ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS The following clinically significant adverse reactions observed with ARAKODA are discussed in detail in the Warnings and Precautions section:oHemolytic Anemia [see Warnings and Precautions (5.2)]oMethemoglobinemia [see Warnings and Precautions (5.3)]oPsychiatric Effects [see Warnings and Precautions (5.4)]oHypersensitivity Reactions [see Warnings and Precautions (5.5)]. oHemolytic Anemia [see Warnings and Precautions (5.2)]. oMethemoglobinemia [see Warnings and Precautions (5.3)]. oPsychiatric Effects [see Warnings and Precautions (5.4)]. oHypersensitivity 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 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 controlled clinical trials (Trials 1, Trial 2, Trial 3, Trial and Trial 5). The mean duration of exposure to ARAKODA in these five clinical trials was 21 weeks (range 10-29 weeks). Trial 1, and were conducted in healthy semi-immune volunteers in Ghana or Kenya and were placebo-controlled; mefloquine arm was included in Trials and as benchmark. Trial 3, an active comparator (mefloquine) controlled trial was conducted in healthy soldiers deployed in East Timor (Timor Leste). placebo-controlled Trial 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 and Pooled Trials 1, 2, 4, and 5Adverse reactions occurring in >=1% of subjects in the ARAKODA group in the placebo-controlled pooled Trials 1, 2, 3, and are presented in Table 3.Table 3: Selected Adverse Reactions Occurring in >=1% of Subjects Receiving ARAKODA in Pooled Trials 1, 2, 4, and (Non-Deployed Subjects)Adverse ReactionARAKODA1 (n=333)%Placebo (n=295) %Mefloquine2 (n=147) %1 ARAKODA was administered as 200 mg daily for days, then 200 mg weekly Mefloquine was administered as 250 mg daily for days, then 250 mg weekly Includes headache, sinus headache, migraine and tension headache. Includes dizziness and dizziness postural Includes abnormal dreams, insomnia, nightmares, sleep disorder, and somnambulism.Nervous system Disorders353447Headache3 323244Dizziness4 5310Musculoskeletal and connective tissue disorders272637Back pain14911Gastrointestinal disorders313346Diarrhea531Nausea522Vomiting221Investigations8711Alanine Aminotransferase (ALT) increased/abnormal423Psychiatric disorders212Any sleep symptom5 110Insomnia110Depression/depressed mood100Adverse reactions occurring in >=1% of subjects in the ARAKODA group in the active-control Trial 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 (Deployed Subjects)Adverse ReactionARAKODA1 (n=492)%Mefloquine2 (n=162)%1 ARAKODA was administered as 200 mg daily for days, then 200 mg weekly Mefloquine was administered as 250 mg daily for days, then 250 mg weekly Includes headache, sinus headache, migraine and tension headache. Includes dizziness and dizziness postural Includes motion sickness, vertigo and vertigo positional. Includes abnormal dreams, insomnia, nightmares, sleep disorder, and somnambulism. Includes abnormal dreams, nightmares Includes anxiety disorder, panic attack and stress.Nervous system Disorders2227Headache3 1519Dizziness4 11Ear and labyrinth Disorders711Motion sicknesss5 56Musculoskeletal and connective tissue disorders2930Back pain1415Gastrointestinal disorders3641Diarrhea1820Nausea79Vomiting56Psychiatric disorders54Any sleep symptom6 44Insomnia21Abnormal dreams7 22Anxiety8 10Clinically Significant Adverse Reactions in Trials to (Overall Safety Population)Clinically significant adverse reactions with ARAKODA (200 mg daily for days, followed by 200 mg weekly) in Trials to (n= 825) are described below:Ocular Adverse ReactionsVortex keratopathy was reported in 21% to 93% of subjects receiving ARAKODA in the trials which included ophthalmic evaluations (Trials 3, 5, and Trial (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 serious ocular adverse reactions (SARs) were reported in ARAKODA-treated subjects in the trials which included ophthalmic evaluations: reports of keratopathy and two reports of retinal disorders. Laboratory AbnormalitiesMethemoglobinemia: Asymptomatic methemoglobin elevations were observed in 13% of subjects receiving ARAKODA. Hemoglobin decrease: Hemoglobin decreases of >= g/dL were observed in 2.3% of subjects receiving ARAKODA.Adverse Reactions Reported in 1% of Subjects Receiving ARAKODA in Trials to 5The following selected adverse reactions were reported in subjects receiving ARAKODA in Trials to at rate of less than 1%.Blood and lymphatic system disorders: hemolytic anemia, anemia, thrombocytopenia Ear and labyrinth disorders: hyperacusis, Menieres diseaseEye disorders: night blindness, photophobia, blurred vision, visual acuity reduced, visual impairment, vitreous floatersHepatobiliary disorders: hyperbilirubinemia, jaundice cholestaticImmune system disorders: hypersensitivityInvestigations: blood bilirubin increased, blood creatinine increased, glomerular filtration rate decreasedNervous system disorders: amnesia, coordination abnormal, hyperesthesia, hypoesthesia, somnolence, syncope, tremor, visual field defectPsychiatric disorders: agitation, neurosisSkin and subcutaneous tissue disorders: urticaria.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisTwo-year oral carcinogenicity studies were conducted in rats and mice. Renal cell adenomas and carcinomas were increased in male rats at doses 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 carcinogenic risk in humans is unclear. MutagenesisTafenoquine did not cause mutations or chromosomal damage in definitive in vitro tests (bacterial mutation assay and mouse lymphoma L5178Y cell assay) or in an in vivo oral rat micronucleus test.Impairment of FertilityIn 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).

