17/20.Capmatinib( TABRECTA) @ (May 2020) - Non small lung cancer drug
Drug Name:17/20.Capmatinib( TABRECTA) @ (May 2020) - Non small lung cancer drug
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS- summary
Strong and Moderate CYP3A Inducers: Avoid concomitant use.
Details
1. Effect of Other Drugs on TABRECTA Strong CYP3A Inhibitors- Coadministration of TABRECTA with a strong CYP3A inhibitor increased capmatinib exposure, which may increase the incidence and severity of adverse reactions of TABRECTA
Closely monitor patients for adverse reactions during coadministration of TABRECTA with strong CYP3A inhibitors.
Strong and Moderate CYP3A Inducers- Coadministration of TABRECTA with a strong CYP3A inducer decreased capmatinib exposure.
Coadministration of TABRECTA with a moderate CYP3A inducer may also decrease capmatinib exposure.
Decreases in capmatinib exposure may decrease TABRECTA anti-tumor activity
Avoid coadministration of TABRECTA with strong and moderate CYP3A inducers
2. Effect of TABRECTA on Other Drugs CYP1A2 Substrates- Coadministration of TABRECTA increased the exposure of a CYP1A2 substrate, which may increase the adverse reactions of these substrates
If coadministration is unavoidable between TABRECTA and CYP1A2 substrates where minimal concentration changes may lead to serious adverse reactions, decrease the CYP1A2 substrate dosage in accordance with the approved prescribing information.
P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) Substrates- Coadministration of TABRECTA increased the exposure of a P-gp substrate and a BCRP substrate, which may increase the adverse reactions of these substrates
If coadministration is unavoidable between TABRECTA and P-gp or BCRP substrates where minimal concentration changes may lead to serious adverse reactions, decrease the P-gp or BCRP substrate dosage in accordance with the approved prescribing information.
MATE1 and MATE2K Substrates- Coadministration of TABRECTA may increase the exposure of MATE1 and MATE2K substrates, which may increase the adverse reactions of these substrates
If coadministration is unavoidable between TABRECTA and MATE1 or MATE2K substrates where minimal concentration changes may lead to serious adverse reactions, decrease the MATE1 or MATE2K substrate dosage in accordance with the approved prescribing information
Indication:
U.S. FDA APPROVED DRUGS DURING 2020
Sr.No- 17
Adverse Reaction:
ADVERSE REACTIONS
The most common adverse reactions (= 20%) are peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite.
Contra-Indications:
CONTRAINDICATIONS- None
WARNINGS AND PRECAUTIONS
Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Permanently discontinue TABRECTA in patients with ILD/pneumonitis.
Hepatotoxicity: Monitor liver function tests. Withhold, dose reduce, or permanently discontinue TABRECTA based on severity.
Risk of Photosensitivity: May cause photosensitivity reactions. Advise patients to limit direct ultraviolet exposure.
Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception.
Dosages/ Overdosage Etc:
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Interstitial Lung Disease (ILD)/Pneumonitis- Inform patients of the risks of severe or fatal ILD/pneumonitis.
Advise patients to immediately contact their healthcare provider for 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
Risk of Photosensitivity Inform patients that there is a potential risk of photosensitivity reactions with TABRECTA.
Advise patients to limit direct ultraviolet exposure by using sunscreen or protective clothing during treatment with TABRECTA
Embryo-Fetal Toxicity- Advise pregnant women 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 TABRECTA and for 1 week after the last dose
Advise males with female partners of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 week after the last dose
Drug Interactions- Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products
Lactation- Advise women not to breastfeed during treatment with TABRECTA and for 1 week after the last dose
Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Nov
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action- Capmatinib is a kinase inhibitor that targets MET, including the mutant variant produced by exon 14 skipping. MET exon 14 skipping results in a protein with a missing regulatory domain that reduces its negative regulation leading to increased downstream MET signaling.
2. Pharmacodynamics- Exposure-Response Reference ID: 4603951 Capmatinib exposure-response relationships and the time course of pharmacodynamics response are unknown.
Cardiac Electrophysiology- No large mean increase in QTc (i.e. > 20 ms) was detected following treatment with TABRECTA at the recommended dosage of 400 mg orally twice daily.
3. Pharmacokinetics- Capmatinib exposure (AUC0-12h and Cmax) increased approximately proportionally over a dose range of 200 mg (0.5 times the recommended dosage) to 400 mg. Capmatinib reached steady-state by day 3 following twice daily dosing, with a mean (% coefficient of variation [%CV]) accumulation ratio of 1.5 (41%).
Absorption-
After administration of TABRECTA 400 mg orally in patients with cancer, capmatinib peak plasma concentrations (Cmax) were reached in approximately 1 to 2 hours (Tmax). The absorption of capmatinib after oral administration is estimated to be greater than 70%.
