Ceritinib – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

Ceritinib inhibits Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246), which is an enzyme that in humans is encoded by the ALK gene. About 4-5% of NSCLCs have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. Ceritinib exerts its therapeutic effect by inhibiting autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells. Ceritinib has been shown to inhibit in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice and rats.

or

Ceritinib is a tyrosine kinase inhibitor that selectively and potently inhibits anaplastic lymphoma kinase (ALK). In normal physiology, ALK functions as a key step in the development and function of nervous system tissue. However, chromosomal translocation and fusion give rise to an oncogenic form of ALK that has been implicated in the progression of NSCLC. Ceritinib thus acts to inhibit this mutated enzyme and stop cell proliferation, ultimately halting cancer progression.[rx] Because ceritinib is considered a targeted cancer therapy, an FDA-approved test is required to determine which patients are candidates for ceritinib. This test, developed by Roche, is the VENTANA ALK (D5F3) CDx Assay and is used to identify ALK-positive NSCLC patients who would benefit from ceritinib treatment.[rx]

Indications

  • Ceritinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
  • Ceritinib is a small molecule tyrosine kinase receptor inhibitor and antineoplastic agent that is used in the therapy of selected forms of advanced non-small cell lung cancer (NSCLC)
  • Zykadia is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK) positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib.
  • Ceritinib is approved to treat Non-small cell lung cancer that is ALK-positive and has metastasized (spread to other parts of the body). It is used in adults.
  • Refractory, locally advanced Nonsmall cell lung cancer
  • Refractory, metastatic Non-small cell lung cancer

Use in Cancer

Ceritinib is approved to treat:

Ceritinib is also being studied in the treatment of other types of cancer.

Contraindications

  • low amount of magnesium in the blood
  • low amount of calcium in the blood
  • low amount of potassium in the blood
  • slow heartbeat
  • prolonged QT interval on EKG
  • chronic heart failure
  • abnormal EKG with QT changes from birth
  • high amount of bilirubin in the blood
  • excessive nausea
  • excessive vomiting
  • excessive diarrhea
  • high blood sugar
  • abnormal liver function tests
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • lung tissue problem
  • pancreatitis

Dosage

Strengths: 150 mg

Non-Small Cell Lung Cancer

  • 450 mg orally once daily at the same time each day until disease progression or unacceptable toxicity
  • Treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib

Dose Adjustments

DOSE MODIFICATIONS:

  • First dose reduction: 300 mg once a day
  • Second dose reduction: 150 mg once a day
  • Discontinue this drug in patients unable to tolerate 150 mg daily.

DOSE MODIFICATIONS FOR ADVERSE REACTIONS:
GI ADVERSE REACTIONS:

  • Severe or intolerable nausea, vomiting, or diarrhea despite antiemetic or antidiarrheal therapy: Withhold therapy until improved; resume at the next lower dose.

HEPATOTOXICITY:

  • ALT or AST elevation greater than 5 times the upper limit of normal (ULN) with total bilirubin elevation less than or equal to 2 x ULN: Withhold therapy until recovery to baseline or less than or equal to 3 x ULN; resume at the next lower dose.
  • ALT or AST elevation greater than 3 x ULN with total bilirubin elevation greater than 2 x ULN in the absence of cholestasis or hemolysis: Permanently discontinue therapy.

INTERSTITIAL LUNG DISEASE (ILD)/PNEUMONITIS:

  • Any Grade therapy-related ILD/pneumonitis: Permanently discontinue therapy.

QT INTERVAL PROLONGATION:

  • QTc interval greater than 500 msec on at least 2 separate ECGs: Withhold therapy until QTc interval is less than 481 msec or recovery to baseline if baseline QTc is greater than or equal to 481 msec; resume at the next lower dose.
  • QTc interval prolongation in combination with Torsades de pointes or polymorphic ventricular tachycardia or serious arrhythmia: Permanently discontinue therapy.

HYPERGLYCEMIA:

  • Persistent hyperglycemia greater than 250 mg/dL despite antihyperglycemic therapy: Withhold therapy until hyperglycemia is adequately controlled; resume at the next lower dose; if adequate hyperglycemic control cannot be achieved with medical management, discontinue this drug.

BRADYCARDIA:

  • Symptomatic bradycardia that is not life-threatening: Withhold therapy until recovery to asymptomatic bradycardia or to the heart rate of 60 bpm or above, evaluate concomitant medications known to cause bradycardia; if bradycardia cannot be attributed to another drug, resume therapy at the next lower dose.
  • Clinically significant bradycardia requiring intervention or life-threatening bradycardia in patients taking a concomitant medication also known to cause bradycardia or a medication known to cause hypotension: Permanently discontinue therapy.

