DRUG INTERACTIONS-                       

Effect of KRINTAFEL 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  which may increase the risk of toxicity of these drugs.                                   

Avoid coadministration of KRINTAFEL 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.

BRIEF SUMMARY

TAFENOQUINE (2018)

Indn-       For the radical cure (prevention of relapse) of  Plasmodium    malaria  

Comp-     Tablets: 150 mg of tafenoquine- It s an antimalarial indicated for the radical cure (prevention of  relapse) of Plasmodium vivax malaria in patients aged 16 years and older who  are receiving appropriate antimalarial therapy for acute P. vivax infection.

ADR-   Common adverse reactions (=5%) were dizziness, nausea, vomiting, headache, and decreased hemoglobin

CI-  Breastfeeding by a lactating woman when the infant is found to be G6PD deficient or if G6PD status is unknown.   

WARNINGS-                                                          

  • 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.

• G6PD Deficiency in Pegnancy or Lactation:                                                           • Known hypersensitivity reactions to tafenoquine, other 8-aminoquinolines, or any component

 Hemolytic Anemia: G6PD testing must be performed before prescribing  due to the risk of hemolytic anemia. Monitor patients for clinical signs or symptoms of hemolysis.

• G6PD Deficiency in Pregnancy or Lactation: KRINTAFEL may cause hemolytic anemia when administered to a pregnant woman with a G6PDdeficient fetus.

Pat Inform-

 G6PD Testing and Hemolytic Anemia-                                                                            Inform patients of the need for testing for G6PD deficiency before starting  the drug..  Advise patients of the symptoms of hemolytic anemia and instruct them to seek medial advice promptly if such symptoms occur.                                                                      Patients should contact their healthcare provider if they develop dark lips or urine as these may be signs of hemolysis or methemoglobinemia

 Important Administration Instructions-                                                                           Advise patients to takewith food to increase absorption.  Advise patients to swallow the tablet whole and not to break, crush, or chew it.                                                           

==================================================================

U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  23

 ADVERSE REACTIONS-

Common adverse reactions (=5%) were dizziness, nausea, vomiting, headache, and decreased hemoglobin

CONTRAINDICATIONS-   

 • G6PD deficiency or unknown G6PD status. 

 • Breastfeeding by a lactating woman when the infant is found to be G6PD deficient or if G6PD status is unknown.                                                                                                    

 • Known hypersensitivity reactions to tafenoquine, other 8-aminoquinolines, or any component of KRINTAFEL.

 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.

• G6PD Deficiency in Pregnancy or Lactation: KRINTAFEL may cause hemolytic anemia when administered to a pregnant woman with a G6PDdeficient 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.   

 • Methemoglobinemia: Asymptomatic elevations in blood methemoglobin have been observed. Initiate appropriate therapy if signs or symptoms of methemoglobinemia occur.  

 • 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.

 • Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., angioedema) have been observed with administration of KRINTAFEL. If hypersensitivity reactions occur, institute appropriate therapy.

• Due to the long half-life of KRINTAFEL (15 days), psychiatric effects and hypersensitivity reactions may be delayed in onset and/or duration.

PATIENT COUNSELING INFORMATION

 Advise the patient to read the FDA-approved patient labeling (Patient Information).

 G6PD Testing and Hemolytic Anemia-                                                                            Inform patients of the need for testing for G6PD deficiency before starting KRINTAFEL. 

 Advise patients of the symptoms of hemolytic anemia and instruct them to seek medical advice promptly if such symptoms occur.        

Patients should contact their healthcare provider if they develop dark lips or urine as these may be signs of hemolysis or methemoglobinemia

 Important Administration Instructions-                                                                           Advise patients to take KRINTAFEL with food to increase absorption.                                Advise patients to swallow the tablet whole and not to break, crush, or chew it.                                                             

Potential Harm to the Fetus-                                                                                             Advise females of reproductive potential of the potential risk of KRINTAFEL to a fetus and to inform their healthcare provider of a known or suspected pregnancy 

 Advise females of reproductive potential to avoid pregnancy or use effective contraception for 3 months after the dose of KRINTAFEL

 Lactation-                                                                                                                            Advise women with a G6PD-deficient infant, or if they do not know the G6PD status of their infant, not to breastfeed for 3 months after the dose of KRINTAFEL.

Use in Specific Populations-                                                                                         Methemoglobinemia-                                                                                                        Inform patients that methemoglobinemia has occurred with KRINTAFEL. Advise patients of the symptoms of methemoglobinemia and instruct them to seek medical advice promptly if such symptoms occur.                                                                                                                                   

  Psychiatric Symptoms-                                                                                               Advise patients with a history of psychiatric illness regarding the potential for new or worsening psychiatric symptoms with KRINTAFEL and instruct them to seek medical advice promptly if such symptoms occur .                                                                                                                              Hypersensitivity Reactions-                                                                                         Inform patients that hypersensitivity reactions have occurred with KRINTAFEL. Advise patients of the symptoms of hypersensitivity reactions and instruct them to seek medical advice promptly if such symptoms occur.

