Ceritinib

Ceritinib is used to treat metastatic non-small cell lung cancer (NSCLC).

Ceritinib is available under the following different brand names: Zykadia.

Dosages of Ceritinib:

Adult Dosage Forms and Strengths

Capsule

• 150 mg

Dosage Considerations – Should be Given as Follows:

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
• Also, see the administration

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 approximately 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 before initiating the strong CYP3A4 inhibitor

ALT/AST elevation

• ALT/AST increase greater than 5 x ULN with total bilirubin up to 2 x ULN: Withhold until recovery to baseline or up to 3 x ULN, then resume with 150-mg dose reduction
• ALT/AST increase greater than 3 x ULN with total bilirubin greater than 2 x ULN in absence of cholestasis or hemolysis: Permanently discontinue

Gastrointestinal

• Lipase or amylase increase 2 x ULN or greater: Withhold and monitor serum lipase and amylase; resume with 150-mg dose reduction after recovery to less than 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 greater 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 ILD/pneumonitis: Permanently discontinue

Prolonged QT interval

• QT interval greater than 500 milliseconds (on at least 2 separate ECGs): Withhold until QTc interval less than 481 milliseconds or recovery to baseline if baseline QTc 481 millisecond or greater, 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 a heart rate of 60 bpm or greater; evaluate concomitant medications known to cause bradycardia, and adjust the dose
• Clinically significant requiring intervention or life-threatening in patients taking the concomitant drug also known to cause bradycardia: Withhold until recovery to asymptomatic bradycardia or a heart rate of 60 bpm or greater; if the 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 approximately 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: http://www.fda.gov/CompanionDiagnostics
• Safety and efficacy not established in pediatric patients

Common side effects of Ceritinib include:

• Increased alanine transaminase (ALT)
• Increased aspartate transaminase (AST)
• 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

Less common side effects of ceritinib include:

• Pericarditis
• Increased lipase

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Severe interactions of ceritinib include:
  • flibanserin
• Ceritinib has serious interactions with at least 80 different drugs.
• Ceritinib has moderate interactions with at least 97 different drugs.
• Mild interactions of ceritinib include:
  • estradiol vaginal

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist. Check with your physician if you have health questions or concerns.

Warnings

• This medication contains ceritinib. Do not take Zykadia if you are allergic to ceritinib or any ingredients contained in this drug.
• Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center immediately.

Contraindications

• None

Effects of Drug Abuse

• No information is available.

Short-Term Effects

• See "What Are Side Effects Associated with Using Ceritinib?"

Long-Term Effects

• See "What Are Side Effects Associated with Using Ceritinib?"

Cautions

• Drug-induced hepatotoxicity reported; monitor ALT, AST, and total bilirubin once monthly and as clinically indicated
• May cause severe, life-threatening, or fatal interstitial lung disease/pneumonitis
• May prolong QT interval; when possible, avoid use in patients with congenital long QT syndrome; periodically monitor ECG and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval
• Hyperglycemia reported; monitor fasting glucose before treatment and periodically thereafter as clinically indicated; initiate or optimize anti-hyperglycemic medications as indicated; withhold then dose reduce, or permanently discontinue therapy
• Pancreatitis reported in less than 1% of patients receiving therapy; monitor lipase and amylase before initiating therapy and periodically thereafter as clinically indicated; based on the severity of laboratory abnormalities, withhold and resume gradually
• Bradycardia reported; avoid coadministration with other drugs known to cause bradycardia
• Based on its mechanism of action, may cause fetal harm when administered to a pregnant woman
• Severe, life-threatening, or fatal ILD/pneumonitis occurred; monitor for pulmonary symptoms indicative of ILD/pneumonitis; exclude other potential causes of ILD/pneumonitis, and permanently discontinue ceritinib in patients diagnosed with treatment-related ILD/pneumonitis

Gastrointestinal adverse reactions

• Diarrhea, nausea, vomiting, or abdominal pain occurs in most patients, of which 14% have severe symptoms; monitor and manage patients using standards of care, including antidiarrheals, antiemetics, or fluid replacement, as indicated; based on the severity of adverse drug reaction, withhold therapy with resumption at reduced dose
• Data in the prescribing information reflect the safety of ceritinib 750 mg daily under fasted conditions in 925 patients with ALK-positive NSCLC across a pool of seven clinical studies at systemic exposures similar to the recommended dose of 450 mg with food
• In a dose optimization study (ASCEND-8), there were no clinically meaningful differences observed in the incidence of toxicities between patients receiving 750 mg daily under fasted conditions and 450 mg with food, except for a reduction in gastrointestinal adverse reactions as described

Drug interactions overview

• Also, see Dosage Modifications
• Coadministration with a strong CYP3A4/P-gp inhibitor (ketoconazole) increased systemic exposure to ceritinib
• Avoid grapefruit and grapefruit juice consumption; may inhibit CYP3A
• Coadministration with a strong CYP3A4/P-gp inducer (rifampin) decreased the systemic exposure to ceritinib
• Avoid concurrent use of CYP3A and CYP2C9 substrates known to have narrow therapeutic indexes or substrates primarily metabolized by CYP3A and CYP2C9 during treatment; if the use of these medications is unavoidable, consider a dose reduction of CYP3A substrates with narrow therapeutic indexes (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) and CYP2C9 substrates with narrow therapeutic indexes (e.g., phenytoin, warfarin)

Pregnancy and Lactation

• 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 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.
• 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.