Arakoda Drug Information

is indicated for the prophylaxis of malaria in patients aged 18 years and older. ARAKODA is an antimalarial indicated for the prophylaxis of malaria in patients aged 18 years and older.

• The following clinically significant adverse reactions observed with ARAKODA are discussed in detail in the Warnings and Precautions section:
• Hemolytic Anemia [see Warnings and Precautions ( 5.2 )]
• Methemoglobinemia [see Warnings and Precautions ( 5.3 )]
• Psychiatric Effects [see Warnings and Precautions ( 5.4 )]
• Hypersensitivity Reactions [see Warnings and Precautions ( 5.5 )] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact 60 Degrees Pharmaceuticals at 1-888-834-0225 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 recommended ARAKODA regimen was evaluated in 825 subjects in 5 controlled clinical trials (Trials 1, Trial 2, Trial 3, Trial 4 and Trial 5). The mean duration of exposure to ARAKODA in these five clinical trials was 21 weeks (range 10-29 weeks). Trial 1, 2 and 4 were conducted in healthy semi-immune volunteers in Ghana or Kenya and were placebo-controlled; a mefloquine arm was included in Trials 2 and 4 as a benchmark. 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. The mean age of the subjects included in the five trials was 29 years (range 17 to 69 years); 84% were male. Adverse Reactions Reported with ARAKODA in Trial 3 and Pooled Trials 1, 2, 4, and 5 Adverse reactions occurring in ≥1% of subjects in the ARAKODA group in the placebo-controlled pooled Trials 1, 2, 3, and 4 are presented in Table 3 . Table 3: Selected Adverse Reactions Occurring in ≥1% of Subjects Receiving ARAKODA in Pooled Trials 1, 2, 4, and 5 (Non-Deployed Subjects) 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 Adverse reactions occurring in ≥1% of subjects in the ARAKODA group in the active-control Trial 3 conducted in military personnel deployed to malaria endemic areas are presented in Table 4 . Table 4: Selected Adverse Reactions Occurring in ≥1% of Subjects Receiving ARAKODA in Trial 3 (Deployed Subjects) Adverse Reaction ARAKODA 1 (n=492) % Mefloquine 2 (n=162) % 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 motion sickness, vertigo and vertigo positional. 6 Includes abnormal dreams, insomnia, nightmares, sleep disorder, and somnambulism. 7 Includes abnormal dreams, nightmares 8 Includes anxiety disorder, panic attack and stress. Nervous system Disorders 22 27 Headache 3 15 19 Dizziness 4 1 1 Ear and labyrinth Disorders 7 11 Motion sicknesss 5 5 6 Musculoskeletal and connective tissue disorders 29 30 Back pain 14 15 Gastrointestinal disorders 36 41 Diarrhea 18 20 Nausea 7 9 Vomiting 5 6 Psychiatric disorders 5 4 Any sleep symptom 6 4 4 Insomnia 2 1 Abnormal dreams 7 2 2 Anxiety 8 1 0 Clinically Significant Adverse Reactions in Trials 1 to 5 (Overall Safety Population) Clinically significant adverse reactions with ARAKODA (200 mg daily for 3 days, followed by 200 mg weekly) in Trials 1 to 5 (n= 825) are described below: Ocular Adverse Reactions Vortex keratopathy was reported in 21% to 93% of subjects receiving ARAKODA in the trials which included ophthalmic evaluations (Trials 3, 5, and Trial 6 (NCT # 01290601, an active-control trial in patients from Thailand with P. vivax malaria. 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. Adverse Reactions Reported in < 1% of Subjects Receiving ARAKODA in Trials 1 to 5 The following selected adverse reactions were reported in subjects receiving ARAKODA in Trials 1 to 5 at a rate of less than 1%. 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.

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 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 2% to 4% and 15% to 20%, 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). 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.

Pediatric Use Safety and effectiveness of ARAKODA in pediatric patients have not been established.

• is contraindicated in:
• patients with G6PD deficiency or unknown G6PD status due to the risk of hemolytic anemia [see Warnings and Precautions ( 5.2 )] .
• breastfeeding by a lactating woman when the infant is found to be G6PD deficient or if the G6PD status of the infant is unknown [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.2 )] .
• patients with a history of psychotic disorders or current psychotic symptoms (i.e., hallucinations, delusions, and/or grossly disorganized behavior) [see Warnings and Precautions ( 5.4 )]
• patients with known hypersensitivity reactions to tafenoquine, other 8-aminoquinolines, or any component of ARAKODA [see Warnings and Precautions ( 5.5 )] .
• G6PD deficiency or unknown G6PD status ( 4 )
• Breastfeeding by a lactating woman when the infant is found to be G6PD deficient or if G6PD status is unknown ( 4 , 8.2 )
• Patients with a history of psychotic disorders or current psychotic symptoms ( 4 , 5.4 )
• Known hypersensitivity reactions to tafenoquine, other 8-aminoquinolines, or any component of ARAKODA. ( 4 )

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.