PANCREATITIS:

  • Lipase or amylase elevation greater than 2 x ULN: Withhold therapy until recovery to less than 1.5 x ULN; resume at the next lower dose.

STRONG CYP450 3A INHIBITORS (e.g. ketoconazole):

  • Avoid use if possible.
  • If users cannot be avoided, reduce the dose of ceritinib by approximately one-third rounded to the nearest multiple of 150 mg.
  • After discontinuation of a strong CYP450 3A inhibitor, resume the ceritinib dose that was taken prior to initiating the strong CYP450 3A inhibitor.

Administration Advice:

  • This drug should be taken with food.
  • Do not consume grapefruit or grapefruit juice because they inhibit CYP450 3A.
  • If a dose is missed, make it up unless it is 12 hours or less until the next dose.
  • Discontinue in patients unable to tolerate 300 mg a day.

Side Effects

The Most Common

  • nausea
  • diarrhea
  • vomiting
  • constipation
  • stomach pain
  • heartburn
  • difficulty swallowing
  • loss of appetite
  • weight loss
  • fatigue
  • rash
  • itching
  • changes in vision
  • muscle, bone, back arm, or leg pain
  • headache
  • pain in the right upper part of the stomach
  • unusual bruising or bleeding
  • dark urine
  • yellowing of the skin and eyes
  • decreased appetite
  • flu-like symptoms
  • itching
  • shortness of breath
  • fever, chills, sore throat, ongoing cough and congestion, or other signs of infection
  • chest pain or discomfort
  • changes in heartbeat
  • heart palpitations
  • dizziness
  • lightheadedness
  • fainting
  • ongoing pain that begins in the upper left or middle of the stomach but may spread to the back
  • seizures

More Common

  • severe pain in your upper stomach spreading to your back;
  • slow heartbeats, weak pulse, weak or shallow breathing;
  • sudden chest pain or discomfort, fever, dry cough or cough with mucus, feeling short of breath;
  • fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness (like you might pass out);
  • high blood sugar–increased thirst, increased urination, hunger, fruity breath odor, headaches, thinking problems, blurred vision, feeling tired; or
  • high blood sugar–increased thirst, increased urination, dry mouth, fruity breath odor;
  • liver problems–right-sided-stomach pain, loss of appetite, unusual tiredness, itching, easy bruising or bleeding, dark urine, or yellowing of the skin or eyes.
  • stomach pain, loss of appetite;
  • nausea, vomiting, diarrhea;
  • feeling tired; or
  • weight loss.

Rare

  • Diarrhea
  • Increased gamma-glutamyl transpeptidase (GGT)
  • Increased alkaline phosphatase
  • Increased creatinine
  • Nausea
  • Vomiting
  • Anemia
  • High blood sugar (hyperglycemia)
  • Fatigue
  • Abdominal pain
  • Increased amylase
  • Decreased phosphate
  • Decreased appetite
  • Low white blood cell count (neutropenia)
  • Cough
  • Weight loss
  • Constipation
  • Non-cardiac chest pain
  • Rash
  • Back pain
  • Fever
  • Headache
  • Low platelet count (thrombocytopenia)
  • Esophageal disorder
  • Increased total bilirubin
  • Dizziness
  • Prolonged QT interval
  • Musculoskeletal pain
  • Itching

Drug Interaction

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Pregnancy and Lactation

FDA Pregnancy Category D

Pregnancy

Based on animal studies and its mechanism of action, ceritinib therapy can cause fetal harm when administered to a pregnant woman. The limited data available on the use of ceritinib in pregnant women are insufficient to inform risk. Administration to rats and rabbits during the period of organogenesis at maternal plasma exposures below the recommended human dose caused increases in skeletal anomalies in rats and rabbits. Pregnant women should be advised of the potential risk to the fetus. Females of reproductive potential are advised to use effective contraception during treatment with ceritinib and for 6 months following the completion of therapy. Based on the potential for genotoxicity, males with female partners of reproductive potential are advised to use condoms during treatment with ceritinib and for 3 months following completion of therapy.

Lactation

No information is available on the clinical use of ceritinib during breastfeeding. Because ceritinib is 97% bound to plasma proteins, the amount in milk is likely to be low. The manufacturer recommends that breastfeeding be discontinued during ceritinib therapy and for 2 weeks after the final dose. There are no data regarding the presence of ceritinib or its metabolites in human milk, the effects of ceritinib on breastfed infants, or its effects on milk production. Because of the potential for serious adverse reactions including gastrointestinal toxicity, hepatotoxicity, pneumonitis, bradycardia, and pancreatitis, breastfeeding is not recommended during treatment with ceritinib and for 2 weeks following completion of therapy.

How should this medicine be used?

