DRUG INTERACTIONS - summary

 Strong or Moderate CYP3A4 Inhibitors or Fluconazole:                                                   Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with KOSELUGO. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce the dose of KOSELUGO. 

 Strong or Moderate CYP3A4 Inducers:                                                                        Avoid concomitant use of strong and moderate CYP3A4 inducers. 

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  12

 PATIENT COUNSELING INFORMATION

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

Cardiomyopathy-                                                                                                    Advise patients and caregivers that KOSELUGO can cause a reduction in LVEF and to immediately report any signs or symptoms of cardiomyopathy to their healthcare provider 

Ocular Toxicity-                                                                                                        Advise patients and caregivers that KOSELUGO can cause ocular toxicity that can lead to blindness and to contact their healthcare provider if the patient experiences any changes in their vision 

Gastrointestinal Toxicity-                                                                                            Advise patients and caregivers that KOSELUGO can cause diarrhea and to contact their healthcare provider at the onset of diarrhea 

Skin Toxicity-                                                                                                           Advise patients and caregivers that KOSELUGO can cause serious skin toxicities and to contact their healthcare provider for severe skin changes

Increased Creatinine Phosphokinase-                                                                Advise patients and caregivers that KOSELUGO can cause increased CPK and to report any signs and symptoms of muscle pain or weakness to their healthcare provider 

Increased Vitamin E Levels and Risk of Bleeding-                                                     Advise patients and caregivers to notify their healthcare provider if they are taking a supplement containing vitamin E, a vitamin-K antagonist or an anti-platelet agent 

Embryo-Fetal Toxicity-                                                                                                   Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy 

Use in Specific Populations-                                                                                       ? Advise females of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose.

 Advise males with female partners of reproductive potential to use effective contraception during treatment with KOSELUGO and for at least 1 week after the last dose 

Lactation-                                                                                                                    Advise women not to breastfeed during treatment with KOSELUGO and for 1 week after the last dose 

Drug Interactions-                                                                                                          Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.

Inform patients to avoid St. John’s wort, grapefruit or grapefruit juice while taking KOSELUGO 

Dosing and Administration-                                                                                     Inform patients and caregivers on how to take KOSELUGO with food and what to do for missed or vomited doses 

Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 © AstraZeneca 2020

 CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                               Selumetinib is an inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2). MEK1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway.

Both MEK and ERK are critical components of the RAS-regulated RAF-MEK-ERK pathway, which is often activated in different types of cancers.

2. Pharmacodynamics-                                                                                             The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of KOSELUGO have not been fully characterized.

Cardiac Electrophysiology-                                                                                         At a dose 1.5 times the maximum recommended dose, KOSELUGO does not prolong the QT/QTc interval to any clinically relevant extent.

3. Pharmacokinetics-                                                                                                   At the recommended dosage of 25 mg/m2 twice daily in pediatric patients (2 to = 18 years old), the mean maximum plasma concentration (Cmax) (coefficient of variation [CV%]) following the first dose and at steady state was 731 (62%) ng/mL and 798 (52%) ng/mL, respectively.

The mean area under the plasma drug concentration curve (AUC0-12h) following the first dose was 2009 (35%) ng•h/mL and the AUC0-6h at steady state was 1958 (41%) ng•h/mL.

Absorption-                                                                                                                The mean absolute oral bioavailability of selumetinib was 62% in healthy adults. The median time to peak plasma concentrations (Tmax) at steady-state in pediatric patients was 1 to 1.5 hours.

Effect of Food-                                                                                                        Mean Cmax and AUC of selumetinib decreased by 50% and 16%, respectively, following a high-fat meal (1000 calories, 50% fat) in healthy adults administered a single-dose of 75 mg (1.5 times the approved maximum recommended dosage).

Tmax was delayed by approximately 1.5 hours following a high-fat meal. Selumetinib Cmax and AUC decreased by 60% and 38%, respectively, following a low-fat meal (400 calories, 25% fat) in healthy adults administered a single-dose of 50 mg. Tmax was delayed by approximately 0.9 hours following a low-fat meal.

Distribution-                                                                                                               The mean apparent volume of distribution at steady state (Vss) of selumetinib across a dose range of 20 mg/m2 to 30 mg/m2 (0.8 to 1.2 times the recommended dosage) ranged from 78 L to 171 L in pediatric patients.

Elimination-                                                                                                                   In pediatric patients, selumetinib had an apparent oral clearance (CL/F) of 8.8 L/hr and a mean elimination half-life of approximately 6.2 hours following a dose of 25 mg/m2 .

