ceritinib

Absorption: Absorption follows oral administration; food significantly ↑ absorption and may ↑ risk of adverse reactions.

Distribution: Slight preference to distribute from plasma into red blood cells.

Metabolism/Excretion: Metabolized in the liver (mostly by CYP3A) and is a substrate of P-glycoprotein (P-gp); 68% eliminated unchanged in feces, 1.3% in urine.

Half-Life: 41 hr.

Time/Action Profile ⬆ ⬇

(clinical response)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	4–6 hr (blood level)	7.1–7.4 mo

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Congenital long QT syndrome;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Moderate to severe hepatic impairment/severe renal impairment (CCr <30 mL/min);
HF, bradycardia, electrolyte abnormalities, or concurrent use of QT prolonging medications;
Concurrent use of strong CYP3A4 inhibitors;
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children.

Adv. Reactions/Side Effects ⬆ ⬇

CV: BRADYCARDIA, QT interval prolongation, TORSADES DE POINTES

Derm: rash, photosensitivity

Endo: hyperglycemia

F and E: hypophosphatemia

GI: ↓appetite, ↑lipase, ↑liver enzymes, abdominal pain, constipation, diarrhea, esophagitis/reflux/dysphagia, nausea, vomiting, HEPATOTOXICITY, PANCREATITIS

GU: ↑serum creatinine

Hemat: anemia

Neuro: fatigue

Resp: INTERSTITIAL LUNG DISEASE/PNEUMONITIS

Interactions ⬆ ⬇

Drug-drug:

Concurrent use of strong CYP3A inhibitors including ketoconazole, nefazodone, and ritonavir↑ levels and risk of toxicity; avoid concurrent use; if unavoidable, ↓ ceritinib dose.
Strong CYP3A inducers, including carbamazepine, phenytoin, and rifampin may ↓ levels and effectiveness; avoid concurrent use.
May ↑ levels and risk of toxicity of CYP3A substrates, including midazolam; avoid concurrent use; if unavoidable, ↓ dose of CYP3A substrate.
May ↑ levels and risk of toxicity of CYP2C9 substrates, including warfarin; avoid concurrent use; if unavoidable, ↓ dose of CYP2C9 substrate.
Beta-blockers, diltiazem, verapamil, digoxin, and clonidine may ↑ risk of bradycardia; avoid concurrent use, if possible.
Concurrent use of QT interval prolonging medications may ↑ risk of QT interval prolongation and torsades de pointes.

Drug-Natural Products:

St. John's wort↓ levels and effectiveness; avoid concurrent use.

Grapefruit/grapefruit juice↑ levels and the risk of toxicity; avoid concurrent ingestion.

Route/Dosage ⬆ ⬇

PO (Adults ): 450 mg once daily; continue until disease progression or unacceptable toxicity; Concurrent use of strong CYP3A inhibitors:↓ dose by ⅓, rounded to the nearest 150-mg strength.

Hepatic Impairment

PO (Adults ): Severe hepatic impairment:↓ dose by ⅓, rounded to the nearest 150-mg strength.

Availability ⬆ ⬇

Assessment ⬆ ⬇

Assess for signs and symptoms of interstitial lung disease or pneumonitis (trouble breathing, shortness of breath, fever, cough with or without mucus, chest pain). If these symptoms occur, discontinue therapy permanently.
Monitor ECG periodically during therapy. If QTc interval is >500 msec on at least 2 separate ECGs, hold ceritinib until QTc interval <481 msec or recovery to baseline if QTc ≥481 msec, then resume ceritinib with a 150-mg dose reduction. If QTc interval prolongation occurs in combination with torsades de pointes or polymorphic ventricular tachycardia or signs and symptoms of serious arrhythmia, discontinue ceritinib permanently.
- If symptomatic bradycardia that is not life-threatening occurs, hold ceritinib until recovery to asymptomatic bradycardia or a heart rate ≥60 bpm, evaluate concurrent medications causing bradycardia, and adjust dose of ceritinib. If clinically significant bradycardia requiring intervention or life-threatening bradycardia in patients taking concurrent medication known to cause bradycardia or a medication known to cause hypotension occurs, hold ceritinib until recovery to asymptomatic bradycardia or a heart rate ≥60 bpm. If concurrent medication can be adjusted or discontinued, resume ceritinib with a 150-mg dose reduction and frequent monitoring. If life-threatening bradycardia occurs in patients not taking medications known to cause bradycardia or hypotension, discontinue ceritinib permanently.
Assess for nausea, vomiting, diarrhea. If severe or intolerable nausea, vomiting, or diarrhea continue despite optimal antiemetic or antidiarrheal therapy, hold ceritinib until improved; then resume with a 150-mg dose reduction.

Lab Test Considerations:

Test patient for ALK positivity in tumor specimens through an FDA approved test prior to starting therapy.
- Monitor liver function tests at least monthly. If ALT or AST >5 times the upper limit of normal (ULN) and total bilirubin is ≤2 times ULN, hold ceritinib until recovery to baseline or ≤3 times ULN, then resume ceritinib with a 150-mg dose reduction. If ALT or AST >3 times ULN and total bilirubin is >2 times ULN in the absence of cholestasis or hemolysis, permanently discontinue ceritinib.
- Monitor fasting blood glucose prior to and periodically during therapy. If persistent hyperglycemia >250 mg/dL despite anti-hyperglycemic therapy, hold ceritinib until hyperglycemia is adequately controlled, then resume with a 150-mg dose reduction. If adequate hyperglycemic control cannot be achieved, discontinue therapy.
- May cause ↓ hemoglobin and serum phosphate; ↑ serum creatinine.
- Monitor serum lipase and amylase prior to and periodically during therapy. May cause ↑ serum lipase and amylase. If ↑ lipase or amylase >2 times ULN, hold ceritinib and monitor serum lipase and amylase. When recovery to <1.5 times ULN, resume with 150-mg dose reduction.

Implementation ⬆ ⬇

PO: Administer on an empty stomach, at least 1 hr before or 2 hr after meals.

Patient/Family Teaching ⬆ ⬇

Instruct patient to take ceritinib as directed. Take missed doses as soon as remembered unless within 12 hr of next dose. If vomiting occurs, do not administer additional dose, continue with next scheduled dose. Instruct patient to read Patient Information prior to starting therapy and with each Rx refill in case of changes.
Inform patient to avoid consuming grapefruit and grapefruit juice during therapy.
Advise patient to notify health care professional if nausea, vomiting, and diarrhea is severe or persistent; if signs and symptoms of hepatotoxicity (feeling tired, itchy skin, skin or whites of eyes turn yellow, nausea and vomiting, decreased appetite, pain on right side of stomach, dark or brown, tea-colored urine, bleed or bruise easily); pneumonitis; QTc interval prolongation or bradycardia (new chest pain, changes in heartbeat, palpitations, dizziness, fainting, or changes in or use of a new heart or BP medication); hyperglycemia (increased thirst, increased hunger, headaches, trouble thinking or concentration, urinating often, blurred vision, tiredness, breath smells like fruit), or pancreatitis (upper abdominal pain that may spread to the back and get worse with eating) occur.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking other Rx, OTC, or herbal products, especially St. John's wort.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraceptives during and for 6 mo and to avoid breastfeeding during and for 2 wk following completion of therapy. Advise patient to notify health care provider if pregnancy is planned or suspected. Advise males with female partners of reproductive potential to use condoms during therapy and for 3 mo following completion of therapy.

section name header

Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