ceritinib

Ceritinib is a medication used to treat anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) in adults. Ceritinib is a small molecule that selectively targets and inhibits the activity of abnormal ALK fusion proteins that cause lung cancer. Ceritinib also inhibits other proteins that promote tumor cell growth, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1.

ALK is an enzyme coded by the ALK gene which helps in the development of the fetal gastrointestinal and nervous systems. The ALK gene is normally turned off in the fetal stage, but in some people, it gets turned on later and fuses with other genes and generates abnormal ALK fusion proteins. ALK fusion proteins alter cell signaling and gene expression which results in proliferation and survival of tumor cells that express this protein.

Ceritinib targets tumor cells that express ALK fusion proteins, including EML4-ALK and NPM-ALK fusion proteins. Ceritinib inhibits the activity of ALK and ALK-mediated activation of downstream signaling protein STAT3 which promotes the proliferation and survival of tumor cells. Ceritinib is used only in the treatment of NSCLCs that are positive for ALK fusion proteins as detected by an FDA-approved test. Ceritinib has shown anti-tumor activity in EML4-ALK-positive cancers that are resistant to crizotinib, a first-generation tyrosine kinase inhibitor.

• Ceritinib can cause severe gastrointestinal (GI) symptoms including nausea, vomiting, diarrhea and abdominal pain. Monitor patients and manage GI symptoms with antidiarrheals, antiemetics and fluid replacement as needed. If the patient does not respond to treatment and if GI symptoms are severe and intolerable, withhold ceritinib and resume at a lower dose after the patient improves.
• Ceritinib is toxic to the liver and can increase liver enzymes ALT and AST, and bilirubin. Monitor patient’s ALT, AST and total bilirubin once a month, or more frequently in patients with elevated levels, as indicated. Based on the severity of liver toxicity, withhold ceritinib and resume at a reduced dose, or discontinue permanently.
• Severe, life-threatening or fatal interstitial lung disease (ILD)/lung inflammation (pneumonitis) occurred in some patients treated with ceritinib. Monitor patients for pulmonary symptoms of ILD/pneumonitis, exclude other causes and permanently discontinue ceritinib in patients with treatment-related ILD/pneumonitis.
• Ceritinib can disturb the heart rhythm and prolong the QT interval, which increases the risk for irregular and rapid ventricular contractions (ventricular tachyarrhythmia/torsades de pointes) and sudden death.
  • Avoid use of ceritinib in patients with congenital long QT syndrome, if possible.
  • Periodically monitor patients with ECGs and electrolyte levels in the following conditions:
    • Congestive heart failure
    • Irregular and slow heart rate (bradyarrhythmia)
    • Electrolyte abnormalities
    • Taking other medications that are known to prolong QT interval
  • Based on the severity of adverse reaction withhold ceritinib and resume at a reduced dose, or discontinue permanently.
• Ceritinib can slow down the heart rate and cause bradycardia.
  • Avoid concurrent use with other medications known to cause bradycardia, as far as possible.
  • Monitor the patient’s heart rate and blood pressure regularly.
  • Based on the severity of adverse reaction withhold ceritinib and resume at a reduced dose after bradycardia is resolved, or discontinue permanently.
• Ceritinib can increase blood glucose levels (hyperglycemia). Check fasting serum glucose levels before starting treatment, monitor periodically and treat appropriately in case of hyperglycemia. Based on the severity of adverse reaction withhold ceritinib and resume at a reduced dose, or discontinue permanently.
• Pancreatitis, including one fatality, has occurred following ceritinib treatment. Check levels of pancreatic enzymes amylase and lipase before starting treatment, and monitor periodically. Based on the severity of enzyme level abnormalities, withhold ceritinib and resume at a reduced dose, or discontinue permanently.
• Ceritinib can cause fetal harm. Advise women of pregnancy potential and men with women partners of pregnancy potential to follow effective contraception for the recommended periods. Advise pregnant women of the potential risk to the fetus.

