Sotorasib (Systemic)

Brand names: Lumakras
Drug class: Antineoplastic Agents

Usage of Sotorasib (Systemic)

Non-small Cell Lung Cancer

Treatment of locally advanced or metastatic KRAS G12C mutation-positive (as detected by an FDA-approved diagnostic test) non-small cell lung cancer (NSCLC) previously treated with ≥1 prior systemic therapy (designated an orphan drug by FDA for this use).

Accelerated approval based on overall response rate and duration of response; continued approval may be contingent on verification and description of clinical benefit of sotorasib in confirmatory studies. In the principal efficacy study, objective response rate was 36% in patients with locally advanced or metastatic KRAS G12C mutated NSCLC previously treated with an anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) monoclonal antibody, platinum-based combination chemotherapy, or both.

Relate drugs

How to use Sotorasib (Systemic)

General

Pretreatment Screening

  • NSCLC: Confirmation of presence of KRAS G12C mutation (as determined by an FDA-approved test) in tumor or plasma specimens; if KRAS G12C mutation is not detected in a plasma specimen, retest with tumor tissue.
  • Baseline liver function tests (i.e., ALT, AST, total bilirubin).

    • Patient Monitoring

  • Monitor liver function tests (i.e., AST, ALT, total bilirubin) every 3 weeks for the first 3 months of therapy, then monthly or as clinically indicated; more frequent monitoring may be necessary in patients who develop hepatotoxicity.
  • Monitor for new or worsening pulmonary symptoms (e.g., dyspnea, cough, fever) indicative of interstitial lung disease or pneumonitis.

    • Dispensing and Administration Precautions

  • Based on the Institute for Safe Medication Practices (ISMP), sotorasib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

    • Administration

    Oral Administration

    Administer orally at the same time each day without regard to food. Swallow tablets whole; do not crush, chew, or split.

    Alternatively, for patients who are unable to swallow whole tablets, disperse tablets in 120 mL (4 ounces) of non-carbonated, room temperature water. Place total number of tablets for the dose (e.g., three 320 mg tablets or eight 120 mg tablets for total dose of 960 mg) into the water, without crushing, and stir or swirl for approximately 3 minutes to disperse the tablets into small pieces (complete dissolution will not occur). Resulting mixture may range in color from pale to bright yellow. Consume entire mixture immediately or within 2 hours of mixing without chewing residual tablet pieces. Rinse any residue remaining in the container with an additional 120 mL of water, stir or swirl again, and then consume immediately.

    If a dose of sotorasib is missed by ≤6 hours, administer the prescribed dose as soon as it is remembered. If a dose is missed by >6 hours, administer the prescribed dose at the next scheduled time; do not administer an additional dose to replace the missed dose.

    If vomiting occurs after taking a dose, administer the next dose at the next scheduled time; do not administer an additional dose to replace the vomited dose.

    Dosage

    Adults

    Non-small Cell Lung Cancer Oral

    960 mg once daily. Continue until disease progression or unacceptable toxicity occurs.

    Dosage Modification

    Dosing interruption and/or dosage reduction of sotorasib may be necessary based on individual safety and tolerability.

    If dosage reduction from 960 mg once daily is necessary, reduce dosage to 480 mg once daily. If toxicity recurs on a dosage of 480 mg once daily, reduce dosage to 240 mg once daily. If toxicity recurs on a dosage of 240 mg once daily, discontinue drug.

    Hepatotoxicity Oral

    If symptomatic grade 2 serum AST/ALT elevations occur, withhold sotorasib therapy. When toxicity resolves or improves to grade 1 or less, resume therapy at next lower dosage.

    If grade 3 or 4 serum AST/ALT elevations occur, withhold sotorasib therapy. When toxicity resolves or improves to grade 1 or less, resume therapy at next lower dosage.

    If serum AST or ALT concentrations >3 times the ULN and serum total bilirubin concentrations >2 times the ULN in the absence of other etiology, permanently discontinue sotorasib therapy.

    Interstitial Lung Disease/Pneumonitis Oral

    If interstitial lung disease/pneumonitis of any grade is suspected, withhold sotorasib therapy. If interstitial lung disease/pneumonitis is confirmed, permanently discontinue sotorasib therapy.

    GI Effects Oral

    If grade 3 or 4 nausea, vomiting, or diarrhea occurs despite appropriate supportive care, withhold sotorasib therapy. When toxicity resolves or improves to grade 1 or less, resume therapy at next lower dosage.

    Other Toxicity Oral

    If other grade 3 or 4 toxicities occur, withhold sotorasib therapy. When toxicity resolves or improves to grade 1 or less, resume therapy at next lower dosage.

    Special Populations

    Hepatic Impairment

    No dosage adjustment recommended in mild to moderate (Child Pugh class A or B) hepatic impairment. No specific dosage recommendations in severe (Child Pugh class C) hepatic impairment.

    Renal Impairment

    No specific dosage recommendations.

    Geriatric Patients

    No specific dosage recommendations.

    Warnings

    Contraindications

  • None.

    • Warnings/Precautions

    Hepatotoxicity

    Hepatotoxicity, including drug-induced liver injury and hepatitis, reported. Median time to onset of serum ALT/AST elevations is 9 weeks.

    Monitor liver function tests (i.e., serum ALT, AST, total bilirubin concentrations) prior to initiation of sotorasib, every 3 weeks for the first 3 months of treatment, then once a month or as clinically indicated. More frequent monitoring may be necessary in patients who develop elevated aminotransferase and/or total bilirubin concentrations. If hepatotoxicity occurs, temporary interruption of sotorasib therapy, dosage reduction, or discontinuance of therapy may be necessary.

