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ceritinib

General

Genetic Implications: Genetic Implications

Pronunciation:
se-ri-ti-nib


Trade Name(s)

  • Zykadia

Ther. Class.
antineoplastics

Pharm. Class.
kinase inhibitors

Indications

Genetic implicationAnaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC).

Action

Acts as a tyrosine kinase inhibitor, inhibiting anaplastic lymphoma kinase as well as other kinases, resulting in decreased growth of certain malignant cell lines.

Therapeutic Effect(s):

Slowed progression of metastatic NSCLC.

Pharmacokinetics

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

Half-life: 41 hr.

TIME/ACTION PROFILE (clinical response)

ROUTEONSETPEAKDURATION
POunknown4–6 hr (blood level)7.1–7.4 mos

Contraindication/Precautions

Contraindicated in:

  • OB: Pregnancy (may cause fetal harm);
  • Lactation:Discontinue ceritinib or discontinue breast feeding;
  • Congenital long QT syndrome.

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.

Adverse Reactions/Side Effects

CNS: fatigue

Resp: INTERSTITIAL LUNG DISEASE/PNEUMONITIS

CV: BRADYCARDIA, TORSADE DE POINTES, QT interval prolongation

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

Derm: rash

Endo: hyperglycemia

F and E: hypophosphatemia

GU: ↑ creatinine

Hemat: anemia

Metabolic: ↑ lipase

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  • Concurrent use of strong CYP3A inhibitors including ketoconazole, and nefazodone ↑ blood levels and the risk of toxicities; avoid concurrent use; if unavoidable, ↓ ceritinib dose.
  • Strong CYP3A inducers including carbamazepine, phenytoin, and rifampin may ↓ blood levels and effectiveness; avoid concurrent use.
  • May ↑ blood levels and the risk of toxicity of CYP3A4 and CYP2C9 substrates, including alfentanil, cyclosporine, dihyroergotamine, ergotamine, fentanyl, phenytoin, pimozide, quinidine, sirolimus, tacrolimus, and warfarin; dose of these medications may need to be ↓.
  • 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 torsade de pointes.

Drug-Food:

  • Grapefruit/grapefruit juice ↑ blood levels and the risk of toxicity; concurrent ingestion should be avoided.
  • St. John's wort ↓ blood levels and effectiveness; concurrent use should be avoided.

Route/Dosage

PO: (Adults) 750 mg once daily; continue until disease progression or unacceptable toxicity; Concurrent use of strong CYP3A inhibitors– ↓ dose by ࡩ rounded to the nearest 150-mg strength.

Availability

Capsules: 150 mg

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, withhold 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, withhold 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, withhold 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, withhold 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 and total bilirubin is ≤2 times the upper limit of normal, withhold ceritinib until recovery to baseline or less than or equal to 3 times the upper limit of normal, then resume ceritinib with a 150 mg dose reduction. If ALT or AST >3 times the upper limit of normal and total bilirubin is >2 times the upper limit of normal in the absence of cholestasis or hemolysis, permanently discontinue ceritinib.
  • Monitor fasting blood glucose prior to and periodically during therapy. If persistent hyperglycemia >250 m g/dL despite anti-hyperglycemic therapy, withhold 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; ↑ creatinine.
  • Monitor serum lipase and amylase prior to and periodically during therapy. May cause ↑ serum lipase and amylase. If ↑ lipase or amylase >2 x upper limit of normal, withhold ceritinib and monitor serum lipase and amylase. When recovery to <1.5 x upper limit of normal, resume with 150 mg dose.

Potential Diagnoses

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 hrs 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)
  • Rep: Advise female patient of reproductive potential to use effective contraceptives during and for at least 6 mo following completion of therapy and to notify health care provider if pregnancy is planned or suspected and to avoid breast feeding during and for at least 2 wks after end of therapy. Advise males with female partners of reproductive potential to use condoms during therapy and for 3 mo following completion of therapy.

Evaluation/Desired Outcomes

Slowed progression of metastatic NSCLC.

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Citation

Quiring, Courtney, et al. "Ceritinib." Davis's Drug Guide, 16th ed., F.A. Davis Company, 2019. Medicine Central, im.unboundmedicine.com/medicine/view/Davis-Drug-Guide/110150/all/ceritinib.
Quiring C, Sanoski CA, Vallerand AH. Ceritinib. Davis's Drug Guide. 16th ed. F.A. Davis Company; 2019. https://im.unboundmedicine.com/medicine/view/Davis-Drug-Guide/110150/all/ceritinib. Accessed April 26, 2019.
Quiring, C., Sanoski, C. A., & Vallerand, A. H. (2019). Ceritinib. In Davis's Drug Guide. Available from https://im.unboundmedicine.com/medicine/view/Davis-Drug-Guide/110150/all/ceritinib
Quiring C, Sanoski CA, Vallerand AH. Ceritinib [Internet]. In: Davis's Drug Guide. F.A. Davis Company; 2019. [cited 2019 April 26]. Available from: https://im.unboundmedicine.com/medicine/view/Davis-Drug-Guide/110150/all/ceritinib.
* Article titles in AMA citation format should be in sentence-case
TY - ELEC T1 - ceritinib ID - 110150 A1 - Quiring,Courtney, AU - Sanoski,Cynthia A, AU - Vallerand,April Hazard, BT - Davis's Drug Guide UR - https://im.unboundmedicine.com/medicine/view/Davis-Drug-Guide/110150/all/ceritinib PB - F.A. Davis Company ET - 16 DB - Medicine Central DP - Unbound Medicine ER -