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tafenoquine is an 8-aminoquinoline antimalarial drug [see Microbiology (12.4)].. 12.2 Pharmacodynamics Cardiac ElectrophysiologyThe effect of tafenoquine on the QT interval was evaluated in study of healthy adult subjects. In this study, subjects received once daily 400 mg (2 times the approved recommended dosage) doses of tafenoquine for days. The results suggest that the mean increase in the QTcF interval for tafenoquine is less than 20 msec.. 12.3 Pharmacokinetics AbsorptionA 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 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 high-calorie, high-fat meal (approximately 1000 calories with 19% protein, 31% carbohydrate, and 50% fat). Table 5. Mean (%CV) Pharmacokinetic Parameters of Tafenoquine Following Single Oral Administration of Two 100-mg ARAKODA Tablets Under Fed Conditions in Healthy Adult Subjects (N=65)ParameterValuea Coefficient of Variance (CV) Median and (Range) Plasma tafenoquine AUCinf increased by 41% when tafenoquine was administered as an investigational capsule formulation with high-calorie, high-fat meal compared with the fasted state. Cmax 147 ng/mL (20.7%)a Tmax 14 hr (6 72 hr)b AUCinf 70 hrmcg/mL (24.6%)a, Following administration of 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 loading dose under fasting conditions, the mean plasma accumulation ratio of tafenoquine was approximately 4.4.DistributionTafenoquine is greater than 99.5% bound to protein in humans. The apparent volume of distribution of tafenoquine in healthy adult subjects is 2470 [Inter-Individual Variability (IIV): 24.1 %].EliminationThe 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.MetabolismNegligible 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 days following the first dose of tafenoquine.ExcretionThe full excretion profile of tafenoquine in humans is unknown.Specific PopulationsThe 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 StudiesClinical StudiesNo 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 ClinicallyTafenoquine 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 substrate of human OATP1B1 or OATP1B3 at clinically relevant concentrations. It is inconclusive as to whether tafenoquine is substrate of P-gp and/or BCRP mediated transport.. 12.4 Microbiology Mechanism of ActionTafenoquine, 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 activityTafenoquine 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)]. ResistanceA potential for development of resistance of Plasmodium species to tafenoquine was not evaluated. Studies with the erythrocytic forms of P. falciparum strains/isolates suggest potential for cross-resistance with primaquine, an 8-aminoquinoline. Clinical relevance of such findings is not known.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES Clinical Trials 1, 2, and 3Three double-blind, randomized, controlled studies have been performed to evaluate the efficacy of ARAKODA. Trial (NCT 02491606) was Phase IIb, placebo-controlled study conducted in Kenya, an area of holoendemic P. falciparum malaria. After taking three-day presumptive course of halofantrine to eliminate any existing parastextia, subjects were randomized into one of four groups (placebo and three different ARAKODA dosing groups; one group received 200 mg once daily for days, then 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 parastextia by weekly blood smears. Protective efficacy at 15 weeks was defined based on the reduced incidence of parastextia 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 below. Table 6: Incidence of Parastextia and Protective Efficacy of ARAKODA at 15 weeks for Trial 1PlaceboARAKODA1 200 mg once daily for days, then 200 mg weekly for 10-15 weeks Protective efficacy is reduced incidence of parastextia relative to placebo (0: no protection; 1: full protection); CI: confidence interval. Bonferroni adjustment was used for multiple comparisons. Missing outcome was considered failure due to parastextia for this analysis.Number of subjects6261Subjects free of parastextia5 (8.1%)46 (75.4)Subjects with parastextia54 (87.1%)7 (11.5%)Subjects with missing data3 (4.8%)8 (13.1%)Protective efficacy [98.3% CI]2 -73.3% [54.0%, 84.5%]Trial (NCT 02488902) was comparison of tafenoquine to placebo for prophylaxis in healthy semi-immune residents of malarious region in Ghana. After treating existing parastextia with quinine/doxycycline/primaquine, subjects were randomized into prophylactic groups including ARAKODA and placebo. Patients were administered loading regimen of daily drug or placebo for days followed by 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. Subjects were evaluated for parastextia by weekly blood smears. Parastextia required blood smear positive for asexual stage of P. falciparum. The incidence of parastextia at week 12 for all randomized subjects who received at least one dose of ARAKODA or placebo is presented in Table below.Table 7: Incidence of Parastextia and Protective Efficacy of ARAKODA at Week 12 for Trial 2PlaceboARAKODA1 200 mg once daily for days, then 200 mg weekly for 12 weeks Protective efficacy is reduced incidence of parastextia relative to placebo; CI: confidence interval. Bonferroni adjustment was used for multiple comparisons. Missing outcome was considered failure due to parastextia for this analysis.Number of subjects9493Subjects free of parastextia6 (6.4%)68 (73.1%)Subjects with parastextia 86 (91.5%)12 (12.9%)Subjects with missing data2 (2.1%)13 (14.0%)Protective efficacy [98.75% CI]2 -71.3% [55.8%, 81.4%]Trial compared ARAKODA with mefloquine for the prophylaxis of both P. falciparum and P. vivax malaria in healthy non-immune soldiers deployed to East Timor (now Timor-Leste). No subject developed malaria during the 26-week prophylactic phase. Subjects were exposed to P. vivax and there is 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 7In 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. Twelve subjects received ARAKODA (200 mg once daily for days, then 200 mg on 10 day) and subjects received placebo. 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 parastextia by Day 34; parastextia was based on detection of P. falciparum 18S ribosomal DNULL by real time polymerase chain reaction assay (PCR). There was statistically significant difference in malaria incidence between the two groups; 4/4 (100%) subjects in the placebo group had detectable parasites from Day 17 compared to 0/12 (0%) subjects on ARAKODA were PCR negative at all visits (p<0.0005).