Common side effects of ceritinib include:

• Diarrhea
• Nausea
• Vomiting
• Abdominal pain and comfort
• Constipation
• Indigestion (dyspepsia)
• Swallowing difficulty (dysphagia)
• Gastroesophageal reflux disease (GERD)
• Increased level of liver enzymes:
  • Alanine aminotransferase (ALT)
  • Aspartate aminotransferase (AGT)
  • Gamma-glutamyl transpeptidase (GGT)
  • Alkaline phosphatase (ALK)
• High total bilirubin in blood (hyperbilirubinemia)
• Increase in creatinine
• High blood sugar levels (hyperglycemia)
• Low phosphate levels (hypophosphatemia)
• Increase in pancreatic enzymes amylase and lipase
• Blood disorders including:
  • Low red blood cell count (anemia)
  • Low count of neutrophil immune cell (neutropenia)
  • Low platelet count (thrombocytopenia)
• Reduced appetite
• Weight loss
• Fatigue
• Weakness (asthenia)
• Non-cardiac chest pain
• Back pain
• Musculoskeletal pain
• Pain in extremity
• Fever (pyrexia)
• Skin reactions including:
  • Rash
  • Acne-like eruptions (dermatitis acneiform)
  • Raised and flat lesions (maculopapular rash)
  • Itching (pruritus)
• Cough
• Headache
• Dizziness
• Disturbance of heart rhythm (prolonged QT interval)
• Fluid around the heart (pericardial effusion)
• Inflammation of the membrane around the heart (pericarditis)
• Slow heart rate (bradycardia)
• Interstitial lung disease
• Lung inflammation (pneumonitis)
• Liver toxicity
• Kidney failure
• Vision disorders including:
  • Vision impairment
  • Blurred vision
  • Light flashes in the field of vision (photopsia)
  • Eye focusing difficulty (accommodation disorder)
  • Loss of near sight (presbyopia)
  • Reduced visual acuity
  • Vitreous floaters
• Peripheral nerve damage (neuropathy)
• Peripheral sensory neuropathy
• Peripheral motor neuropathy
• Polyneuropathy
• Reduced skin sensation (hypoesthesia)
• Skin prickling sensation (paresthesia)
• Muscular weakness
• Gait disturbance
• Abnormal skin sensations including pain, burning, stinging or itching (dysesthesia)
• Nerve pain (neuralgia)
• Low muscle tone (hypotonia)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Capsule

• 150 mg

Adult:

Non-Small Cell Lung Cancer

• Indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test
• 450 mg orally once daily with food
• Continue until disease progression or unacceptable toxicity

Dosage Modifications

Dose reduction increments

• Starting dose: 450 mg once daily
• First dose reduction: 300 mg once daily
• Second dose reduction: 150 mg once daily
• Unable to tolerate 150 mg/day: Discontinue

Coadministration with strong CYP3A4 inhibitors

• Avoid concurrent use of strong CYP3A inhibitors during treatment
• If coadministration with a strong CYP3A inhibitor is unavoidable, reduce the dose by one-third, rounded to the nearest multiple of the 150 mg dosage strength
• After discontinuation of a strong CYP3A inhibitor, resume the dose that was taken prior to initiating the strong CYP3A4 inhibitor

ALT/AST elevation

• ALT/AST increase above 5 times upper limit normal (ULN) with total bilirubin 2 times or more above ULN: Withhold until recovery to baseline or 3 times or less above ULN, then resume with 150-mg dose reduction
• ALT/AST increase above 3 times ULN with total bilirubin above 2 times ULN in absence of cholestasis or hemolysis: Permanently discontinue

Gastrointestinal

• Lipase or amylase increase 2 times or more above ULN: Withhold and monitor serum lipase and amylase; resume with 150-mg dose reduction after recovery to below 1.5 times ULN
• Severe or intolerable nausea, vomiting, or diarrhea despite optimal antiemetic therapy: Withhold until improved, then resume with 150-mg dose reduction

Hyperglycemia

• Persistent hyperglycemia higher than 250 mg/dL despite optimal antihyperglycemic therapy: Withhold ceritinib until hyperglycemia is adequately controlled, then resume with 150-mg dose reduction
• If adequate hyperglycemic control cannot be achieved with optimal medical management, discontinue ceritinib

Pneumonitis

• Any grade treatment-related interstitial lung disease (ILD)/pneumonitis: Permanently discontinue

