DRUG INTERACTIONS- summary

­ • Acid-Reducing Agents:                                                                                           Avoid coadministration. If coadministration cannot be avoided, take RETEVMO with food (with PPI) or modify its administration time (with H2 receptor antagonist or locally-acting antacid). 

• Strong and Moderate CYP3A Inhibitors:                                                                       Avoid coadministration. If coadministration cannot be avoided, reduce the RETEVMO dose. 

• Strong and Moderate CYP3A Inducers:                                                                      Avoid coadministration. 

 • CYP2C8 and CYP3A Substrates:                                                                          Avoid coadministration. If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. 

DRUG INTERACTIONS- details

1. Effects of Other Drugs on RETEVMO Acid-Reducing Agents-               Concomitant use of RETEVMO with acid-reducing agents decreases selpercatinib plasma concentrations , which may reduce RETEVMO anti-tumor activity. Avoid concomitant use of PPIs, H2 receptor antagonists, and locally-acting antacids with RETEVMO.

If coadministration cannot be avoided, take RETEVMO with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid) 

Strong and Moderate CYP3A Inhibitors -                                                         Concomitant use of RETEVMO with a strong or moderate CYP3A inhibitor increases selpercatinib plasma concentrations , which may increase the risk of RETEVMO adverse reactions, including QTc interval prolongation.

Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO.

If concomitant use of strong and moderate CYP3A inhibitors cannot be avoided, reduce the RETEVMO dosage and monitor the QT interval with ECGs more frequently 

Strong and Moderate CYP3A Inducers-                                                               Concomitant use of RETEVMO with a strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations , which may reduce RETEVMO anti-tumor activity.

Avoid coadministration of strong or moderate CYP3A inducers with RETEVMO.

2 Effects of RETEVMO on Other Drugs-                                                           CYP2C8 and CYP3A Substrates RETEVMO is a moderate CYP2C8 inhibitor and a weak CYP3A inhibitor.

Concomitant use of RETEVMO with CYP2C8 and CYP3A substrates increases their plasma concentrations], which may increase the risk of adverse reactions related to these substrates.

Avoid coadministration of RETEVMO with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions.

If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling. 

3 Drugs that Prolong QT Interval-                                                                      RETEVMO is associated with QTc interval prolongation

Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.

U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  18

ADVERSE REACTIONS

­ The most common adverse reactions, including laboratory abnormalities, (= 25%) were increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased glucose, decreased leukocytes, decreased albumin, decreased calcium, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, edema, decreased platelets, increased total cholesterol, rash, decreased sodium, and constipation.

 PATIENT COUNSELING INFORMATION

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

Hepatotoxicity-                                                                                                             Advise patients that hepatotoxicity can occur and to immediately contact their healthcare provider for signs or symptoms of hepatotoxicity

Hypertension-                                                                                                        Advise patients that they will require regular blood pressure monitoring and to contact their healthcare provider if they experience symptoms of increased blood pressure or elevated readings.

QT Prolongation-                                                                                                    Advise patients that RETEVMO can cause QTc interval prolongation and to inform their healthcare provider if they have any QTc interval prolongation symptoms, such as syncope 

Hemorrhagic Events-                                                                                                   Advise patients that RETEVMO may increase the risk for bleeding and to contact their healthcare provider if they experience any signs or symptoms of bleeding 

Hypersensitivity Reactions-                                                                                       Advise patients to monitor for signs and symptoms of hypersensitivity reactions, particularly during the first month of treatment 

Risk of Impaired Wound Healing-                                                                         Advise patients that RETEVMO may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [

Embryo-Fetal Toxicity -                                                                                           Advise pregnant women and females of reproductive potential of the possible 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 the treatment with RETEVMO and for at least 1 week after the final dose 

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

Lactation-                                                                                                                Advise women not to breastfeed during treatment with RETEVMO and for 1 week following the final dose 

Infertility-                                                                                                                Advise males and females of reproductive potential that RETEVMO may impair fertility 

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, proton pump inhibitors, H2 receptor antagonists, and antacids while taking RETEVMO.

If PPIs are required, instruct patients to take RETEVMO with food.

If H2 receptor antagonists are required, instruct patients to take RETEVMO 2 hours before or 10 hours after the H2 receptor antagonist.

If locally-acting antacids are required, instruct patients to take RETEVMO 2 hours before or 2 hours after the locally-acting antacid 

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2020, Eli Lilly and Company. All rights reserved. RET-0001-USPI-202005

 CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                Selpercatinib is a kinase inhibitor. Selpercatinib inhibited wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3 with IC50 values ranging from 0.92 nM to 67.8 nM.

2. Pharmacodynamics-                                                                                    Exposure-Response Relationship Selpercatinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.

Cardiac Electrophysiology-                                                                                      The effect of RETEVMO on the QTc interval was evaluated in a thorough QT study in healthy subjects. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state maximum concentration (Cmax) observed in patients after administration of 160 mg twice daily. The increase in QTc was concentration-dependent.

3.Pharmacokinetics-                                                                                                 The pharmacokinetics of selpercatinib were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified.

Absorption-                                                                                                                   The median tmax of selpercatinib is 2 hours. The mean absolute bioavailability of RETEVMO capsules is 73% (60% to 82%) in healthy subjects.

Effect of Food-                                                                                                            No clinically significant differences in selpercatinib AUC or Cmax were observed following administration of a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) in healthy subjects.

Distribution-                                                                                                                 The apparent volume of distribution (Vss/F) of selpercatinib is 191 L. Protein binding of selpercatinib is 97% in vitro and is independent of concentration. The bloodto-plasma concentration ratio is 0.7.

Elimination-                                                                                                                The apparent clearance (CL/F) of selpercatinib is 6 L/h in patients and the half-life is 32 hours following oral administration of RETEVMO in healthy subjects.

Metabolism-                                                                                                 Selpercatinib is metabolized predominantly by CYP3A4. Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, unchanged selpercatinib constituted 86% of the radioactive drug components in plasma.

Excretion-                                                                                                             Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, 69% of the administered dose was recovered in feces (14% unchanged) and 24% in urine (12% unchanged).

Specific Populations-                                                                                                The apparent volume of distribution and clearance of selpercatinib increase with increasing body weight (27 kg to 177 kg). No clinically significant differences in the pharmacokinetics of selpercatinib were observed based on age (15 years to 90 years), sex, or mild or moderate renal impairment (CLcr > 30 mL/min as estimated by Cockcroft-Gault).

The effect of severe renal impairment (CLcr < 30 mL/min) on selpercatinib pharmacokinetics has not been adequately studied.

Patients with Hepatic Impairment-                                                                            The selpercatinib AUC0-INF increased by 7%, 32%, and 77% in subjects with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST ), moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST), and severe (total bilirubin greater than 3 to 10 times ULN and any AST) hepatic impairment, respectively, compared to subjects with normal hepatic function.

Drug Interaction Studies-                                                                                    Clinical Studies and Model-Informed Approaches Proton-Pump Inhibitors (PPI): Coadministration with multiple daily doses of omeprazole (PPI) decreased selpercatinib AUC0-INF and Cmax when RETEVMO was administered fasting.

Coadministration with multiple daily doses of omeprazole did not significantly change the selpercatinib AUC0-INF and Cmax when RETEVMO was administered with food 

High-fat meal: approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively; approximately 800 to 1000 calories total.

 Low-fat meal: approximately 390 calories and 10 g of fat H2 Receptor Antagonists: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with multiple daily doses of ranitidine (H2 receptor antagonist) given 10 hours prior to and 2 hours after the RETEVMO dose (administered fasting).

Strong CYP3A Inhibitors:                                                                                 Coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) increased the selpercatinib AUC0-INF by 133% and Cmax by 30%. 

Moderate CYP3A Inhibitors:                                                                          Coadministration of multiple doses of diltiazem, fluconazole, or verapamil (moderate CYP3A inhibitors) is predicted to increase the selpercatinib AUC by 60-99% and Cmax by 46-76%.

Strong CYP3A Inducers:                                                                                       Coadministration of multiple doses of rifampin (strong CYP3A inducer) decreased the selpercatinib AUC0-INF by 87% and Cmax by 70%.

Moderate CYP3A Inducers:                                                                            Coadministration of multiple doses of bosentan or efavirenz (moderate CYP3A inducers) is predicted to decrease the selpercatinib AUC by 40-70% and Cmax by 34-57%.

Weak CYP3A Inducers:                                                                           Coadministration of multiple doses of modafinil (weak CYP3A inducer) is predicted to decrease the selpercatinib AUC by 33% and Cmax by 26%.

CYP2C8 Substrates:                                                                             Coadministration of RETEVMO with repaglinide (sensitive CYP2C8 substrate) increased the repaglinide AUC0-INF by 188% and Cmax by 91%.

CYP3A Substrates:                                                                               Coadministration of RETEVMO with midazolam (sensitive CYP3A) increased the midazolam AUC0-INF by 54% and Cmax by 39%.

P-glycoprotein (P-gp) Inhibitors:                                                                                No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampin (P-gp inhibitor).

MATE1 Substrates:                                                                                                     No clinically significant differences in glucose levels were observed when metformin (MATE1 substrate) was coadministered with selpercatinib.

In Vitro Studies CYP Enzymes:                                                                    Selpercatinib does not inhibit or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations.

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary -                                                                                Based on findings from animal studies, and its mechanism of action, RETEVMO can cause fetal harm when administered to a pregnant woman.

There are no available data on RETEVMO use in pregnant women to inform drug-associated risk.

Advise pregnant women of the potential risk to a 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 selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production.

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with RETEVMO and for 1 week after the final dose.

3. Females and Males of Reproductive Potential-                                                   Based on animal data, RETEVMO can cause embryolethality and malformations at doses resulting in exposures less than or equal to the human exposure at the clinical dose of 160 mg twice daily.

Pregnancy testing-                                                                                                 Verify pregnancy status in females of reproductive potential prior to initiating RETEVMO 

Contraception Females-                                                                                        Advise female patients of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the final dose.

Males-                                                                                                                       Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the final dose.

Infertility-                                                                                                                   RETEVMO may impair fertility in females and males of reproductive potential.

4. Pediatric Use -                                                                                                       The safety and effectiveness of RETEVMO have been established in pediatric patients aged 12 years and older for medullary thyroid cancer (MTC) who require systemic therapy and for advanced RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate).

Use of RETEVMO for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older.

 The safety and effectiveness of RETEVMO have not been established in these indications in patients less than 12 years of age. The safety and effectiveness of RETEVMO have not been established in pediatric patients for other indications.

5. Geriatric Use-                                                                                                           Of 702 patients who received RETEVMO, 34% (239 patients) were = 65 years of age and 10% (67 patients) were = 75 years of age. No overall differences were observed in the safety or effectiveness of RETEVMO between patients who were = 65 years of age and younger patients.

6 Renal Impairment-                                                                                                    No dosage modification is recommended for patients with mild to .moderate renal impairment (creatinine clearance [CLcr] > 30 mL/min, estimated by Cockcroft-Gault).

The recommended dosage has not been established for patients with severe renal impairment (CLcr < 30 mL/min) or end-stage renal disease 

7.Hepatic Impairment-                                                                                              Reduce the dose when administering RETEVMO to patients with severe [total bilirubin greater than 3 to 10 times upper limit of normal (ULN) and any AST] hepatic impairment.

No dosage modification is recommended for patients with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) or moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST) hepatic impairment.