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS ARAKODA is contraindicated in: opatients with G6PD deficiency or unknown G6PD status due to the risk of hemolytic anemia [see Warnings and Precautions (5.2)]. obreastfeeding by 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)].opatients with history of psychotic disorders or current psychotic symptoms (i.e., hallucinations, delusions, and/or grossly disorganized behavior) [see Warnings and Precautions (5.4)]opatients with known hypersensitivity reactions to tafenoquine, other 8-aminoquinolines, or any component of ARAKODA [see Warnings and Precautions (5.5)].. opatients with G6PD deficiency or unknown G6PD status due to the risk of hemolytic anemia [see Warnings and Precautions (5.2)]. obreastfeeding by 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)].. opatients with history of psychotic disorders or current psychotic symptoms (i.e., hallucinations, delusions, and/or grossly disorganized behavior) [see Warnings and Precautions (5.4)]. opatients with known hypersensitivity reactions to tafenoquine, other 8-aminoquinolines, or any component of ARAKODA [see Warnings and Precautions (5.5)].. oG6PD deficiency or unknown G6PD status (4)oBreastfeeding by lactating woman when the infant is found to be G6PD deficient or if G6PD status is unknown (4, 8.2)oPatients with history of psychotic disorders or current psychotic symptoms (4, 5.4)oKnown hypersensitivity reactions to tafenoquine, other 8-aminoquinolines, or any component of ARAKODA. (4). oG6PD deficiency or unknown G6PD status (4). oBreastfeeding by lactating woman when the infant is found to be G6PD deficient or if G6PD status is unknown (4, 8.2). oPatients with history of psychotic disorders or current psychotic symptoms (4, 5.4). oKnown hypersensitivity reactions to tafenoquine, other 8-aminoquinolines, or any component of ARAKODA. (4).

DESCRIPTION SECTION.


11 DESCRIPTION ARAKODA contains tafenoquine succinate, an antimalarial agent for oral administration. The structural formula of tafenoquine succinate is:Figure 1: Tafenoquine Succinate StructureThe chemical name of tafenoquine succinate is (+-)-8-[(4-amino-1-methylbutyl) amino]-2,6-dimethoxy-4-methyl-5-[3-(trifluoromethyl) phenoxy]quinoline succinate. The molecular formula of tafenoquine succinate is C24H28F3N3O3C4H6O4 and its molecular weight is 581.6 as the succinate salt (463.49 as free base).Each ARAKODA tablet contains 100 mg of tafenoquine (equivalent to 125.5 mg of tafenoquine succinate). Inactive ingredients include magnesium stearate, mannitol, and microcrystalline cellulose. The tablet film coating inactive ingredients include: hypromellose, iron oxide red, macrogol/polyethylene glycol and titanium dioxide.. Figure 1: Tafenoquine Succinate Structure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION oAll patients must be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to prescribing ARAKODA. (2.1)oPregnancy testing is recommended for females of reproductive potential prior to initiating treatment with ARAKODA. (2.1)Regimen NameTimingDosageLoading regimenFor each of the days before travel to malarious area200 mg (2 of the 100 mg tablets) once daily for daysMaintenance regimenWhile in the malarious area200 mg (2 of the 100 mg tablets) once weekly start days after the last loading regimen doseTerminal prophylaxis regimenIn the week following exit from the malarious area200 mg (2 of the 100 mg tablets) one-time days after the last maintenance doseoAdminister ARAKODA with food. (2.2)oSee full prescribing information for instructions on how to replace missed doses. (2.2). oAll patients must be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to prescribing ARAKODA. (2.1). oPregnancy testing is recommended for females of reproductive potential prior to initiating treatment with ARAKODA. (2.1). oAdminister ARAKODA with food. (2.2). oSee 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 below. ARAKODA can be administered for up to months of continuous dosing.Table 1: Recommended Dosage of ARAKODA in Patients (18 Years of Age and Older)Regimen NameTimingDosageLoading regimenFor each of the days before travel to malarious area200 mg (2 of the 100 mg tablets) once daily for daysMaintenance regimenWhile in the malarious area200 mg (2 of the 100 mg tablets) once weekly start days after the last loading regimen doseTerminal prophylaxis regimenIn the week following exit from the malarious area200 mg (2 of the 100 mg tablets) taken one time, days after the last maintenance doseoAdminister ARAKODA with food. [see Clinical Pharmacology (12.3)]. oSwallow the tablet whole. Do not break, crush or chew the tablets. oComplete the full course of ARAKODA including the loading dose and the terminal dose.Table 2: How to Replace Missed Doses of ARAKODADose(s) MissedHow to Replace Missed Dose(s): Loading dose1 dose of 200 mg (2 of the 100 mg tablets) so that total of daily loading doses have been taken. Begin maintenance dose week after the last loading dose.2 Loading doses2 doses of 200 mg (2 of the 100 mg tablets) on consecutive days so that total of daily loading doses have been taken. Begin maintenance dose week after the last loading dose.1 Maintenance (weekly) dose 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) doses1 dose of 200 mg (2 of the 100 mg tablets) on any day up to the time of the next scheduled weekly dose. or more Maintenance (weekly) doses2 doses of 200 mg (2 of the 100 mg tablets), taken as 200 mg (2 of the 100 mg tablets) once daily for days up to the time of the next weekly dose. Terminal prophylaxis dose1 dose of 200 mg (2 of the 100 mg tablets) as soon as remembered.. oAdminister ARAKODA with food. [see Clinical Pharmacology (12.3)]. oSwallow the tablet whole. Do not break, crush or chew the tablets. oComplete the full course of ARAKODA including the loading dose and the terminal dose.

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS ARAKODA tablets are dark pink, film-coated, capsule-shaped tablets debossed with TQ100 on one side containing 100 mg of tafenoquine. Tablets: 100 mg of tafenoquine (3).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS Avoid co-administration with drugs that are substrates of organic cation transporter-2 (OCT2) or multidrug and toxin extrusion (MATE) transporters (7.1). 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.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.