Ceritinib comes as a capsule and a tablet to take by mouth. It is usually taken with food once a day. Take ceritinib at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take ceritinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

If you vomit after taking ceritinib, do not take another dose. Continue your regular dosing schedule.

Your doctor may decrease your dose of ceritinib, treat you with other medications, or tell you to stop taking ceritinib for a period of time during your treatment. This will depend on how well the medication works for you and any side effects you may experience. Be sure to tell your doctor how you are feeling during your treatment with ceritinib.

What special precautions should I follow?

Before taking ceritinib,

  • tell your doctor and pharmacist if you are allergic to ceritinib, any other medications, or any of the ingredients in ceritinib capsules or tablets. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: amiodarone (Nexterone, Pacerone); anagrelide (Agrylin); anticoagulants (‘blood thinners’) such as warfarin (Coumadin, Jantoven); beta blockers such as atenolol (Tenormin), labetalol (Normodyne), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), propranolol (Inderal) and sotalol (Betapace, Sorine, Sotylize); carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, Teril); certain medications for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) such as efavirenz (Sustiva, in Atripla), indinavir (Crixivan), nelfinavir (Viracept), nevirapine (Viramune), ritonavir (Norvir, in Kaletra), and saquinavir (Invirase); chloroquine; chlorpromazine; cilostazol; ciprofloxacin (Cipro); citalopram (Celexa); clarithromycin; clonidine (Catapres, Kapvay); corticosteroids; cyclosporine (Gengraf, Neoral, Sandimmune); digoxin (Lanoxin); diltiazem (Cardizem, Dilacor, Tiazac); disopyramide (Norpace); dofetilide (Tikosyn); donepezil (Aricept); dronedarone (Multaq); escitalopram (Lexapro); fentanyl (Abstral, Actiq, Duragesic, Fentora, Subsys); flecainide (Tambocor); fluconazole (Diflucan); haloperidol (Haldol); ibutilide (Corvert); itraconazole (Onmel, Sporanox, Tolsura); ketoconazole; levofloxacin; methadone (Dolophine, Methadose); moxifloxacin (Avelox); nefazodone; ondansetron (Zuplenz, Zofran); pentamidine (Pentam); phenobarbital; phenytoin (Dilantin, Phenytek); pimozide (Orap); pioglitazone (Actos, in Duetact, Oseni); procainamide; quinidine (in Nuedexta); rifabutin (Mycobutin); rifampin (Rifadin, Rimactane, in Rifater); sildenafil (Revatio); sirolimus (Rapamune); tacrolimus (Astagraf, Prograf); thioridazine; vardenafil (Levitra, Staxyn); and verapamil (Calan, Covera, Isoptin, Verelan). Many other medications may interact with ceritinib, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor what herbal products you are taking, especially St. John’s Wort.
  • tell your doctor if you have or have ever had diabetes or high blood sugar, heart failure, an irregular heartbeat, QT prolongation (an irregular heart rhythm that can lead to fainting, loss of consciousness, seizures, or sudden death), a low level of potassium or magnesium in your blood, pancreatitis (inflammation of the pancreas), or liverdisease.
  • tell your doctor if you are pregnant, or plan to become pregnant. You should not become pregnant while you are taking ceritinib. You will need to have a pregnancy test before you start treatment, and you should use birth control to prevent pregnancy during your treatment and for at least 6 months after your final dose. If you are a male with a female partner who may become pregnant, you should use birth control to prevent pregnancy during you treatment and for at least 3 months after your final dose. Talk to your doctor about birth control methods that will work for you. Ceritinib may harm your unborn baby. If you or your partner become pregnant during your treatment with ceritinib, call your doctor immediately.
  • tell your doctor if you are breastfeeding. You should not breastfeed while you are taking ceritinib and for at least 2 weeks after your final dose.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking ceritinib.
  • you should know that you may experience hyperglycemia (an increase in your blood sugar) while you are taking this medication. Tell your doctor immediately if you have any of the following symptoms while you are taking ceritinib: extreme thirst, frequent urination, extreme hunger, blurred vision, headache, trouble thinking or concentrating, breath that smells like fruit or tiredness.

References

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205755s009lbl.pdf
  2. https://www.cancer.gov/about-cancer/treatment/drugs/ceritinib
  3. https://pubchem.ncbi.nlm.nih.gov/compound/Ceritinib
  4. https://pubchem.ncbi.nlm.nih.gov/compound/Ceritinib-dihydrochloride
  5. https://medlineplus.gov/druginfo/meds/a614027.html
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  8. https://www.rxlist.com/consumer_zykadia_ceritinib/drugs-condition.htm
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    2,4-Pyrimidinediamine, 5-chloro-N4-[2-[(1-methylethyl)sulfonyl]phenyl]-N2-[5-methyl-2-(1-methylethoxy)-4-(4-piperidinyl)phenyl]-
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    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
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