Krintafel

5 WARNINGS AND PRECAUTIONS • Hemolytic Anemia : G6PD testing must be performed before prescribing KRINTAFEL due to the risk of hemolytic anemia. Monitor patients for clinical signs or symptoms of hemolysis. ( 5.1 ) • G6PD Deficiency in Pregnancy or Lactation : KRINTAFEL may cause hemolytic anemia when administered to a pregnant woman with a G6PD-deficient fetus. KRINTAFEL is not recommended during pregnancy. A G6PD-deficient infant may be at risk for hemolytic anemia from exposure to KRINTAFEL 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 psychiatric adverse reactions have been observed in patients with a previous history of psychiatric conditions at doses higher than the approved dose. The benefit of treatment with KRINTAFEL must be weighed against the potential risk for psychiatric adverse reactions in patients with a history of psychiatric illness. ( 5.4 ) • Hypersensitivity Reactions : Serious hypersensitivity reactions (e.g., angioedema) have been observed with administration of KRINTAFEL. If hypersensitivity reactions occur, institute appropriate therapy. ( 5.5 ) • Due to the long half-life of KRINTAFEL (15 days), psychiatric effects and hypersensitivity reactions may be delayed in onset and/or duration. ( 5.4 , 5.5 , 12.3 ) • Risk of P. vivax Malaria Recurrence: Lack of efficacy in reducing P. vivax malaria recurrence in patients treated with KRINTAFEL combined with dihydroartemisinin/piperaquine (not approved artemisinin-containing antimalarial) was seen in a clinical trial. Use with antimalarials other than chloroquine is not recommended. ( 1 , 5.6 ) 5.1 Hemolytic Anemia Due to the risk of hemolytic anemia in patients with G6PD deficiency, G6PD testing must be performed before prescribing KRINTAFEL [see Dosage and Administration ( 2.1 )] . Due to the limitations of 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 KRINTAFEL is contraindicated in patients with G6PD deficiency or unknown G6PD status [see Contraindications ( 4 )] . Patients were excluded from clinical trials of KRINTAFEL if they had a G6PD enzyme activity level <70% of the site median value for G6PD normal activity [see Clinical Studies ( 14 )]. 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. Advise patients to seek medical attention if signs of hemolysis occur. 5.2 G6PD Deficiency in Pregnancy or Lactation Potential Harm to the Fetus The use of KRINTAFEL 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 KRINTAFEL during pregnancy is not recommended and to avoid pregnancy or use effective contraception for 3 months after the dose of KRINTAFEL [see Use in Specific Populations ( 8.1 , 8.3 )] . Potential Harm to the Breastfeeding Infant A G6PD-deficient infant may be at risk for hemolytic anemia from exposure to KRINTAFEL through breast milk. Infant G6PD status should be checked before breastfeeding begins. KRINTAFEL 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 for 3 months after the dose of KRINTAFEL [see Use in Specific Populations ( 8.2 )] . 5.3 Methemoglobinemia Asymptomatic elevations in methemoglobin have been observed in the clinical trials of KRINTAFEL [see Adverse Reactions ( 6.1 )]. Institute appropriate therapy if signs or symptoms of methemoglobinemia occur. Carefully monitor individuals with nicotinamide adenine dinucleotide (NADH)-dependent methemoglobin reductase deficiency. Advise patients to seek medical attention if signs of methemoglobinemia occur. 5.4 Psychiatric Effects Psychiatric adverse reactions including anxiety (<1%), abnormal dreams (<1%), and insomnia (3%) have been reported in clinical trials of KRINTAFEL [see Adverse Reactions ( 6.1 )] . Two cases of depression and 2 cases of psychosis have occurred primarily in patients with a history of psychiatric disorders following receipt of single doses of tafenoquine that were higher than the approved 300-mg dose (350 mg to 600 mg). Safety and effectiveness of KRINTAFEL have not been established at doses or regimens other than the approved regimen; use of KRINTAFEL at doses or regimens other than a 300-mg single dose is not approved by FDA. The benefit of treatment with KRINTAFEL must be weighed against the potential risk for psychiatric adverse reactions in patients with a history of psychiatric illness. Due to the long half-life of KRINTAFEL (approximately 15 days), signs or symptoms of psychiatric adverse reactions that may occur could be delayed in onset and/or duration [see Clinical Pharmacology ( 12.3 )] . 5.5 Hypersensitivity Reactions Serious hypersensitivity reactions (e.g., angioedema, urticaria) have been observed with administration of KRINTAFEL [see Adverse Reactions ( 6.1 )] . Institute appropriate therapy if hypersensitivity reactions occur. Do not re-administer KRINTAFEL. KRINTAFEL is contraindicated in patients who develop hypersensitivity to tafenoquine or any component of KRINTAFEL or other 8-aminoquinolines [see Contraindications ( 4 )] . Due to the long half-life of KRINTAFEL (approximately 15 days), signs or symptoms of hypersensitivity adverse reactions that may occur could be delayed in onset and/or duration [see Clinical Pharmacology ( 12.3 )] . Advise patients to seek medical attention if signs of hypersensitivity occur. 5.6 Risk of P. vivax Malaria Recurrence Lack of efficacy in reducing P. vivax malaria recurrence in patients treated with KRINTAFEL combined with an artemisinin-containing antimalarial was seen in a clinical trial (NCT02802501). In this double-blind, randomized, placebo-controlled trial in which all patients with P. vivax malaria were treated with dihydroartemisinin/piperaquine (not approved artemisinin-containing antimalarial) and were coadministered KRINTAFEL, primaquine, or placebo, lack of efficacy (recurrence rates at 6 months following treatment) was seen in patients treated with KRINTAFEL. Concomitant administration of KRINTAFEL with antimalarials other than chloroquine is not recommended.