Prolonged QT interval

• QT interval longer than 500 msec (on at least 2 separate ECGs): Withhold until QTc interval is below 481 msec or recovery to baseline if baseline QTc 481 or longer msec, then resume with a 150-mg dose reduction
• QTc interval prolongation in combination with torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia: Permanently discontinue

Bradycardia

• Symptomatic (not life-threatening): Withhold until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or higher; evaluate concomitant medications known to cause bradycardia, and adjust the dose
• Clinically significant requiring intervention or life-threatening in patients taking concomitant drug also known to cause bradycardia: Withhold until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or higher; if concomitant medication can be adjusted or discontinued, resume with a 150-mg dose reduction, with frequent monitoring
• Life-threatening bradycardia in patients who are not taking a concomitant medication also known to cause bradycardia or known to cause hypotension: Permanently discontinue

Hepatic impairment

• Mild-to-moderate (Child Pugh A to B): No dosage adjustment is necessary
• Severe (Child Pugh C): Reduce dose by ~one-third, round to the nearest multiple of 150 mg dosage strength

Dosing Considerations

Selection for ceritinib treatment is based on the presence of ALK positivity in tumor specimens

• Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at: https://www.fda.gov/CompanionDiagnostics

Pediatric:

• Safety and efficacy not established

Overdose

There is no information on ceritinib overdose. Overdose will likely increase the severity of the drug’s side effects. Ceritinib is toxic to the liver and can also cause lung disease. Overdose treatment may be symptomatic and supportive care.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Severe interactions of ceritinib include:
  • alfuzosin
  • cisapride
  • clofazimine
  • conivaptan
  • dihydroergotamine
  • dronedarone
  • flibanserin
  • fluconazole
  • gadobenate
  • lonafarnib
  • lurasidone
  • methylergonovine
  • posaconazole
  • ranolazine
  • saquinavir
  • simvastatin
  • thioridazine
  • ubrogepant
  • venetoclax
  • voclosporin
• Ceritinib has serious interactions with at least 277 different drugs.
• Ceritinib has moderate interactions with at least 206 different drugs.
• Mild interactions of ceritinib include:
  • armodafinil
  • aspirin
  • delavirdine
  • estradiol vaginal
  • exemestane
  • warfarin

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There is limited data on the use of ceritinib in pregnant women, however, animal studies show ceritinib can cause fetal harm.
• Women of pregnancy potential should use effective contraception during treatment with ceritinib and for 6 months following completion of therapy. Men with reproductive potential who have women partners that can get pregnant should use effective contraception during treatment and for 3 months after completion of therapy.
• There are no data on the presence of ceritinib in breast milk or its effects on milk production or the breastfed infant. Nursing mothers should not breastfeed during treatment and for 2 weeks after completing treatment, because of the potential for serious adverse reactions in the breastfed infant.

• Take ceritinib exactly as prescribed, with food. You may take a missed dose after the scheduled time, unless the next dose is due within 12 hours.
• Do not take an additional dose if vomiting occurs during the course of treatment, but continue with the next scheduled dose.
• Ceritinib will cause gastrointestinal (GI) symptoms such as nausea, vomiting, diarrhea and abdominal pain. Take medications prescribed to you for the control of GI symptoms. If symptoms are severe and intolerable, inform your physician.
• Report immediately to your physician if you experience:
  • Worsening of respiratory symptoms including shortness of breath (dyspnea), cough and fever
  • Liver injury symptoms such as dark urine, abdominal pain, nausea and vomiting
  • Symptoms of hyperglycemia such as increased thirst and urination, tiredness and recurrent infections
• Ceritinib can disturb the heart rhythm. Report to your physician immediately in case of new chest pain or discomfort, changes in heartbeat, palpitations, dizziness, lightheadedness, fainting, and changes in or new use of heart or blood pressure medications.
• Ceritinib can cause pancreatitis and you will need periodic tests to monitor pancreatic enzyme levels. Report to your physician if you develop upper abdominal pain, nausea, vomiting, bloating or loss of appetite.
• Store ceritinib safely out of reach of children.
• In case of overdose, seek medical help by contacting Poison Control.