2.1 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 [see Contraindications (4), Warnings and Precautions (5.1)].

Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with ARAKODA [see Use in Specific Populations (8.1 and 8.3)].

2.2 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.

•

Administer ARAKODA with food. [see Clinical Pharmacology (12.3)].

•

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.

5.1 Hemolytic Anemia

Due to the risk of hemolytic anemia in patients with G6PD deficiency, G6PD testing must be performed before prescribing ARAKODA [see Contraindications (4)]. 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 [see Contraindications (4)]. In clinical trials, declines in hemoglobin levels were reported in some G6PD-normal patients [see Adverse Reactions (6.1)]. Monitor patients for clinical signs or symptoms of hemolysis [see Warnings and Precautions (5.6)]. Advise patients to discontinue ARAKODA and seek medical attention if signs of hemolysis occur.

5.2 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 [see Use in Specific Populations (8.1 and 8.3)].

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 [see Contraindications (4)]. 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 [see Use in Specific Populations (8.2)].

5.3 Methemoglobinemia

Asymptomatic elevations in methemoglobin have been observed in the clinical trials of ARAKODA [see Adverse Reactions (6.1)]. Institute appropriate therapy if signs or symptoms of methemoglobinemia occur [see Warnings and Precautions (5.6)]. Carefully monitor individuals with nicotinamide adenine dinucleotide (NADH)-dependent methemoglobin reductase deficiency. Advise patients to discontinue ARAKODA and seek medical attention if signs of methemoglobinemia occur.

5.4 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%) [see Adverse Reactions (6.1)]. 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 [see Contraindication (4)]. 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 [see Warnings and Precautions (5.6)].

5.5 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 [see Adverse Reactions (6.1)]. Discontinue prophylaxis with ARAKODA and institute appropriate therapy if hypersensitivity reactions occur [see Warnings and Precautions (5.6)]. ARAKODA is contraindicated in patients who develop hypersensitivity to tafenoquine or any component of ARAKODA or other 8-aminoquinolines [see Contraindications (4)].

5.6 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 [see Warnings and Precautions (5.1, 5.3, 5.4, 5.5)]. 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. Advise patients to seek medical attention if signs of hypersensitivity occur [see Clinical Pharmacology (12.3)].

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.

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.

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.

7.1 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 [see Clinical Pharmacology (12.3)] 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.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

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

8.5 Geriatric Use

Clinical trials of 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 [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

The pharmacokinetics of ARAKODA have not been studied in patients with renal impairment. If ARAKODA is administered to such patients, monitoring for adverse reactions associated with ARAKODA is needed [see Warnings and Precautions (5), Adverse Reactions (6)].

8.7 Hepatic Impairment

The pharmacokinetics of ARAKODA have not been studied in patients with hepatic impairment. If ARAKODA is administered to such patients, monitoring for adverse reactions associated with ARAKODA is needed [see Warnings and Precautions (5), Adverse Reactions (6)].

12.1 Mechanism of Action

Tafenoquine is an 8-aminoquinoline antimalarial drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of tafenoquine on the QT interval was evaluated in a study of healthy adult subjects. In this study, subjects received once daily 400 mg (2 times the approved recommended dosage) doses of tafenoquine for 3 days. The results suggest that the mean increase in the QTcF interval for tafenoquine is less than 20 msec.

12.3 Pharmacokinetics

Absorption

A food effect study was not conducted with the 100 mg ARAKODA tablet. In majority of the clinical trials, tafenoquine was administered under fed conditions. Table 5 provides the pharmacokinetics of tafenoquine following single dose administration of 200 mg ARAKODA (two 100-mg ARAKODA tablets) in 65 healthy adult subjects under fed conditions. In this study, ARAKODA was administered with a high-calorie, high-fat meal (approximately 1000 calories with 19% protein, 31% carbohydrate, and 50% fat).

Following administration of a single dose of tafenoquine orally under fasted conditions in healthy adult subjects, AUC and Cmax increased dose proportionally over the dose range from 100 mg to 400 mg. When healthy adult subjects received once-weekly administrations of 200 mg tafenoquine orally for ten weeks without a loading dose under fasting conditions, the mean plasma accumulation ratio of tafenoquine was approximately 4.4.