8.3 Females and Males of Reproductive Potential Pregnancy Testing. Verify the pregnancy status in females of reproductive potential prior to initiating treatment with ARAKODA. [see Dosage and Administration (2.2), Warnings and Precautions, (5.2), and Use in Specific Populations (8.1)].. Contraception. ARAKODA may cause hemolytic anemia in G6PD-deficient fetus [see Warnings and Precautions (5.2), Use in Specific Populations (8.1)]. Advise females of reproductive potential that treatment with ARAKODA during pregnancy is not recommended and to avoid pregnancy or use effective contraception for months after the final dose of ARAKODA.

GERIATRIC USE SECTION.


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)].

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING How SuppliedARAKODA tablets contain 100 mg of tafenoquine (equivalent to 125.5 mg of tafenoquine succinate) and are dark pink, film-coated, capsule-shaped, and debossed with TQ100 on one side. ARAKODA tablets are packed in polyamide aluminum and PVC formable laminate backed blisters with polyethylene terephthalate aluminum foil cover. Each blister card contains tablets. Each package contains blister cards (16 tablets) housed in contiguous outer paperboard child-resistant carton component (NDC 71475-257-01). StorageStore at 20C to 25C (68F to 77F). Temperature excursions are permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense only in the original carton.

INDICATIONS & USAGE SECTION.


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).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).G6PD Testing and Hemolytic AnemiaInform patients of the need for testing for G6PD deficiency before starting ARAKODA. Advise patients on the symptoms of hemolytic anemia and instruct them to seek medical advice promptly if such symptoms occur. Patients should contact their health care provider if they have darker lips or urine as these may be signs of hemolysis or methemoglobinemia [see Warnings and Precautions (5.1)].Important Administration InstructionsoAdvise patients to take ARAKODA with food.oAdvise patients to swallow the tablet whole and not to break, crush or chew it.oAdvise patients to complete the full course of ARAKODA including the loading dose, maintenance dose and terminal dose.Potential Harm to the FetusAdvise females of reproductive potential of the potential risk of ARAKODA to fetus and to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to avoid pregnancy or use effective contraception during treatment with ARAKODA and for months after the final dose [see Use in Specific Populations (8.3)].LactationAdvise women with G6PD-deficient infant, or if they do not know the G6PD status of their infant, not to breastfeed during treatment with ARAKODA and for months after the final dose [see Contraindication (4), Warnings and Precautions (5.2), Use in Specific Populations (8.2)].MethemoglobinemiaInform patients that methemoglobinemia has occurred with ARAKODA. Advise patients on the symptoms of methemoglobinemia and instruct them to seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.3)].Psychiatric SymptomsAdvise patients who experience hallucinations, delusions, or confused thinking while taking ARAKODA to seek medical attention as soon as possible. Other psychiatric symptoms, such as changes in mood, anxiety, insomnia, and nightmares, should be promptly evaluated by medical professional if they last more than three days or severe [see Warnings and Precautions (5.4)]. Hypersensitivity ReactionsInform patients that hypersensitivity reactions have occurred with ARAKODA. Advise patients on the symptoms of hypersensitivity reactions and instruct them to seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.5)].Manufactured For: 60 Degrees Pharmaceuticals LLC, 1025 Connecticut Avenue NW, Suite 1000, Washington DC 200361217a. oAdvise patients to take ARAKODA with food.. oAdvise patients to swallow the tablet whole and not to break, crush or chew it.. oAdvise patients to complete the full course of ARAKODA including the loading dose, maintenance dose and terminal dose.

LACTATION SECTION.


8.2 Lactation Risk Summary. breastfed infant with G6PD deficiency is at risk for hemolytic anemia from exposure to ARAKODA. 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) and Clinical Considerations]. There is no information regarding the presence of ARAKODA in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. In breastfed infant with normal G6PD, the developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ARAKODA and any potential effects on the breastfed infant from ARAKODA or from the underlying maternal condition.. Clinical Considerations. Check the infants G6PD status before maternal breastfeeding commences. If an infant is G6PD-deficient, exposure to ARAKODA during breastfeeding may result in hemolytic anemia in the infant; therefore, advise the woman with an infant who has G6PD deficiency or whose G6PD status is unknown, not to breastfeed during treatment with ARAKODA and for months after the final dose of ARAKODA.

MECHANISM OF ACTION SECTION.


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

MICROBIOLOGY SECTION.


12.4 Microbiology Mechanism of ActionTafenoquine, 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 activityTafenoquine 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)]. ResistanceA potential for development of resistance of Plasmodium species to tafenoquine was not evaluated. Studies with the erythrocytic forms of P. falciparum strains/isolates suggest potential for cross-resistance with primaquine, an 8-aminoquinoline. Clinical relevance of such findings is not known.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisTwo-year oral carcinogenicity studies were conducted in rats and mice. Renal cell adenomas and carcinomas were increased in male rats at doses 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 carcinogenic risk in humans is unclear. MutagenesisTafenoquine did not cause mutations or chromosomal damage in definitive in vitro tests (bacterial mutation assay and mouse lymphoma L5178Y cell assay) or in an in vivo oral rat micronucleus test.Impairment of FertilityIn 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).

OVERDOSAGE SECTION.


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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL Carton Label Carton LabelRx onlyNDC 71475-257-01KEEP OUT OF REACH OF CHILDRENULLTTENTION: Dispense the enclosedMedication Guide to each patientArakoda(TM) (tafenoquine) tablets, for oral use100 mg16 (2 8)Unit Dose TabletsSixtyDegreesPharmaEach tablet contains 100 mg tafenoquine (equivalent to 125.5 mg tafenoquine succinate). Store at 20C to 25C (68F to 77F); excursions permitted to 15 to 30C (59 to 86F).Protect from moisture. Dispense only in the original carton.See Prescribing Information for Dosage and Administration information.Two blister packs are contained in each carton. Each blister pack contains eight 100 mg tablets of Arakoda(TM) (tafenoquine), for oral use.Manufactured for: 60 Pharmaceuticals, LLC.1025 Connecticut Ave., NW, Suite 1000Washington DC 20036Country of Origin: IndiaSixtyDegreesPharmaArakoda(TM)(tafenoquine) tablets, for oral useLotEXP MMMYYYYGTINSN. Principal Display Panel Carton Label.