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 CLINICAL PHARMACOLOGY -

1. Mechanism of Action-                                                                                                      Tafenoquine is an 8-aminoquinoline antimalarial drug .

2. Pharmacodynamics Cardiac Electrophysiology-                                                         The effect of tafenoquine on the QTc interval was evaluated in a Phase 1 randomized, singleblind, placebo-and positive-controlled, parallel-group thorough QTc study in 260 healthy adult subjects.

At a cumulative dose of 1,200 mg (400 mg/day for 3 days; 4 times the maximum recommended dose), tafenoquine did not prolong the QTc interval to any clinically relevant extent.

3. Pharmacokinetics-                                                                                                          Absorption-                                                                                                                      Maximum plasma concentrations were generally observed 12 to 15 hours following oral administration.                                                                                                                                                                                                                                                                Food Effect:                                                                                                           Plasma tafenoquine AUC increased by 41% and Cmax increased by 31% when administered as an investigational capsule formulation with a high-calorie, high-fat meal (approximately 1,000 calories with 15% protein, 25% carbohydrate, and 60% fat) compared with the fasted state.

Distribution-                                                                                                                        Protein binding of tafenoquine is >99.5%. The apparent oral volume of distribution is ~1,600 L. Following single-and multiple-oral-dose administration, tafenoquine whole blood concentrations were on average 67% higher than corresponding plasma values.

Elimination.                                                                                                                      The apparent oral clearance of tafenoquine is approximately 3 L/h.                                 The average terminal half-life is approximately 15 days.

Metabolism:                                                                                                                        Tafenoquine undergoes slow metabolism. Unchanged tafenoquine represented the only notable drug-related component in human plasma after a single oral dose of tafenoquine.

Excretion:                                                                                                                             The full excretion profile of tafenoquine in humans is unknown. Over a 6-day collection period, renal elimination of unchanged tafenoquine was low.

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

Drug Interaction Studies Clinical Studies:                                                                       No clinically significant effects on tafenoquine pharmacokinetics were observed following coadministration with chloroquine, dihydroartemisinin-piperaquine, or artemether-lumefantrine in healthy subjects.

No clinically significant effects on the pharmacokinetics of dihydroartemisinin, piperaquine, artemether, lumefantrine, or substrates of cytochrome P450 isoenzymes (CYP)1A2 (caffeine), CYP2D6 (desipramine), CYP2C8 (chloroquine), CYP2C9 (flurbiprofen), or CYP3A4 (midazolam, chloroquine) were observed following coadministration of tafenoquine in healthy subjects.  

USE IN SPECIFIC POPULATIONS-.

1.Pregnancy Risk Summary-                                                                                             The use of KRINTAFEL during pregnancy may cause hemolytic anemia in a fetus who is G6PD deficient. Treatment with KRINTAFEL during pregnancy is not recommended.   

 Available data with use of KRINTAFEL in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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.

2. Lactation Risk Summary-                                                                                               A breastfed infant with G6PD deficiency is at risk for hemolytic anemia from exposure to KRINTAFEL. 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.

There is no information regarding the presence of KRINTAFEL in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production.

In a breastfed infant with normal G6PD, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KRINTAFEL and any potential effects on the breastfed infant from KRINTAFEL or from the underlying maternal condition.

 Clinical Considerations-                                                                                                   Check the infant’s G6PD status before maternal breastfeeding commences. If an infant is G6PD deficient, exposure to KRINTAFEL 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 for 3 months after the dose of KRINTAFEL.

3. Females and Males of Reproductive Potential Pregnancy Testing -                          Verify the pregnancy status in females of reproductive potential prior to initiating treatment with KRINTAFEL

 Contraception-                                                                                               KRINTAFEL may cause hemolytic anemia in a G6PD-deficient fetus  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.

4. Pediatric Use-                                                                                                                 The safety and effectiveness of KRINTAFEL have been established in pediatric patients aged 16 years and older. Use of KRINTAFEL in these pediatric patients is supported by evidence from adequate and well-controlled studies of KRINTAFEL.                         

 Safety and effectiveness of KRINTAFEL in pediatric patients younger than 16 years have not been established.

5. Geriatric Use-                                                                                                                    Clinical trials of KRINTAFEL 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

6. Renal Impairment-                                                                                                           The pharmacokinetics of KRINTAFEL have not been studied in patients with renal impairment. If KRINTAFEL is administered to such patients, monitoring for adverse reactions associated with KRINTAFEL is needed.

7. Hepatic Impairment-                                                                                                       The pharmacokinetics of KRINTAFEL have not been studied in patients with hepatic impairment. If KRINTAFEL is administered to such patients, monitoring for adverse reactions associated with KRINTAFEL is needed

OVERDOSAGE-                                                                                                                  Hemoglobin decline and methemoglobinemia may be encountered in an overdose with KRINTAFEL. Treatment of overdosage consists of institution of appropriate symptomatic and/or supportive therapy.