adagrasib

High Alert

KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have previously received ≥1 systemic therapy.
KRAS G12C-mutated locally advanced or metastatic colorectal cancer in patients who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy (in combination with cetuximab).

Action ⬆ ⬇

Inhibits KRAS G12C, which inhibits tumor growth and facilitates apoptosis in tumor cells.

Therapeutic effects:

Decreased progression of NSCLC and colorectal cancer.

Pharmacokinetics ⬆ ⬇

Absorption: Extent of absorption following oral administration unknown.

Distribution: Extensively distributed to tissues.

Protein Binding: 98%.

Metabolism/Excretion: Primarily metabolized in the liver via the CYP3A4 isoenzyme. Primarily excreted in the feces (75%; 14% as unchanged drug), with 4.5% excreted in the urine (2% as unchanged drug).

Half-Life: 23 hr.

Time/Action Profile ⬆ ⬇

(plasma concentration)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	6 hr	12 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Congenital long QT syndrome or baseline QT interval prolongation;
Lactation: Lactation.

Use Cautiously in:

HF, bradyarrhythmia, hypokalemia, or hypomagnesemia (↑ risk of QT interval prolongation);
OB: Safety not established in pregnancy;
Pedi: Safety and effectiveness not established in children.

Adv. Reactions/Side Effects ⬆ ⬇

CV: QT interval prolongation, edema, hypotension

F and E: hypokalemia, hypomagnesemia, hyponatremia, dehydration

GI: abdominal pain, constipation, diarrhea, hepatotoxicity, hypoalbuminemia, ↑lipase, ↑liver enzymes, nausea, vomiting, colitis, GI BLEEDING, GI OBSTRUCTION, ileus

GU: renal impairment, ↓fertility

Hemat: anemia, lymphocytopenia, thrombocytopenia, leukopenia, neutropenia

Metab: ↓appetite

MS: pain, muscle weakness

Neuro: dizziness, fatigue

Resp: cough, dyspnea, pneumonia, INTERSTITIAL LUNG DISEASE (ILD)/PNEUMONITIS, pleural effusion, RESPIRATORY FAILURE

Misc: fever

Interactions ⬆ ⬇

Drug-drug:

Strong CYP3A4 inducers, including rifampin, may ↓ levels and effectiveness; avoid concurrent use.
Strong CYP3A4 inhibitors, including itraconazole, may ↑ levels and risk of toxicity; avoid concurrent use until adagrasib steady state concentrations have been achieved (~8 days).
May ↑ levels and risk of toxicity of CYP3A substrates; avoid concurrent use.
May ↑ levels and risk of toxicity of CYP2C9 substrates, including warfarin; avoid concurrent use.
May ↑ levels and risk of toxicity of CYP2D6 substrates, including dextromethorphan; avoid concurrent use.
May ↑ levels and risk of toxicity of P-glycoprotein substrates, including digoxin.
QT interval prolonging medications can ↑ risk of QT interval prolongation and torsades de pointes; avoid concurrent use.

Route/Dosage ⬆ ⬇

PO (Adults ): 600 mg twice daily until disease progression or unacceptable toxicity.

Availability ⬆ ⬇

Assessment ⬆ ⬇

Monitor ECG for QTc interval prolongation). If QTc interval >500 msec or ↑ by >60 msec from baseline, withhold therapy until QTc interval <481 msec or returns to baseline. Resume at next lower dose level. If torsades de pointes, polymorphic ventricular tachycardia, or signs or symptoms of serious or life-threatening arrhythmia occur, permanently discontinue therapy.
Monitor for GI obstruction (nausea/vomiting), bloody stool, and diarrhea. Provide supportive care (antiemetic, antidiarrheal, fluids). If Grade 3 or 4, withhold therapy until recovery to ≤Grade 1 or return to baseline. Resume at next lower dose level.
Assess for signs and symptoms of ILD/pneumonitis (worsening of respiratory symptoms, dyspnea, cough, fever). If any Grade, withhold therapy if suspected. Permanently discontinue therapy if confirmed.
Monitor and assess for adverse reactions (fatigue, musculoskeletal pain, renal impairment, edema, ↓ appetite) If Grade 3 or 4, withhold therapy until ≤Grade 1 or return to baseline. Resume at next lower dose level.

Lab Test Considerations:

Monitor serum potassium and magnesium. Correct abnormalities.
May cause hepatotoxicity. Monitor AST, ALT, alkaline phosphatase, and total bilirubin prior to therapy, monthly for 3 mo, and as clinically indicated. If Grade 2 ↑ AST or ALT, ↓to next lower dose level. If Grade 3 or 4 ↑ AST or ALT, withhold therapy until recovery to ≤Grade 1 or return to baseline. Resume at next lower dose level. If AST or ALT >3 times upper limit of normal (ULN) with total bilirubin > 2 times ULN, in the absence of alternative causes, permanently discontinue therapy.

Implementation ⬆ ⬇

Heightened risk of causing significant patient harm when used in error. Use safe medication administration practices.
PO: Dosage Reductions for Adverse Reactions: If adverse reactions occur, a maximum of two dose reductions are permitted. Permanently discontinue therapy if unable to tolerate 600 mg once daily.1st dose reduction: 400 mg twice daily.2nd dose reduction: 600 mg once daily.
DNC: Swallow tablets whole. Do not chew, crush, or split tablets.
Administer twice daily, at same time each day, with or without food.
If administered in combination with cetuximab, withhold or permanently discontinue treatment with cetuximab when withholding or permanently discontinuing adagrasib.

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult a health care professional before taking other medications.
Advise patient if vomiting occurs after taking, do not take an additional dose. Resume at next scheduled time. If dose is missed by >4 hr, resume dosing at the next scheduled time.
Educate patient on GI complications, hepatotoxicity, cardiac dysfunction, and respiratory distress. If any occur, advise to immediately notify a health care professional or seek immediate medical treatment.
Rep: May cause fetal harm. Advise females of reproductive potential to notify a health care professional if pregnancy is planned or suspected. Advise not to breastfeed during treatment and for 1 wk after last dose. May cause infertility.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