PEDIATRIC USE SECTION.


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

PHARMACODYNULLMICS SECTION.


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

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics AbsorptionA 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 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 high-calorie, high-fat meal (approximately 1000 calories with 19% protein, 31% carbohydrate, and 50% fat). Table 5. Mean (%CV) Pharmacokinetic Parameters of Tafenoquine Following Single Oral Administration of Two 100-mg ARAKODA Tablets Under Fed Conditions in Healthy Adult Subjects (N=65)ParameterValuea Coefficient of Variance (CV) Median and (Range) Plasma tafenoquine AUCinf increased by 41% when tafenoquine was administered as an investigational capsule formulation with high-calorie, high-fat meal compared with the fasted state. Cmax 147 ng/mL (20.7%)a Tmax 14 hr (6 72 hr)b AUCinf 70 hrmcg/mL (24.6%)a, Following administration of 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 loading dose under fasting conditions, the mean plasma accumulation ratio of tafenoquine was approximately 4.4.DistributionTafenoquine is greater than 99.5% bound to protein in humans. The apparent volume of distribution of tafenoquine in healthy adult subjects is 2470 [Inter-Individual Variability (IIV): 24.1 %].EliminationThe 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.MetabolismNegligible 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 days following the first dose of tafenoquine.ExcretionThe full excretion profile of tafenoquine in humans is unknown.Specific PopulationsThe 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 StudiesClinical StudiesNo 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 ClinicallyTafenoquine 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 substrate of human OATP1B1 or OATP1B3 at clinically relevant concentrations. It is inconclusive as to whether tafenoquine is substrate of P-gp and/or BCRP mediated transport.

PREGNULLNCY SECTION.


8.1 Pregnancy Risk Summary. The use of ARAKODA during pregnancy may cause hemolytic anemia in fetus who is G6PD-deficient. Treatment with ARAKODA during pregnancy is not recommended. If pregnancy is detected during ARAKODA use, discontinue ARAKODA as soon as possible and switch to an alternative prophylactic drug for malaria during pregnancy [see Warnings and Precautions (5.2)]. Available data with use of ARAKODA in pregnant women are insufficient to establish 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 similar study in rats.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 18), at doses of mg/kg (about 0.4 times the clinical exposure based on body surface area comparisons) and above. Doses higher than mg/kg were also associated with maternal toxicity (mortality and reduced body weight gain). In 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 pre- and postnatal development study in rats, tafenoquine administered throughout pregnancy and lactation produced maternal toxicity and 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.

RISKS.


Risk Summary. The use of ARAKODA during pregnancy may cause hemolytic anemia in fetus who is G6PD-deficient. Treatment with ARAKODA during pregnancy is not recommended. If pregnancy is detected during ARAKODA use, discontinue ARAKODA as soon as possible and switch to an alternative prophylactic drug for malaria during pregnancy [see Warnings and Precautions (5.2)]. Available data with use of ARAKODA in pregnant women are insufficient to establish 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 similar study in rats.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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.

SPL MEDGUIDE SECTION.


