Ceritinib – Uses, Dosage, Side Effects, Interaction

Use in Cancer

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.

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

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.

References