    Interstitial Lung Disease/Pneumonitis

    Interstitial lung disease/pneumonitis, sometimes fatal, reported. Median time to onset is 2 weeks.

    Monitor patients for new or worsening pulmonary symptoms indicative of interstitial lung disease/pneumonitis (e.g., dyspnea, cough, fever). If interstitial lung disease/pneumonitis is suspected, promptly withhold sotorasib. Permanently discontinue drug if no other etiology is identified.

    Specific Populations

    Pregnancy

    No available data in pregnant women.

    No adverse developmental effects or embryo-lethality observed in animal studies.

    Lactation

    Not known whether sotorasib or its metabolites distribute into human milk or if the drug has any effect on milk production or the breast-fed infant. Because of the potential for adverse reactions to sotorasib in breast-fed infants, advise females not to breast-feed while receiving the drug and for 7 days after the drug is discontinued.

    Pediatric Use

    Safety and efficacy of sotorasib not established in pediatric patients.

    Geriatric Use

    Although data are limited, no clinically important differences in safety or efficacy observed between geriatric patients and younger adults.

    Age (28–86 years) does not appear to have clinically important effects on pharmacokinetics of sotorasib.

    Hepatic Impairment

    Patients with hepatic impairment may experience more frequent adverse reactions.

    Mild to moderate hepatic impairment (Child Pugh class A or B): dosage adjustments not necessary. Severe hepatic impairment (Child Pugh class C): safety of sotorasib unknown.

    Renal Impairment

    Mild to moderate renal impairment (estimated GFR ≥30 mL/minute per 1.73 m2): Pharmacokinetics not substantially altered; no dosage adjustment needed.

    Severe renal impairment: Pharmacokinetics not studied.

    Common Adverse Effects

    Adverse effects (≥20%) include diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. Laboratory abnormalities (≥25%) include decreased lymphocytes, decreased hemoglobin, increased ALT and/or AST concentrations, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium concentrations.

    What other drugs will affect Sotorasib (Systemic)

    Metabolized principally by nonenzymatic conjugation and oxidative metabolism with CYP3A.

    Sotorasib is a CYP3A4 substrate and inducer and a P-glycoprotein inhibitor. In vitro, may induce CYP2C8, CYP2C9, and CYP2B6. Inhibits breast cancer resistance protein (BCRP).

    Does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.

    Drugs Affecting or Affected by Hepatic Microsomal Enzymes

    Potent Inducers of CYP3A4: Possible decrease in systemic exposure to sotorasib and reduced sotorasib efficacy. Avoid concomitant use.

    Substrates of CYP3A4: Possible decrease in plasma concentrations of CYP3A4 substrate drug and reduced efficacy of the CYP3A4 substrate. Avoid concomitant use with sensitive CYP3A4 substrates that have a narrow therapeutic index. If concomitant administration cannot be avoided, consult manufacturer's labeling of the sensitive CYP3A4 substrate drug for dosage adjustments of the CYP3A4 substrate.

    Drugs Affecting or Affected by Transport Systems

    Substrates of P-gp: Possible increase in plasma concentrations of the P-gp substrate drug and increased toxicity of the P-gp substrate. Avoid concomitant use with P-gp substrates where minimal concentration changes may lead to serious toxicities. If concomitant administration cannot be avoided, consult manufacturer's labeling of the P-gp substrate drug for dosage adjustments of the P-gp substrate.

    Substrates of BCRP

    Possible increase in plasma concentrations of the BCRP substrate drug and increased toxicity of the BCRP substrate. Monitor for adverse reactions of the BCRP substrate and potentially reduce the dosage if coadministered with sotorasib.

    Drugs Affecting Gastric Acidity

    Possible decrease in systemic exposure to sotorasib.

    Avoid concomitant use with proton-pump inhibitors, H2-receptor antagonists, and locally acting antacids. If concomitant use of a locally-acting antacid cannot be avoided, administer sotorasib 4 hours before or 10 hours after the locally-acting antacid.

    Specific Drugs

    Drug

    Interaction

    Comments

    Antacid, locally-acting

    Possible decrease in systemic exposure to sotorasib

    Avoid concomitant use; if concomitant use cannot be avoided, administer sotorasib 4 hours before or 10 hours after the locally-acting antacid

    Digoxin

    P-gp substrate: Increased peak plasma concentrations and AUC of digoxin by 91 and 21%, respectively

    Avoid concomitant use; if concomitant use cannot be avoided, adjust dosage of digoxin as needed

    Famotidine

    When famotidine was administered 10 hours before and 2 hours after a single dose of sotorasib under fed conditions, peak plasma concentrations or AUC of sotorasib decreased by 35 or 38%, respectively

    Avoid concomitant use

    Metformin

    Multidrug and toxin extrusion (MATE) transporter 1 and MATE2-K substrate: No meaningful change in metformin exposure

    Midazolam

    Sensitive CYP3A4 substrate: Decreased peak plasma concentrations and AUC of midazolam by 48 and 53%, respectively

    Avoid concomitant use; if concomitant use cannot be avoided, adjust dosage of midazolam as needed

    Omeprazole

    Decreased peak plasma concentrations or AUC of sotorasib by 65 or 57%, respectively, under fed conditions, and by 57 or 42%, respectively, under fasted conditions

    Avoid concomitant use

    Rifampin

    Potent CYP3A4 inducer: Decreased peak plasma concentrations and AUC of sotorasib by 35 and 51%, respectively

    Avoid concomitant use

    Rosuvastatin

    BCRP substrate: Increased peak plasma concentrations and AUC of rosuvastatin by 70% and 34%, respectively

    Monitor for adverse reactions and adjust dosage of rosuvastatin as needed

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