Tafenoquine

1 INDICATIONS AND USAGE ARAKODA 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. ( 1 )

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

2 DOSAGE AND ADMINISTRATION • All patients must be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to prescribing ARAKODA. ( 2.1 ) • Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with ARAKODA. ( 2.1 ) 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 • Administer ARAKODA with food. ( 2.2 ) • See full prescribing information for instructions on how to replace missed doses. ( 2.2 ) 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. Table 1: Recommended Dosage of ARAKODA in Patients (18 Years of Age and Older) 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 • 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. Table 2: How to Replace Missed Doses of ARAKODA 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.

6 ADVERSE REACTIONS 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

5 WARNINGS AND PRECAUTIONS • Hemolytic Anemia : G6PD testing must be performed before prescribing ARAKODA due to the risk of hemolytic anemia. Monitor patients for signs or symptoms of hemolysis. ( 5.1 ) • G6PD Deficiency in Pregnancy or Lactation : ARAKODA may cause fetal harm when administered to a pregnant woman with a G6PD-deficient fetus. ARAKODA is not recommended during pregnancy. A G6PD-deficient infant may be at risk for hemolytic anemia from exposure to ARAKODA through breast milk. Check infant’s G6PD status before breastfeeding begins. ( 5.2 , 8.1 , 8.2 ) • Methemoglobinemia : Asymptomatic elevations in blood methemoglobin have been observed. Initiate appropriate therapy if signs or symptoms of methemoglobinemia occur. ( 5.3 ) • Psychiatric Effects : Serious psychotic adverse reactions have been observed in patients with a history of psychosis or schizophrenia, at doses different from the approved dose. If psychotic symptoms (hallucinations, delusions, or grossly disorganized thinking or behavior) occur, consider discontinuation of ARAKODA therapy and, evaluation by a mental health professional as soon as possible. ( 5.4 ) • Hypersensitivity Reactions : Serious hypersensitivity reactions have been observed with administration of ARAKODA. If hypersensitivity reactions occur, institute appropriate therapy. ( 5.5 ) • Delayed Adverse Reactions : Due to the long half-life of ARAKODA (approximately 17 days), psychiatric effects, hemolytic anemia, methemoglobinemia, and hypersensitivity reactions may be delayed in onset and/or duration. ( 5.6 , 12.3 ) 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 individ

4 CONTRAINDICATIONS ARAKODA 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 )

10 OVERDOSAGE 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.