Medication Guide MEDICATION GUIDEARAKODA (AIR-uh-KOH-duh)(tafenoquine)tablets, for oral useWhat is the most important information should know about ARAKODAARAKODA can cause serious side effects including: oBreakdown of red blood cells (hemolytic anemia). See Do not take ARAKODA if you:ARAKODA can cause breakdown of red blood cells (hemolysis) in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Your healthcare provider will test you for G6PD deficiency before you start taking ARAKODA. Signs of hemolytic anemia may not happen right away (delayed reaction).Tell your healthcare provider or get emergency medical help right away if you develop signs of hemolytic anemia which include darkening of the urine, dizziness, confusion, feeling tired, light-headedness, or shortness of breath, pale skin or yellowing of the skin and whites of the eyes.oDecrease of oxygen in your blood caused by certain type of abnormal red blood cell (methemoglobinemia). Signs and symptoms of methemoglobinemia may not happen right away (delayed reaction). Get medical help right away if you have bluish coloring of the lips or skin, headache, fatigue, shortness of breath, or lack of energy.oMental health (psychiatric) symptoms. See Do not take ARAKODA if you:Sleep problems, depression, anxiety and psychosis have happened while taking ARAKODA. Psychiatric symptoms may not happen right away (delayed reaction). Get emergency medical help right away if you develop hallucinations (seeing or hearing things that are really not there), delusions (false or strange thoughts or beliefs), or if you get confused or have problems thinking while taking ARAKODA. Call your healthcare provider if you develop changes in your mood, anxiety, trouble sleeping (insomnia), or nightmares for days or longer while taking ARAKODA.oARAKODA can have other serious side effects. See What are the possible side effects of ARAKODAWhat is ARAKODAoARAKODA is prescription medicine used to help prevent malaria in people 18 years of age and older. oMalaria is serious disease of the blood that is spread by infected mosquitos. oIt is not known if ARAKODA is safe and effective in children.Do not take ARAKODA if you:ohave G6PD deficiency. oare breastfeeding child known to have G6PD deficiency or breastfeeding child that has not been tested for G6PD deficiency.ohave history of psychotic disorders, or you currently have psychotic symptoms including hallucinations (seeing or hearing things that are not really there), delusions (false or strange thoughts or beliefs), or disorganized thinking or behavior. oare allergic to tafenoquine, other 8-aminoquinolines, or any of the ingredients in ARAKODA. See the end of this Medication Guide for complete list of ingredients in ARAKODA.Before taking ARAKODA, tell your health care provider about all your medical conditions, including if you:ohave nicotinamide adenine dinucleotide (NULLDH) reductase deficiency. People with NULLDH reductase deficiency have higher risk for methemoglobinemia if they take ARAKODA. ohave or have had mental health problems. oare pregnant or plan to become pregnant. ARAKODA can harm an unborn baby who has G6PD deficiency.oYou should not become pregnant during treatment with ARAKODA.oFemales who are able to become pregnant should use effective birth control (contraception) during treatment with ARAKODA. Talk with your healthcare provider about birth control methods that may be right for you.oYour healthcare provider may suggest you take pregnancy test before you start taking ARAKODA. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with ARAKODA.oare breastfeeding or plan to breastfeed. It is not known if ARAKODA passes into breast milk. See Do not take ARAKODA if you:oYour healthcare provider should check your child for G6PD deficiency before you start breastfeeding.oIf you know your child has G6PD deficiency, do not breastfeed during treatment with ARAKODA and for months after your last dose of ARAKODA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ARAKODA and other medicines may affect each other causing side effects.How should take ARAKODAoTake ARAKODA exactly as your healthcare provider tells you to take it. oARAKODA is given as tablets that you will take together as single dose. Each ARAKODA tablet has 100 mg of tafenoquine.oYou will start taking ARAKODA days before you travel to malaria area.oTake tablets, time each day for days. oYou will continue to take ARAKODA while you are in the malaria area.oTake tablets, time each week.oStart taking this dose of ARAKODA days after the last dose of ARAKODA that you took before your travel to the malaria area. oYou will take your last dose of ARAKODA after you leave the malaria area.oTake tablets.oTake this dose of ARAKODA days after the last dose of ARAKODA that you took while you were in the malaria area. oTake ARAKODA tablets whole. Do not break, crush, or chew the tablets before swallowing.oTake ARAKODA with food. oIt is important that you take the full course of treatment with ARAKODA. Do not stop taking ARAKODA without first talking to your healthcare provider because the medicine may not work as well to prevent malaria.oIf you miss or daily doses of ARAKODA before your travel to the malaria area:o1 daily dose: take tablets (missed dose), and then continue to take your daily dose of ARAKODA until you have taken total of daily doses before your travel to the malaria area. Start taking your weekly doses or ARAKODA week after your last daily dose.o2 daily doses: take tablets (missed dose), time each day for days in row (consecutive days) so that you have taken total of daily doses before your travel to the malaria area. Start taking your weekly doses of ARAKODA week after your last daily dose.oIf you miss any weekly doses of ARAKODA while you are in the malaria area:o1 weekly dose: take tablets, time on any day up to the time of your next scheduled weekly dose.o2 weekly doses: take tablets, time on any day before your next scheduled weekly dose. o3 or more weekly doses: take tablets, time each day for days up to the time of your next scheduled weekly dose. oIf you miss taking your last dose of ARAKODA days after the last dose of ARAKODA you took while you were in the malaria area, take this last dose of ARAKODA as soon as you remember.What are the possible side effects of ARAKODAARAKODA may cause serious side effects, including: oSee What is the most important information should know about ARAKODAoAllergic (hypersensitivity) reactions. See Do not take ARAKODA if you:Allergic reactions can happen after you take ARAKODA. Signs and symptoms of an allergic reaction may not happen right away (delayed reaction). Get medical help right away if you have any signs or symptoms of an allergic reaction including:oswelling of the face, lips, tongue or throatoitchingotrouble breathing or wheezingovomitingofainting and feeling lightheadedorashohives The most common side effects of ARAKODA include: diarrhea, headache, back pain, nausea, vomiting, dizziness, increased liver enzyme levels in your blood, motion sickness, insomnia, depression, abnormal dreams and anxiety.Other side effects of ARAKODA include eye problems. Some people who take ARAKODA can have problem with the cornea of the eye called vortex keratopathy. This problem can be seen during an eye exam. Vortex keratopathy does not cause vision problems and will usually go away after you stop taking ARAKODA.These are not all the possible side effects of ARAKODA.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Sixty Degrees Pharmaceuticals, LLC at 1-888-834-0225.How should store ARAKODAoStore ARAKODA at room temperature between 68F to 77F (20C to 25C). oProtect tablets from moisture. Keep ARAKODA and all medicines out of the reach of children.General information about the safe and effective use of ARAKODA.