Effect of Food- A high-fat meal (containing approximately 1000 calories and 50% fat) in healthy subjects increased capmatinib AUC0-INF by 46% with no change in Cmax compared to under fasted conditions.
A low-fat meal (containing approximately 300 calories and 20% fat) in healthy subjects had no clinically meaningful effect on capmatinib exposur
When capmatinib was administered at 400 mg orally twice daily in cancer patients, exposure (AUC0-12h) was similar after administration of capmatinib with food and under fasted conditions.
Distribution- Capmatinib plasma protein binding is 96%, independent of capmatinib concentration. The apparent mean volume of distribution at steady-state is 164 L. The blood-to-plasma ratio was 1.5, but decreased at higher concentrations to 0.9.
Elimination- The effective elimination half-life of capmatinib is 6.5 hours. The mean (%CV) steady-state apparent clearance of capmatinib is 24 L/hr (82%).
Metabolism- Capmatinib is primarily metabolized by CYP3A4 and aldehyde oxidase.
Excretion- Following a single oral administration of radiolabeled-capmatinib to healthy subjects, 78% of the total radioactivity was recovered in feces with 42% as unchanged and 22% was recovered in urine with negligible as unchanged.
Specific Populations- No clinically significant effects on the pharmacokinetic parameters of capmatinib were identified for the following covariates assessed: age (26 to 90 years), sex, race (White, Asian, Native American, Black, unknown), body weight (35 to 131 kg), mild to moderate renal impairment (baseline CLcr 30 to 89 mL/min by Cockcroft-Gault) and mild, moderate or severe hepatic impairment (Child-Pugh classification).
The effect of severe renal impairment (baseline CLcr 15 to 29 mL/min) on capmatinib pharmacokinetics has not been studied.
Drug Interaction Studies- Clinical Studies and Model-Informed Approaches Strong CYP3A Inhibitors: Coadministration with itraconazole (a strong CYP3A inhibitor) increased capmatinib AUC0-INF by 42% with no change in capmatinib Cmax.
Strong CYP3A Inducers: Coadministration with rifampicin (a strong CYP3A inducer) decreased capmatinib AUC0-INF by 67% and decreased Cmax by 56%.
Moderate CYP3A Inducers: Coadministration with efavirenz (a moderate CYP3A inducer) was predicted to decrease capmatinib AUC0-12h by 44% and decrease Cmax by 34%.
Proton Pump Inhibitors: Coadministration with rabeprazole (a proton pump inhibitor) decreased capmatinib AUC0-INF by 25% and decreased Cmax by 38%.
Substrates of CYP Enzymes: Coadministration of capmatinib increased caffeine (a CYP1A2 substrate) AUC0-INF by 134% with no change in its Cmax.
Coadministration of capmatinib had no clinically meaningful effect on exposure of midazolam (a CYP3A substrate).
P-gp Substrates: Coadministration of capmatinib increased digoxin (a P-gp substrate) AUC0-INF by 47% and increased Cmax by 74%.
BCRP Substrates: Coadministration of capmatinib increased rosuvastatin (a BCRP substrate) AUC0-INF by 108% and increased Cmax by 204%.
In Vitro Studies Transporter Systems: Capmatinib is a substrate of P-gp, but not a substrate of BCRP or MRP2. Capmatinib reversibly inhibits MATE1 and MATE2K, but does not inhibit OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or MRP2.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy Risk Summary- Based on findings from animal studies and its mechanism of action, TABRECTA can cause fetal harm when administered to a pregnant woman.
There are no available data on TABRECTA use 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 on the presence of capmatinib or its metabolites in either human or animal milk or its 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 TABRECTA and for 1 week after the last dose.
3 Females and Males of Reproductive Potential- TABRECTA can cause malformations at doses less than the human exposure based on AUC at the 400 mg twice daily clinical dose.
Pregnancy Testing- Verify pregnancy status for females of reproductive potential prior to starting treatment with TABRECTA.
Contraception Females- Advise females of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 week after the last dose.
Males- Advise males with female partners of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 week after the last dose.
4 Pediatric Use- Safety and effectiveness of TABRECTA in pediatric patients have not been established.
5. Geriatric Use- In the tests, 57% of the 334 patients were 65 years or older and 16% were 75 years or older. No overall differences in the safety or effectiveness were observed between these patients and younger patients.
6. Renal Impairment- No dosage adjustment is recommended in patients with mild (baseline creatinine clearance [CLcr] 60 to 89 mL/min by Cockcroft-Gault) or moderate renal impairment (CLcr 30 to 59 mL/min)
TABRECTA has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min).