Distribution

Tafenoquine is greater than 99.5% bound to protein in humans. The apparent volume of distribution of tafenoquine in healthy adult subjects is 2470 L [Inter-Individual Variability (IIV): 24.1 %].

Elimination

The apparent oral clearance of tafenoquine is approximately 4.2 L/hr (IIV: 23.6 %) in healthy adult subjects. The mean terminal half-life following administration of ARAKODA is approximately 16.5 days (range: 10.8 days to 27.3 days) in healthy adult subjects.

Metabolism

Negligible metabolism of tafenoquine was observed in vitro in human liver microsomes and hepatocytes. Following administration of tafenoquine orally, once daily for three days to healthy adult subjects, unchanged tafenoquine represented the only notable drug-related component in plasma at approximately 3 days following the first dose of tafenoquine.

Excretion

The full excretion profile of tafenoquine in humans is unknown.

Specific Populations

The pharmacokinetics of tafenoquine were not significantly impacted by age, sex, ethnicity, and body weight. The effect of renal or hepatic impairment on tafenoquine pharmacokinetics is unknown.

Drug Interaction Studies

Clinical Studies

No clinically significant effects on the pharmacokinetics of substrates of cytochrome P450 isoenzymes (CYP)1A2 (caffeine), CYP2D6 (desipramine), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam) were observed following coadministration with tafenoquine in healthy adult subjects.

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

Tafenoquine inhibited metformin transport via human OCT2, MATE1 and MATE2-K transporters [see Drug Interactions (7)].

Tafenoquine is not an inhibitor of human breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), Organic anion transporter 1/3 (OAT1 or OAT3), Organic anion transporting polypeptide 1B1/1B3 (OATP1B1 or OATP1B3) mediated transport at clinically relevant concentrations. Tafenoquine is also not a substrate of human OATP1B1 or OATP1B3 at clinically relevant concentrations. It is inconclusive as to whether tafenoquine is a substrate of P-gp and/or BCRP mediated transport.

12.4 Microbiology

Mechanism of Action

Tafenoquine, an 8-aminoquinoline antimalarial, is active against all the stages of Plasmodium species that include the hypnozoite (dormant stage) in the liver. Studies in vitro with the erythrocytic forms of Plasmodium falciparum suggest that tafenoquine may exert its effect by inhibiting hematin polymerization and inducing apoptotic like death of the parasite. In addition to its effect on the parasite, tafenoquine causes red blood cell shrinkage in vitro. The molecular target of tafenoquine is not known.

Antimicrobial activity

Tafenoquine is active against pre-erythrocytic (liver) and erythrocytic (asexual) forms as well as gametocytes of Plasmodium species that include P. falciparum and P. vivax. The activity of tafenoquine against the pre-erythrocytic liver stages of the parasite, prevents the development of the erythrocytic forms of the parasite [see Clinical Studies (14)].

Resistance

A potential for development of resistance of Plasmodium species to tafenoquine was not evaluated.

Studies with the erythrocytic forms of P. falciparum strains/isolates suggest a potential for cross-resistance with primaquine, an 8-aminoquinoline. Clinical relevance of such findings is not known.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year oral carcinogenicity studies were conducted in rats and mice. Renal cell adenomas and carcinomas were increased in male rats at doses 1 mg/kg/day and above (0.5 times the clinical exposure based on AUC comparisons). Tafenoquine was not carcinogenic in mice. The relevance of these findings to a carcinogenic risk in humans is unclear.

Mutagenesis

Tafenoquine did not cause mutations or chromosomal damage in 2 definitive in vitro tests (bacterial mutation assay and mouse lymphoma L5178Y cell assay) or in an in vivo oral rat micronucleus test.

Impairment of Fertility

In a rat fertility study, tafenoquine was given orally at 1.5, 5, and 15 mg/kg/day (up to about 0.5 times the human dose based on body surface area comparisons) to males for at least 67 days, including 29 days prior to mating, and to females from 15 days prior to mating through early pregnancy. Tafenoquine resulted in reduced number of viable fetuses, implantation sites, and corpora lutea at 15 mg/kg in the presence of maternal toxicity (mortality, piloerection, rough coat, and reduced body weight).