Tepmetko
(tepotinib)Dosage & Administration
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Tepmetko Prescribing Information
TEPMETKO is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations.
Patient Selection for METex14 Skipping Alterations
Select patients for treatment with TEPMETKO based on the presence of MET exon 14 skipping alterations in plasma or tumor specimens. Testing for the presence of MET exon 14 skipping alterations in plasma specimens is recommended only in patients for whom a tumor biopsy cannot be obtained. If an alteration is not detected in a plasma specimen, re-evaluate the feasibility of biopsy for tumor tissue testing. An FDA-approved test for detection of MET exon 14 skipping alterations in NSCLC for selecting patients for treatment with TEPMETKO is not available.
Recommended Dosage
The recommended dosage of TEPMETKO is 450 mg orally once daily with food [see Clinical Pharmacology (12.3)] until disease progression or unacceptable toxicity.
Instruct patients to take their dose of TEPMETKO at approximately the same time every day and to swallow tablets whole. Do not chew, crush or split tablets. Patients who have difficulty swallowing solids can disperse tablets in water [see Dosage and Administration (2.3)].
Advise patients not to make up a missed dose within 8 hours of the next scheduled dose.
If vomiting occurs after taking a dose of TEPMETKO, advise patients to take the next dose at the scheduled time.
Administration to Patients Who Have Difficulty Swallowing Solids
Place TEPMETKO tablet(s) in a glass containing 30 mL (1 ounce) of non-carbonated water. No other liquids should be used or added. Stir, without crushing, until the tablet(s) is dispersed into small pieces (tablets will not completely dissolve) and drink immediately or within 1 hour. Swallow the tablet dispersion. Do not chew pieces of the tablet. Rinse the glass with an additional 30 mL and drink immediately ensuring no residue remains in the glass and the full dose is administered.
If an administration via a naso-gastric tube (with at least 8 French gauge) is required, disperse the tablet(s) in 30 mL of non-carbonated water as described above. Administer the 30 mL of liquid immediately or within 1 hour as per naso-gastric tube manufacturer's instructions. Immediately rinse twice with 30 mL each time to ensure that no residue remains in the glass or syringe and the full dose is administered.
Dose Modifications for Adverse Reactions
The recommended dose reduction of TEPMETKO for the management of adverse reactions is 225 mg orally once daily.
Permanently discontinue TEPMETKO in patients who are unable to tolerate 225 mg orally once daily.
The recommended dosage modifications of TEPMETKO for adverse reactions are provided in Table 1.
| Adverse Reaction | Severity * | Dose Modification |
|---|---|---|
| ||
| Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.1)] | Any Grade | Withhold TEPMETKO if ILD is suspected. Permanently discontinue TEPMETKO if ILD is confirmed. |
| Increased ALT and/or AST without increased total bilirubin [see Warnings and Precautions (5.2)] | Grade 3 | Withhold TEPMETKO until recovery to baseline ALT/AST. If recovered to baseline within 7 days, then resume TEPMETKO at the same dose; otherwise resume TEPMETKO at a reduced dose. |
| Grade 4 | Permanently discontinue TEPMETKO. | |
| Increased ALT and/or AST with increased total bilirubin in the absence of cholestasis or hemolysis [see Warnings and Precautions (5.2)] | ALT and/or AST greater than 3 times ULN with total bilirubin greater than 2 times ULN | Permanently discontinue TEPMETKO. |
| Increased total bilirubin without concurrent increased ALT and/or AST [see Warnings and Precautions (5.2)] | Grade 3 | Withhold TEPMETKO until recovery to baseline bilirubin. If recovered to baseline within 7 days, then resume TEPMETKO at a reduced dose; otherwise permanently discontinue. |
| Grade 4 | Permanently discontinue TEPMETKO. | |
| Increased lipase or amylase [see Warnings and Precautions (5.3)] | Grade 3 | Withhold TEPMETKO until ≤ Grade 2 or baseline. If recovered to baseline or ≤ Grade 2 within 14 days, resume TEPMETKO at a reduced dose; otherwise permanently discontinue TEPMETKO. |
| Grade 4 | Permanently discontinue TEPMETKO. | |
| Pancreatitis [see Warnings and Precautions (5.3)] | Grade 3 or 4 | Permanently discontinue TEPMETKO. |
| Other adverse reactions [see Adverse Reactions (6.1)] | Grade 2 | Maintain dose level. If intolerable, consider withholding TEPMETKO until resolved, then resume TEPMETKO at a reduced dose. |
| Grade 3 | Withhold TEPMETKO until resolved, then resume TEPMETKO at a reduced dose. | |
| Grade 4 | Permanently discontinue TEPMETKO. | |
Tablets: 225 mg, white-pink, oval, biconvex film-coated tablets with embossment "M" on one side and plain on the other side.