Metabolism-                                                                                                                 Selumetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C19, CYP1A2, CYP2C9, CYP2E1, and CYP3A5.

Selumetinib also undergoes glucuronidation by UGT1A1 and UGT1A3. It is estimated that 56% of the observed intrinsic clearance of selumetinib could be attributed to CYP metabolism and about 29% attributed to direct glucuronidation by UGT enzymes in vitro.

Excretion-                                                                                                                 After a single oral dose of radiolabeled selumetinib 75 mg (1.5 times the recommended dose) to healthy adults, 59% of the dose was recovered in feces (19% as unchanged) and 33% in urine (< 1% as parent).

Specific Populations-                                                                                                   Racial or Ethnic Groups- No clinically meaningful effect on the pharmacokinetics of selumetinib or N-desmethyl selumetinib were observed based on race (White, Asian, Black).

Patients with Renal Impairment-                                                                                   Following administration of a single dose of 50 mg, selumetinib exposures were similar in subjects with end stage renal disease (CLcr < 15 mL/min) who required dialysis compared to subjects with normal renal function (CLcr = 90 mL/min).

Patients with Hepatic Impairment-                                                                           Following administration of a single-dose of selumetinib, dose normalized total AUC0-INF decreased by 14% in subjects with mild hepatic impairment (Child-Pugh A), and increased by 59% in subjects with moderate hepatic impairment (Child-Pugh B) and by 57% in subjects with severe hepatic impairment (Child-Pugh class C) compared to subjects with normal hepatic function.

Drug Interaction Studies-                                                                                              Clinical Studies and Model-Informed Approaches-                                                  Effect of Strong or Moderate CYP3A4 Inhibitors:                                                         Concomitant use of itraconazole (strong CYP3A4 inhibitor) increased selumetinib AUC by 49% and Cmax by 19%. Concomitant use of erythromycin (moderate CYP3A4 inhibitor) is predicted to increase selumetinib AUC by 41% and Cmax by 23%.

Effect of Fluconazole:                                                                                            Concomitant use of fluconazole (strong CYP2C19 inhibitor and moderate CYP3A4 inhibitor) increased selumetinib AUC by 53% and Cmax by 26%.

Effect of Strong or Moderate CYP3A4 Inducers:                                                 Concomitant use of rifampicin (strong CYP3A4 inducer) decreased selumetinib AUC by 51% and Cmax by 26%. Concomitant use of efavirenz (moderate CYP3A4 inducer) is predicted to decrease selumetinib AUC by 38% and Cmax by 22%.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                   Based on findings from animal studies and its mechanism of action,KOSELUGO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of KOSELUGO in pregnant women to evaluate drug-associated risk.

Advise pregnant women of the potential risk to the fetus.

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-                                                                                      There are no data on the presence of selumetinib or its active metabolite in human milk or their effects on the breastfed child or milk production.

Due to the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with KOSELUGO and for 1 week after the last dose.

Data Animal Data Selumetinib and its active metabolite were present in milk from mice dosed with selumetinib throughout gestation and lactation, with a mean plasma/milk ratio of 1.5 in lactating dams dosed at 5 mg/kg twice daily.

3. Females and Males of Reproductive Potential -                                                 KOSELUGO can cause fetal harm when administered to a pregnant woman

Pregnancy Testing- Verify the pregnancy status of females of reproductive potential prior to initiating KOSELUGO 

Contraception-                                                                                                          Females-                                                                                                                 Advise females of reproductive potential to use effective contraception during treatment and for 1 week after the last dose. 

Males -                                                                                                                      Advise male patients with female partners of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose.

4. Pediatric Use-                                                                                                        The safety and effectiveness have been established in pediatric patients 2 years of age and older with NF1 who have inoperable PN and the information on this use is discussed throughout the labeling.

The safety and effectiveness of KOSELUGO have not been established in pediatric patients younger than 2 years of age.

5. Geriatric Use-                                                                                                    Clinical studies did not include patients 65 years of age and older.

6. Renal Impairment-                                                                                                     No dose adjustment is recommended in patients with renal impairment or those with End Stage Renal Disease 

7. Hepatic Impairment-                                                                                          Selumetinib exposures increased in patients with moderate or severe hepatic impairment 

Reduce the dose of KOSELUGO for patients with moderate hepatic impairment (Child-Pugh B).

A recommended dosage of KOSELUGO for use in patients with severe hepatic impairment (Child-Pugh C) has not been established 

 OVERDOSAGE -                                                                                                         Dialysis is not helpful as KOSELUGO is highly protein bound and is extensively metabolized.