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use ARAKODA for condition for which it was not prescribed. Do not give ARAKODA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ARAKODA that is written for health professionals.What are the ingredients in ARAKODAActive ingredient: tafenoquine succinate Inactive ingredients: microcrystalline cellulose, mannitol, and magnesium stearate. The tablet film-coating contains the following inactive ingredients: hypromellose, iron oxide red, titanium dioxide, and macrogol/polyethylene glycol.Manufactured for:Sixty Degrees Pharmaceuticals, LLCWashington, DC 20036For more information, go to https://60degreespharma.com or call 1-888-834-0225.This Medication Guide has been approved by the U.S. Food and Drug AdministrationIssued: August 2018. oBreakdown of red blood cells (hemolytic anemia). See Do not take ARAKODA if you:ARAKODA can cause breakdown of red blood cells (hemolysis) in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Your healthcare provider will test you for G6PD deficiency before you start taking ARAKODA. Signs of hemolytic anemia may not happen right away (delayed reaction).Tell your healthcare provider or get emergency medical help right away if you develop signs of hemolytic anemia which include darkening of the urine, dizziness, confusion, feeling tired, light-headedness, or shortness of breath, pale skin or yellowing of the skin and whites of the eyes.. oDecrease of oxygen in your blood caused by certain type of abnormal red blood cell (methemoglobinemia). Signs and symptoms of methemoglobinemia may not happen right away (delayed reaction). Get medical help right away if you have bluish coloring of the lips or skin, headache, fatigue, shortness of breath, or lack of energy.. oMental health (psychiatric) symptoms. See Do not take ARAKODA if you:Sleep problems, depression, anxiety and psychosis have happened while taking ARAKODA. Psychiatric symptoms may not happen right away (delayed reaction). Get emergency medical help right away if you develop hallucinations (seeing or hearing things that are really not there), delusions (false or strange thoughts or beliefs), or if you get confused or have problems thinking while taking ARAKODA. Call your healthcare provider if you develop changes in your mood, anxiety, trouble sleeping (insomnia), or nightmares for days or longer while taking ARAKODA.. oARAKODA can have other serious side effects. See What are the possible side effects of ARAKODA. oARAKODA is prescription medicine used to help prevent malaria in people 18 years of age and older. oMalaria is serious disease of the blood that is spread by infected mosquitos. oIt is not known if ARAKODA is safe and effective in children.. ohave G6PD deficiency. oare breastfeeding child known to have G6PD deficiency or breastfeeding child that has not been tested for G6PD deficiency.. ohave history of psychotic disorders, or you currently have psychotic symptoms including hallucinations (seeing or hearing things that are not really there), delusions (false or strange thoughts or beliefs), or disorganized thinking or behavior. oare allergic to tafenoquine, other 8-aminoquinolines, or any of the ingredients in ARAKODA. See the end of this Medication Guide for complete list of ingredients in ARAKODA.. ohave nicotinamide adenine dinucleotide (NULLDH) reductase deficiency. People with NULLDH reductase deficiency have higher risk for methemoglobinemia if they take ARAKODA. ohave or have had mental health problems. oare pregnant or plan to become pregnant. ARAKODA can harm an unborn baby who has G6PD deficiency.oYou should not become pregnant during treatment with ARAKODA.oFemales who are able to become pregnant should use effective birth control (contraception) during treatment with ARAKODA. Talk with your healthcare provider about birth control methods that may be right for you.oYour healthcare provider may suggest you take pregnancy test before you start taking ARAKODA. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with ARAKODA.. oYou should not become pregnant during treatment with ARAKODA.. oFemales who are able to become pregnant should use effective birth control (contraception) during treatment with ARAKODA. Talk with your healthcare provider about birth control methods that may be right for you.. oYour healthcare provider may suggest you take pregnancy test before you start taking ARAKODA. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with ARAKODA.. oare breastfeeding or plan to breastfeed. It is not known if ARAKODA passes into breast milk. See Do not take ARAKODA if you:oYour healthcare provider should check your child for G6PD deficiency before you start breastfeeding.oIf you know your child has G6PD deficiency, do not breastfeed during treatment with ARAKODA and for months after your last dose of ARAKODA. oYour healthcare provider should check your child for G6PD deficiency before you start breastfeeding.. oIf you know your child has G6PD deficiency, do not breastfeed during treatment with ARAKODA and for months after your last dose of ARAKODA.. oTake ARAKODA exactly as your healthcare provider tells you to take it. oARAKODA is given as tablets that you will take together as single dose. Each ARAKODA tablet has 100 mg of tafenoquine.. oYou will start taking ARAKODA days before you travel to malaria area.oTake tablets, time each day for days. oTake tablets, time each day for days.. oYou will continue to take ARAKODA while you are in the malaria area.oTake tablets, time each week.oStart taking this dose of ARAKODA days after the last dose of ARAKODA that you took before your travel to the malaria area. oTake tablets, time each week.. oStart taking this dose of ARAKODA days after the last dose of ARAKODA that you took before your travel to the malaria area.. oYou will take your last dose of ARAKODA after you leave the malaria area.oTake tablets.oTake this dose of ARAKODA days after the last dose of ARAKODA that you took while you were in the malaria area. oTake tablets.. oTake this dose of ARAKODA days after the last dose of ARAKODA that you took while you were in the malaria area.. oTake ARAKODA tablets whole. Do not break, crush, or chew the tablets before swallowing.. oTake ARAKODA with food. oIt is important that you take the full course of treatment with ARAKODA. Do not stop taking ARAKODA without first talking to your healthcare provider because the medicine may not work as well to prevent malaria.. oIf you miss or daily doses of ARAKODA before your travel to the malaria area:o1 daily dose: take tablets (missed dose), and then continue to take your daily dose of ARAKODA until you have taken total of daily doses before your travel to the malaria area. Start taking your weekly doses or ARAKODA week after your last daily dose.o2 daily doses: take tablets (missed dose), time each day for days in row (consecutive days) so that you have taken total of daily doses before your travel to the malaria area. Start taking your weekly doses of ARAKODA week after your last daily dose.. o1 daily dose: take tablets (missed dose), and then continue to take your daily dose of ARAKODA until you have taken total of daily doses before your travel to the malaria area. Start taking your weekly doses or ARAKODA week after your last daily dose.. o2 daily doses: take tablets (missed dose), time each day for days in row (consecutive days) so that you have taken total of daily doses before your travel to the malaria area. Start taking your weekly doses of ARAKODA week after your last daily dose.. oIf you miss any weekly doses of ARAKODA while you are in the malaria area:o1 weekly dose: take tablets, time on any day up to the time of your next scheduled weekly dose.o2 weekly doses: take tablets, time on any day before your next scheduled weekly dose. o3 or more weekly doses: take tablets, time each day for days up to the time of your next scheduled weekly dose. o1 weekly dose: take tablets, time on any day up to the time of your next scheduled weekly dose.. o2 weekly doses: take tablets, time on any day before your next scheduled weekly dose. o3 or more weekly doses: take tablets, time each day for days up to the time of your next scheduled weekly dose. oIf you miss taking your last dose of ARAKODA days after the last dose of ARAKODA you took while you were in the malaria area, take this last dose of ARAKODA as soon as you remember.. oSee What is the most important information should know about ARAKODA. oAllergic (hypersensitivity) reactions. See Do not take ARAKODA if you:Allergic reactions can happen after you take ARAKODA. Signs and symptoms of an allergic reaction may not happen right away (delayed reaction). Get medical help right away if you have any signs or symptoms of an allergic reaction including:oswelling of the face, lips, tongue or throatoitchingotrouble breathing or wheezingovomitingofainting and feeling lightheadedorashohives oswelling of the face, lips, tongue or throat. oitching. otrouble breathing or wheezing. ovomiting. ofainting and feeling lightheaded. orash. ohives. oStore ARAKODA at room temperature between 68F to 77F (20C to 25C). oProtect tablets from moisture. Company Logo.