6 ADVERSE REACTIONS The following clinically significant adverse reactions have been observed with KRINTAFEL and are discussed in detail in the Warnings and Precautions section: • Hemolytic anemia [see Warnings and Precautions ( 5.1 )] • Methemoglobinemia [see Warnings and Precautions ( 5.3 )] • Psychiatric effects [see Warnings and Precautions ( 5.4 )] • Hypersensitivity reactions [see Warnings and Precautions ( 5.5 )] Common adverse reactions (≥5%) were dizziness, nausea, vomiting, headache, and decreased hemoglobin. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 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 data described below reflect exposure to 4,129 subjects, of whom 810 received a 300-mg single dose of KRINTAFEL. KRINTAFEL was evaluated in patients with P. vivax malaria (n = 483) in 3 randomized, double-blind trials including a placebo-controlled trial comparing KRINTAFEL plus chloroquine (n = 260) with chloroquine alone (Trial 1), a placebo-controlled dose-ranging trial (Trial 2) (n = 57) [see Clinical Studies ( 14 )] , and a hematologic safety trial (Trial 3, NCT02216123) (n = 166). In Trial 1, in patients with P. vivax malaria, the most common adverse reactions reported in ≥5% of patients treated with KRINTAFEL are listed in Table 1 . Patients included in the trial had a mean age of 35 (range: 16 to 79 years), were 75% male and from the following regions: 70% Latin America (Brazil and Peru), 19% Southeast (SE) Asia (Thailand, Cambodia, and the Philippines), and 11% Africa (Ethiopia). Table 1. Selected Adverse Reactions a Reported in ≥5% of Patients with P. vivax Malaria Receiving KRINTAFEL in a Randomized, Active-Controlled Trial (Trial 1) a Adverse reactions reported prior to Day 29 as subsequent adverse reactions can be confounded by recurrence of malaria or retreatment with another agent from the quinoline class. Adverse Reaction Chloroquine KRINTAFEL + Chloroquine (n = 133) (n = 260) % % Dizziness 3 8 Nausea 7 6 Vomiting 5 6 Decreased Hemoglobin 2 5 Headache 7 5 Other Adverse Reactions Reported with KRINTAFEL Clinically significant adverse reactions with KRINTAFEL 300-mg single dose in clinical trials (n = 810) in ≤3% of subjects are listed below: Psychiatric Disorders: Anxiety, insomnia, abnormal dreams. Nervous System Disorders: Somnolence. Laboratory Investigations: Increased blood creatinine, increased blood methemoglobin, increased alanine aminotransferase. Immune System Disorders: Hypersensitivity reactions (e.g., angioedema, urticaria) [see Contraindications ( 4 ), Warnings and Precautions ( 5.5 )] . Eye Disorders: Vortex keratopathy, photophobia.

<table ID="_Ref88048913" cellpadding="0pt" width="100%"><caption>Table 1. Selected Adverse Reactions^a Reported in &#x2265;5% of Patients with P. vivax Malaria Receiving KRINTAFEL in a Randomized, Active-Controlled Trial (Trial 1)</caption><col width="33%"/><col width="33%"/><col width="33%"/><tfoot><tr><td align="left" colspan="3" valign="top">^a Adverse reactions reported prior to Day 29 as subsequent adverse reactions can be confounded by recurrence of malaria or retreatment with another agent from the quinoline class.</td></tr></tfoot><tbody><tr><td align="center" rowspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Chloroquine</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">KRINTAFEL</content></paragraph><paragraph><content styleCode="bold">+ Chloroquine</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule " valign="bottom"><paragraph><content styleCode="bold">(n = 133)</content></paragraph></td><td align="center" styleCode="Rrule Lrule " valign="bottom"><paragraph><content styleCode="bold">(n = 260)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Dizziness</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>8</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Decreased Hemoglobin</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>5</paragraph></td></tr></tbody></table>