18/20. Selpercartinib-(RETEVMO)- (May 2020- to treat lung and thyroid cancers
Drug Name:18/20. Selpercartinib-(RETEVMO)- (May 2020- to treat lung and thyroid cancers
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-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.
Drugs that Prolong QT Interval- RETEVMO is associated with QTc interval prolongation [see Warnings and Precautions
Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval
Indication:
U.S. FDA APPROVED DRUGS DURING 2020
Sr.No- 18
Adverse Reaction:
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,
Contra-Indications:
CONTRAINDICATIONS-
None.
WARNINGS AND PRECAUTIONS-
• Hepatotoxicity: Monitor ALT and AST prior to initiating RETEVMO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose, or permanently discontinue RETEVMO based on severity.
• Hypertension: Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure (BP) prior to initiating RETEVMO. Monitor BP after 1 week, at least monthly thereafter and as clinically indicated. Withhold, reduce dose, or permanently discontinue RETEVMO based on severity.
• QT Interval Prolongation: Monitor patients who are at significant risk of developing QTc prolongation. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment. Monitor QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and dose reduce or permanently discontinue RETEVMO based on severity.
• Hemorrhagic Events: Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage.
• Hypersensitivity: Withhold RETEVMO and initiate corticosteroids. Upon resolution, resume at a reduced dose and increase dose by 1 dose level each week until reaching the dose taken prior to onset of hypersensitivity. Continue steroids until patient reaches target dose and then taper.
• Risk of Impaired Wound Healing: Withhold RETEVMO for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of RETEVMO after resolution of wound healing complications has not been established.
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the possible risk to the fetus and to use effective contraceptio
QT Interval Prolongation: Monitor patients who are at significant risk of developing QTc prolongation. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment. Monitor QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and dose reduce or permanently discontinue RETEVMO based on severity.
• Hemorrhagic Events: Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage.
• Hypersensitivity: Withhold RETEVMO and initiate corticosteroids. Upon resolution, resume at a reduced dose and increase dose by 1 dose level each week until reaching the dose taken prior to onset of hypersensitivity. Continue steroids until patient reaches target dose and then taper.
• Risk of Impaired Wound Healing: Withhold RETEVMO for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of RETEVMO after resolution of wound healing complications has not been established.
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the possible risk to the 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).
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
Pharmacology/ Pharmacokinetics:
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. Reference ID: 4605720
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.
Pregnancy and lactation:
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).
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 [see Dosage and Administration (2.7)].
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. Monitor for RETEVMO-related adverse reactions in patients with hepatic impairment