SPL UNCLASSIFIED SECTION.


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)].

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed G6PD-deficient infant or infant with unknown G6PD status during treatment and for months after the last dose of ARAKODA. (5.2, 8.2). 8.1 Pregnancy Risk Summary. The use of ARAKODA during pregnancy may cause hemolytic anemia in fetus who is G6PD-deficient. Treatment with ARAKODA during pregnancy is not recommended. If pregnancy is detected during ARAKODA use, discontinue ARAKODA as soon as possible and switch to an alternative prophylactic drug for malaria during pregnancy [see Warnings and Precautions (5.2)]. Available data with use of ARAKODA in pregnant women are insufficient to establish 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 similar study in rats.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 18), at doses of mg/kg (about 0.4 times the clinical exposure based on body surface area comparisons) and above. Doses higher than mg/kg were also associated with maternal toxicity (mortality and reduced body weight gain). In 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 pre- and postnatal development study in rats, tafenoquine administered throughout pregnancy and lactation produced maternal toxicity and 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.. 8.2 Lactation Risk Summary. breastfed infant with G6PD deficiency is at risk for hemolytic anemia from exposure to ARAKODA. 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) and Clinical Considerations]. There is no information regarding the presence of ARAKODA in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. In breastfed infant with normal G6PD, the developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ARAKODA and any potential effects on the breastfed infant from ARAKODA or from the underlying maternal condition.. Clinical Considerations. Check the infants G6PD status before maternal breastfeeding commences. If an infant is G6PD-deficient, exposure to ARAKODA during breastfeeding may result in hemolytic anemia in the infant; therefore, advise the woman with an infant who has G6PD deficiency or whose G6PD status is unknown, not to breastfeed during treatment with ARAKODA and for months after the final dose of ARAKODA.. 8.3 Females and Males of Reproductive Potential Pregnancy Testing. Verify the pregnancy status in females of reproductive potential prior to initiating treatment with ARAKODA. [see Dosage and Administration (2.2), Warnings and Precautions, (5.2), and Use in Specific Populations (8.1)].. Contraception. ARAKODA may cause hemolytic anemia in G6PD-deficient fetus [see Warnings and Precautions (5.2), Use in Specific Populations (8.1)]. Advise females of reproductive potential that treatment with ARAKODA during pregnancy is not recommended and to avoid pregnancy or use effective contraception for months after the final dose of ARAKODA.. 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)].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS oHemolytic 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)oG6PD Deficiency in Pregnancy or Lactation: ARAKODA may cause fetal harm when administered to pregnant woman with G6PD-deficient fetus. ARAKODA is not recommended during pregnancy. G6PD-deficient infant may be at risk for hemolytic anemia from exposure to ARAKODA through breast milk. Check infants G6PD status before breastfeeding begins. (5.2, 8.1, 8.2)oMethemoglobinemia: Asymptomatic elevations in blood methemoglobin have been observed. Initiate appropriate therapy if signs or symptoms of methemoglobinemia occur. (5.3)oPsychiatric Effects: Serious psychotic adverse reactions have been observed in patients with 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 mental health professional as soon as possible. (5.4) oHypersensitivity Reactions: Serious hypersensitivity reactions have been observed with administration of ARAKODA. If hypersensitivity reactions occur, institute appropriate therapy. (5.5)oDelayed 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). oHemolytic 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). oG6PD Deficiency in Pregnancy or Lactation: ARAKODA may cause fetal harm when administered to pregnant woman with G6PD-deficient fetus. ARAKODA is not recommended during pregnancy. G6PD-deficient infant may be at risk for hemolytic anemia from exposure to ARAKODA through breast milk. Check infants G6PD status before breastfeeding begins. (5.2, 8.1, 8.2). oMethemoglobinemia: Asymptomatic elevations in blood methemoglobin have been observed. Initiate appropriate therapy if signs or symptoms of methemoglobinemia occur. (5.3). oPsychiatric Effects: Serious psychotic adverse reactions have been observed in patients with 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 mental health professional as soon as possible. (5.4) oHypersensitivity Reactions: Serious hypersensitivity reactions have been observed with administration of ARAKODA. If hypersensitivity reactions occur, institute appropriate therapy. (5.5). oDelayed 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 FetusThe use of ARAKODA during pregnancy may cause hemolytic anemia in G6PD-deficient fetus. Even if 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 months after the last dose of ARAKODA. If 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 InfantA 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 G6PD-deficient infant or if the G6PD status of the infant is unknown not to breastfeed during treatment with ARAKODA and for 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 (NULLDH)-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 subject with an adverse reaction of suicide attempt (0.1%). Subjects with history of psychiatric disorders were excluded from three of five ARAKODA trials in which mefloquine was included as comparator. Psychosis was reported in three patients with history of psychosis or schizophrenia who received tafenoquine doses (350 mg to 500 mg single dose, or 400 mg daily for 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 200-mg weekly dose is not approved by FDA.ARAKODA is contraindicated in patients with 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 mental health professional as soon as possible. Other psychiatric symptoms, such as changes in mood, anxiety, insomnia, and nightmares, should be promptly evaluated by 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)].