Pregnancy
Risk Summary
Based on findings in animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], TEPMETKO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of TEPMETKO in pregnant women. Oral administration of tepotinib to pregnant rabbits during the period of organogenesis resulted in malformations (teratogenicity) and anomalies at maternal exposures less than the human exposure based on area under the curve (AUC) at the 450 mg daily clinical dose (see Data). 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.
Data
Animal Data
In embryo-fetal development studies, pregnant rabbits received oral doses of 0.5, 5, 25, 50, 150, or 450 mg/kg tepotinib hydrochloride hydrate daily during organogenesis. Severe maternal toxicity occurred at the 450 mg/kg dose (approximately 0.75 times the human exposure at the 450 mg clinical dose). At 150 mg/kg (approximately 0.5 times the human exposure by AUC at the 450 mg clinical dose), two animals aborted and one animal died prematurely; mean fetal body weight was also decreased. A dose-dependent increase of skeletal malformations, including malrotations of fore and/or hind paws with concomitant misshapen scapula and/or malpositioned clavicle and/or calcaneus and/or talus, occurred at doses ≥ 5 mg/kg (approximately 0.003 times the human exposure by AUC at the 450 mg clinical dose); there was also an incidence of spina bifida at the 5 mg/kg dose level.
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 last dose.
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 [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating TEPMETKO [see Use in Specific Populations (8.1)].
Contraception
Females
Advise females of reproductive potential to use effective contraception during TEPMETKO treatment and for one week after the last dose.
Males
Advise male patients with female partners of reproductive potential to use effective contraception during TEPMETKO treatment and for one week after the last dose.
Pediatric Use
The safety and efficacy of TEPMETKO in pediatric patients have not been established.
Geriatric Use
Of 313 patients with NSCLC positive for METex14 skipping alterations in VISION who received 450 mg TEPMETKO once daily, 79% were 65 years or older, and 41% 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.
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) [see Clinical Pharmacology (12.3)].
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 [see Clinical Pharmacology (12.3)].
None.
Interstitial Lung Disease (ILD)/Pneumonitis
ILD/pneumonitis, which can be fatal, occurred in patients treated with TEPMETKO [see Adverse Reactions (6.1)]. ILD/pneumonitis occurred in 2% patients treated with TEPMETKO, with one patient experiencing a Grade 3 or higher event; this event resulted in death. Five patients (1%) discontinued TEPMETKO due to ILD/pneumonitis.
Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold TEPMETKO in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified [see Dosage and Administration (2.4)].
Hepatotoxicity
Hepatotoxicity occurred in patients treated with TEPMETKO [see Adverse Reactions (6.1)]. Increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST) occurred in 18% of patients treated with TEPMETKO. Grade 3 or 4 increased ALT/AST occurred in 4.7% of patients. A fatal adverse reaction of hepatic failure occurred in one patient (0.2%). Four patients (0.8%) discontinued TEPMETKO due to increased ALT/AST. The median time-to-onset of Grade 3 or higher increased ALT/AST was 47 days (range 1 to 262).
Monitor liver function tests (including ALT, AST, and total bilirubin) prior to the start of TEPMETKO, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop increased transaminases or bilirubin. Based on the severity of the adverse reaction, withhold, dose reduce, or permanently discontinue TEPMETKO [see Dosage and Administration (2.4)].
Pancreatic Toxicity
Elevations in amylase and lipase levels occurred in patients treated with TEPMETKO [see Adverse Reactions (6.1)]. Increased amylase and/or lipase occurred in 13% of patients treated with TEPMETKO. Grade 3 and 4 increased amylase and/or lipase occurred in 5% and 1.2% of patients, respectively. Monitor amylase and lipase at baseline and regularly during treatment with TEPMETKO. Based on the severity of the adverse drug reaction, temporarily withhold, dose reduce, or permanently discontinue TEPMETKO [see Dosage and Administration (2.4)].
Embryo-Fetal Toxicity
Based on findings in animal studies and its mechanism of action TEPMETKO can cause fetal harm when administered to a pregnant woman. Oral administration of tepotinib to pregnant rabbits during the period of organogenesis resulted in malformations (teratogenicity) and anomalies at exposures less than the human exposure based on area under the curve (AUC) at the 450 mg daily clinical dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential or males with female partners of reproductive potential to use effective contraception during treatment with TEPMETKO and for one week after the last dose. [See Use in Specific Populations (8.1, 8.3)]