Ceritinib

Grapefruit and grapefruit juice may interact with ceritinib and lead to unwanted side effects. Avoid the use of grapefruit products while taking ceritinib.

Many drugs can interact with ceritinib. Not all possible interactions are listed here. Tell your doctor about all your medications and any you start or stop using during treatment with ceritinib, especially:

• celecoxib;
• nefazodone;
• St. John's wort;
• tolbutamide;
• warfarin (Coumadin, Jantoven);
• an antibiotic--clarithromycin, telithromycin;
• antifungal medicine--itraconazole, ketoconazole, posaconazole, voriconazole;
• heart or blood pressure medicine--nicardipine, quinidine;
• antiviral medicine to treat hepatitis or HIV/AIDS--atazanavir, boceprevir, cobicistat, delavirdine, efavirenz, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, telaprevir;
• seizure medicine--carbamazepine, phenytoin; or
• tuberculosis medicine--isoniazid, rifampin.

This list is not complete and many other drugs can interact with ceritinib. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

Serious side effects have been reported with ceritinib. See the “Ceritinib Precautions” section.

• diarrhea
• nausea
• vomiting
• constipation
• abdominal pain
• fatigue
• decreased appetite
• elevated liver enzymes

This is not a complete list of ceritinib side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if ceritinib crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using ceritinib.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• other medications you are taking
• certain side effects

The recommended dose of ceritinib for the treatment of non-small cell lung cancer is 750 mg once daily.

Ceritinib is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Ceritinib is used to treat non-small cell lung cancer that has spread to other parts of the body. Ceritinib is used only if your tumor has a specific genetic marker, for which your doctor will test.

Ceritinib may also be used for purposes not listed in this medication guide.

Usual Adult Dose for Non-Small Cell Lung Cancer:

750 mg orally once daily on an empty stomach.

Duration of therapy: Until disease progression or unacceptable toxicity

Comments:
-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.
-An improvement in survival or disease-related symptoms has not been established

Use: 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.

Sometimes it is not safe to use certain medications at the same time. Some drugs can affect your blood levels of other drugs you take, which may increase side effects or make the medications less effective.

Many drugs can interact with ceritinib. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Tell your doctor about all your current medicines and any medicine you start or stop using.

Antineoplastic agent; an inhibitor of several receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK).1 2 3

General

• Monitor liver function tests monthly and as clinically indicated.1 More frequent repeat testing recommended in patients who develop elevated serum transaminase concentrations during therapy.1 (See Hepatic Toxicity under Dosage and Administration.)

• Monitor serum glucose concentrations as clinically indicated.1 (See Hyperglycemia under Dosage and Administration.)

Restricted Distribution Program

• