DRUG INTERACTIONS-(summary)

 • Dual strong CYP3A inhibitors and P-gp inhibitors: Avoid concomitant use.

 • Strong CYP3A inducers: Avoid concomitant use.

• Certain P-gp substrates: Avoid coadministration of TEPMETKO with P-gp substrates where minimal concentration changes may lead to serious or lifethreatening toxiciti 

DRUG INTERACTIONS-(details)

1. Effects of Other Drugs on TEPMETKO-                                                                        Dual Strong CYP3A Inhibitors and P-gp Inhibitors The effect of strong CYP3A inhibitors or P-gp inhibitors on TEPMETKO has not been studied clinically.

However, metabolism and in vitro data suggest concomitant use of drugs that are strong CYP3A inhibitors and P-gp inhibitors may increase tepotinib exposure ], which may increase the incidence and severity of adverse reactions of TEPMETKO.

Avoid concomitant use of TEPMETKO with dual strong CYP3A inhibitors and P-gp inhibitors. 

Strong CYP3A Inducers-                                                                                              The effect of strong CYP3A inducers on TEPMETKO has not been studied clinically. However, metabolism and in vitro data suggest concomitant use may decrease tepotinib exposure ], which may reduce TEPMETKO efficacy.

Avoid concomitant use of TEPMETKO with strong CYP3A inducers.

2 Effects of TEPMETKO on Other Drugs-                                                             Certain P-gp Substrates Tepotinib is a P-gp inhibitor. Concomitant use of TEPMETKO increases the concentration of P-gp substrates , which may increase the incidence and severity of adverse reactions of these substrates.

Avoid concomitant use of TEPMETKO with certain P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling

BRIEF SUMMARY-

TEPMRTKO- (Feb 2021)

Indn- To treat non small lung cancer

Comp- Tablets: 225 mg. Recommended dosage: 450 mg orally once daily with food until disease progression or unacceptable toxicity.

ADR- Most common adverse reactions were edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea.

CI- None. 

WARNING- 

• Interstitial Lung Disease (ILD)/Pneumonitis:                                                        Immediately withhold TEPMETKO in patients with suspected ILD/pneumonitis.

• Hepatotoxicity:                                                                                                     Monitor liver function tests. Withhold, dose reduce, or permanently discontinue .

 Pat inform-

Interstitial Lung Disease (ILD)/Pneumonitis Inform patients of the risk of severe or fatal ILD/pneumonitis  or worsening respiratory symptoms

Hepatotoxicity- Inform patients that they will need to undergo lab tests to monitor liver function. 

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

U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 4

Name of the Drug-    TEPMETKO

Active Ingredient -     Tepotinib

Pharmacological Classification-   To treat non small lung cancer

Date of Approval-          2/3/2021

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                    TEPMETKO safely and effectively.                                                                                    See full prescribing information for TEPMETKO. TEPMETKO® (tepotinib) tablets, for oral use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE

 TEPMETKO is a kinase inhibitor indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymalepithelial transition (MET) exon 14 skipping alterations.

 This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

ADVERSE REACTIONS-

 Most common adverse reactions (= 20%) were edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea.

The most common Grade 3 to 4 laboratory abnormalities (= 2%) were decreased lymphocytes, decreased albumin, decreased sodium, increased gamma-glutamyltransferase, increased amylase, increased ALT, increased AST, and decreased hemoglobin.

CONTRAINDICATIONS-                                                                                            None. 

WARNINGS AND PRECAUTIONS

 • Interstitial Lung Disease (ILD)/Pneumonitis:                                                        Immediately withhold TEPMETKO in patients with suspected ILD/pneumonitis. Permanently discontinue TEPMETKO in patients diagnosed with ILD/pneumonitis of any severity.

• Hepatotoxicity:                                                                                                     Monitor liver function tests. Withhold, dose reduce, or permanently discontinue TEPMETKO based on severity.

 • Embryo-fetal toxicity: TEPMETKO can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. 

ADVERSE REACTIONS------------------------------ Most common adverse reactions (= 20%) were edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea. The most common Grade 3 to 4 laboratory abnormalities (= 2%) were decreased lymphocytes, decreased albumin, decreased sodium, increased gamma-glutamyltransferase, increased amylase, increased ALT, increased AST, and decreased hemoglobin. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono at 1-800-283-8088 ext. 5563 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

-------------------------------DRUG INTERACTIONS------------------------------ • Dual strong CYP3A inhibitors and P-gp inhibitors: Avoid concomitant use. (7.1) • Strong CYP3A inducers: Avoid concomitant use. (7.1) • Certain P-gp substrates: Avoid coadministration of TEPMETKO with P-gp substrates where minimal concentration changes may lead to serious or lifethreatening toxiciti

DOSAGE AND ADMINISTRATION

 • Select patients for treatment with TEPMETKO on the presence of METex14 skipping. 

• Recommended dosage: 450 mg orally once daily with food until disease progression or unacceptable toxicity.

DOSAGE FORMS AND STRENGTHS-                                                                            Tablets: 225 mg.

 PATIENT COUNSELING INFORMATION

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

Interstitial Lung Disease (ILD)/Pneumonitis Inform patients of the risk of severe or fatal ILD/pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms

Hepatotoxicity Inform patients that they will need to undergo lab tests to monitor liver function. Advise patients to immediately contact their healthcare provider for signs and symptoms of liver dysfunction 

Embryo-Fetal Toxicity Advise males and females of reproductive potential that TEPMETKO can cause fetal harm.

Advise females of reproductive potential to use effective contraception during and for one week after the final dose of TEPMETKO.

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TEPMETKO and for one week after the final dose of TEPMETKO].

Lactation Advise women not to breastfeed during treatment with TEPMETKO and for one week after the final dose 

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

Dosing and Administration-                                                                                       Instruct patients to take 450 mg TEPMETKO once daily with food.

Missed Dose -                                                                                                                   Advise patients that a missed dose of TEPMETKO can be taken as soon as remembered on the same day, unless the next dose is due within 8 hours.

If vomiting occurs after taking a dose of TEPMETKO, advise patients to take the next dose at the scheduled time

Manufactured for: EMD Serono, Inc. Rockland, MA 02370 U.S.A.

TEPMETKO is a trademark of Merck KGaA, Darmstadt, Germany

 CLINICAL PHARMACOLOGY

1 Mechanism of Action Tepotinib is a kinase inhibitor that targets MET, including variants with exon 14 skipping alterations. Tepotinib inhibits hepatocyte growth factor (HGF)-dependent and -independent MET phosphorylation and MET-dependent downstream signaling pathways.

2. Pharmacokinetics -                                                                                                   The pharmacokinetics of tepotinib were evaluated in patients with cancer administered 450 mg once daily unless otherwise specified. Tepotinib exposure (AUC0-12h and Cmax) increases dose-proportionally over the dose range of 27 mg (0.06 times the recommended daily dosage) to 450 mg.

At the recommended dosage, the geometric mean (coefficient of variation [CV] %) steady state Cmax was 1,291 ng/mL (48.1%) and the AUC0-24h was 27,438 ng?h/mL (51.7%).

The oral clearance of tepotinib did not change with respect to time. The median accumulation was 2.5-fold for Cmax and 3.3-fold for AUC0-24h after multiple daily doses of tepotinib.

Absorption-                                                                                                                    The median Tmax of tepotinib is 8 hours (range from 6 to 12 hours). The geometric mean (CV%) absolute bioavailability of TEPMETKO in the fed state was 71.6% (10.8%) in healthy subjects.

Effect of Food-                                                                                                              The mean AUC0-INF of tepotinib increased by 1.6-fold and Cmax increased by 2-fold, following administration of a high-fat, high-calorie meal (approximately 800 to 1,000 calories, 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat). The median Tmax shifted from 12 hours to 8 hours.

Distribution -                                                                                                                 The geometric mean (CV%) apparent volume of distribution (VZ/F) of tepotinib is 1,038 L (24.3%). Protein binding of tepotinib is 98% and is independent of drug concentration at clinically relevant exposures.

Elimination -                                                                                                                  The apparent clearance (CL/F) of tepotinib is 23.8 L/h (87.5%) and the half-life is 32 hours following oral administration of TEPMETKO in patients with cancer.

Metabolism-                                                                                                                   Tepotinib is primarily metabolized by CYP3A4 and CYP2C8. One major circulating plasma metabolite (M506) has been identified.

Excretion                                                                                                                    Following a single oral administration of a radiolabeled dose of 450 mg tepotinib, approximately 85% of the dose was recovered in feces (45% unchanged) and 13.6% in urine (7% unchanged).

The major circulating metabolite M506 accounted for about 40.4% of the total radioactivity in plasma.

Specific Populations- No clinically significant effects on tepotinib pharmacokinetics were observed based on age (18 to 89 years), race/ethnicity (White, Black, Asian, Japanese, and Hispanic), sex, body weight (35.5 to 136 kg), mild to moderate renal impairment (CLcr 30 to 89 mL/min), or mild to moderate hepatic impairment (Child-Pugh A and B).

The effect of severe renal impairment (CLcr < 30 mL/min) and severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of tepotinib has not been studied.

Drug Interaction Studies-                                                                                       Clinical Studies and Model-Informed Approaches P-gp Substrates: Coadministration of TEPMETKO with dabigatran etexilate (P-gp substrate) increased dabigatran Cmax by 40% and AUC0-INF by 50%.

Acid-Reducing Agents:                                                                                                 No clinically significant differences in tepotinib pharmacokinetics were observed when coadministered with multiple daily doses (40 mg daily for 5 days) of omeprazole (proton pump inhibitor) under fed conditions.

CYP3A Substrates:                                                                                              Coadministration of TEPMETKO had no clinically significant effect on the pharmacokinetics of midazolam (sensitive CYP3A substrate). MATE2 and OCT2 Substrates: No clinically relevant differences in glucose levels were observed when metformin (MATE2 and OCT2 substrate) was coadministered with tepotinib.

CYP2C9 Substrates: Physiologically based pharmacokinetic modeling suggested CYP2C9 inhibition is not clinically significant.

 Tepotinib and its major circulating metabolite were not mutagenic in vitro in the bacterial reverse mutation (Ames) assay, or a mouse lymphoma assay. In vivo, tepotinib was not genotoxic i

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                  Based on findings in animal studies and the mechanism of action 

TEPMETKO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of TEPMETKO in pregnant women.

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 regarding the secretion of tepotinib or its metabolites in human milk or its effects on the breastfed infant or milk production. Advise women not to breastfeed during treatment with TEPMETKO and for one week after the final dose.

3. Females and Males of Reproductive Potential-                                                            Based on animal data, TEPMETKO can cause malformations at doses less than the human exposure based on AUC at the 450 mg clinical dose [

Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating TEPMETKO.

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

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

4 Pediatric Use -                                                                                                           The safety and efficacy of TEPMETKO in pediatric patients have not been established.

5. Geriatric Use Of 255 patients with METex14 skipping alterations in VISION who received 450 mg TEMETKO once daily, 79% were 65 years or older, and 43% were 75 years or older.

No clinically important differences in safety or efficacy were observed between patients aged 65 years or older and younger patients.

6. Renal Impairment-                                                                                                      No dosage modification is recommended in patients with mild or moderate renal impairment (creatinine clearance [CLcr] 30 to 89 mL/min, estimated by Cockcroft-Gault). The recommended dosage has not been established for patients with severe renal impairment (CLcr < 30 mL/min) 

7. Hepatic Impairment-                                                                                                   No dosage modification is recommended in patients with mild (Child Pugh Class A) or moderate (Child Pugh Class B) hepatic impairment. The pharmacokinetics and safety of tepotinib in patients with severe hepatic impairment (Child Pugh Class C) have not been studied .