Arakoda: Package Insert and Label Information

ARAKODA- tafenoquine tablet, film coated
60 Degrees Pharmaceuticals, LLC

1 INDICATIONS AND USAGE

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

2 DOSAGE AND ADMINISTRATION

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.

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.

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)].

5 WARNINGS AND PRECAUTIONS

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 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)]

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 ARAKODA1 (n=333)% Placebo (n=295) % Mefloquine2 (n=147) %
1 ARAKODA was administered as 200 mg daily for 3 days, then 200 mg weekly2 Mefloquine was administered as 250 mg daily for 3 days, then 250 mg weekly3 Includes headache, sinus headache, migraine and tension headache.4 Includes dizziness and dizziness postural5 Includes abnormal dreams, insomnia, nightmares, sleep disorder, and somnambulism.

Nervous system Disorders

35

34

47

Headache3

32

32

44

Dizziness4

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 symptom5

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 ARAKODA1 (n=492)% Mefloquine2 (n=162)%
1 ARAKODA was administered as 200 mg daily for 3 days, then 200 mg weekly2 Mefloquine was administered as 250 mg daily for 3 days, then 250 mg weekly3 Includes headache, sinus headache, migraine and tension headache.4 Includes dizziness and dizziness postural5 Includes motion sickness, vertigo and vertigo positional.6 Includes abnormal dreams, insomnia, nightmares, sleep disorder, and somnambulism.7 Includes abnormal dreams, nightmares8 Includes anxiety disorder, panic attack and stress.

Nervous system Disorders

22

27

Headache3

15

19

Dizziness4

1

1

Ear and labyrinth Disorders

7

11

Motion sicknesss5

5

6

Musculoskeletal and connective tissue disorders

29

30

Back pain

14

15

Gastrointestinal disorders

36

41

Diarrhea

18

20

Nausea

7

9

Vomiting

5

6

Psychiatric disorders

5

4

Any sleep symptom6

4

4

Insomnia

2

1

Abnormal dreams7

2

2

Anxiety8

1

0

Clinically Significant Adverse Reactions in Trials 1 to 5 (Overall Safety Population)

Clinically significant adverse reactions with ARAKODA (200 mg daily for 3 days, followed by 200 mg weekly) in Trials 1 to 5 (n= 825) are described below:

Ocular Adverse Reactions

Vortex keratopathy was reported in 21% to 93% of subjects receiving ARAKODA in the trials which included ophthalmic evaluations (Trials 3, 5, and Trial 6 (NCT # 01290601, an active-control trial in patients from Thailand with P. vivax malaria. The keratopathy did not result in any apparent functional visual changes and resolved within one year after drug cessation in all patients. Retinal abnormalities were noted in less than 1% of subjects receiving ARAKODA.

A total of 7 serious ocular adverse reactions (SARs) were reported in ARAKODA-treated subjects in the trials which included ophthalmic evaluations: 5 reports of keratopathy and two reports of retinal disorders.

Laboratory Abnormalities

Methemoglobinemia: Asymptomatic methemoglobin elevations were observed in 13% of subjects receiving ARAKODA.

Hemoglobin decrease: Hemoglobin decreases of ≥ 3 g/dL were observed in 2.3% of subjects receiving ARAKODA.

Adverse Reactions Reported in < 1% of Subjects Receiving ARAKODA in Trials 1 to 5

The following selected adverse reactions were reported in subjects receiving ARAKODA in Trials 1 to 5 at a rate of less than 1%.

Blood and lymphatic system disorders: hemolytic anemia, anemia, thrombocytopenia

Ear and labyrinth disorders: hyperacusis, Meniere’s disease

Eye disorders: night blindness, photophobia, blurred vision, visual acuity reduced, visual impairment, vitreous floaters

Hepatobiliary disorders: hyperbilirubinemia, jaundice cholestatic

Immune system disorders: hypersensitivity

Investigations: blood bilirubin increased, blood creatinine increased, glomerular filtration rate decreased

Nervous system disorders: amnesia, coordination abnormal, hyperesthesia, hypoesthesia, somnolence, syncope, tremor, visual field defect

Psychiatric disorders: agitation, neurosis

Skin and subcutaneous tissue disorders: urticaria.

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