deficiency.
Psychiatric Effects
In patients receiving ARAKODA in clinical trials, psychiatric adverse reactions included sleep disturbances (2.5%), depression/depressed mood (0.3%), and anxiety (0.2%). ARAKODA 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 ARAKODA 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 ARAKODA regimen. Safety and effectiveness of ARAKODA have not been established at doses or regimens other than the approved regimen; use of ARAKODA at doses or regimens other than a 200-mg weekly dose is not approved by FDA. 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 ARAKODA 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 ARAKODA. Discontinue prophylaxis with ARAKODA and institute appropriate therapy if hypersensitivity reactions occur.
ARAKODA is contraindicated in patients who develop hypersensitivity to tafenoquine or any component of ARAKODA or other 8-aminoquinolines.
Delayed Adverse Reactions, Including Hemolytic Anemia, Methemoglobinemia, Psychiatric Effects, and Hypersensitivity Reactions Adverse reactions including hemolytic anemia, methemoglobinemia, psychiatric effects, and hypersensitivity reactions were reported with the use of ARAKODA or tafenoquine in clinical trials. Due to the long half-life of ARAKODA (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.
Drug Interactions with Arakoda
Effect of ARAKODA 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 ARAKODA 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 Safety for Arakoda
Pregnancy Risk Summary The use of ARAKODA during pregnancy may cause hemolytic anemia in a fetus who is G6PD-deficient. Treatment with ARAKODA during pregnancy is not recommended. If a pregnancy is detected during ARAKODA use, discontinue ARAKODA as soon as possible and switch to an alternative prophylactic drug for malaria during pregnancy.
Available data with use of ARAKODA 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 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 of Arakoda
Pediatric Use Safety and effectiveness of ARAKODA in pediatric patients have not been established.
Contraindications for Arakoda
- ARAKODA 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 a history of psychotic disorders or current psychotic symptoms (i.e., hallucinations, delusions, and/or grossly disorganized behavior)
- Patients with known hypersensitivity reactions to tafenoquine, other 8-aminoquinolines, or any component of ARAKODA.
- G6PD deficiency or unknown G6PD status
- Patients with a history of psychotic disorders or current psychotic symptoms
Overdosage Information for Arakoda
There were no reported cases of ARAKODA overdose. Hemoglobin decline and methemoglobinemia may be encountered in an overdose with ARAKODA. Treatment of overdosage consists of institution of appropriate symptomatic and/or supportive therapy.
Clinical Studies of Arakoda
Clinical Trials 1, 2, and 3 Three double-blind, randomized, controlled studies have been performed to evaluate the efficacy of ARAKODA. Trial 1 (NCT #02491606) was a Phase IIb, placebo-controlled study conducted in Kenya, an area of holoendemic P. falciparum malaria. After taking a three-day presumptive course of halofantrine to eliminate any existing parasitemia, subjects were randomized into one of four groups (placebo and three different ARAKODA dosing groups; one group received 200 mg once daily for 3 days, then a maintenance regimen of weekly dose of 200 mg for 10-15 weeks).
Sixty-one percent of subjects were male. The mean age was 32.4 years (range 17-55). Subjects were evaluated for parasitemia by weekly blood smears.
Protective efficacy at 15 weeks was defined based on the reduced incidence of parasitemia during the prophylaxis phase relative to placebo. The results in the intention-to-treat population, which included all subjects who received three doses of halofantrine and were randomized, are shown in Table 6 below. After treating existing parasitemia with quinine/doxycycline/primaquine, subjects were randomized into prophylactic groups including ARAKODA and placebo.
Patients were administered a loading regimen of daily drug or placebo for 3 days followed by a maintenance regimen of weekly drug or placebo for 12 weeks. For the ARAKODA and placebo groups, males were 65% of the total population. The mean age was 38.4 years and 53.5 years for males and females, respectively, as women in reproductive ages were excluded from the study.
The mean weight was 55.4 kg and 47.5 kg for males and females, respectively. Parasitemia required a blood smear positive for asexual stage of P. falciparum. The incidence of parasitemia at week 12 for all randomized subjects who received at least one dose of ARAKODA or placebo is presented in Table 7 below.
No subject developed malaria during the 26-week prophylactic phase. Subjects were exposed to P. vivax and there is a high likelihood that the study subjects were also exposed to P. falciparum. Since the precise degree of exposure to malaria in study subjects is unknown, this study provides only supportive evidence of efficacy.
Clinical Trial 7 In a randomized, double-blind, placebo-controlled trial (Trial 7) in healthy, non-immune volunteers, ARAKODA was shown to have prophylactic activity directed against blood-stage P. falciparum parasites. On Day 13, subjects were inoculated with erythrocytes containing viable P. falciparum parasites. Fifteen subjects (93.8%) were of white race.
The mean age was 27.5 years (range 20-42). The mean body weight was 72.3 kg (range 56-97.7). The efficacy endpoint was parasitemia by Day 34; parasitemia was based on detection of P. falciparum 18S ribosomal DNA by real time polymerase chain reaction assay (PCR).
| Placebo | ARAKODA 1 | |
|---|---|---|
| 1 200 mg once daily for 3 days, then 200 mg weekly for 10-15 weeks 2 Protective efficacy is reduced incidence of parasitemia relative to placebo (0: no protection; 1: full protection); CI: confidence interval. Bonferroni adjustment was used for multiple comparisons. Missing outcome was considered a failure due to parasitemia for this analysis. | ||
| Number of subjects | 62 | 61 |
| Subjects free of parasitemia | 5 (8.1%) | 46 (75.4) |
| Subjects with parasitemia | 54 (87.1%) | 7 (11.5%) |
| Subjects with missing data | 3 (4.8%) | 8 (13.1%) |
| Protective efficacy [98.3% CI] 2 | – | 73.3% [54.0%, 84.5%] |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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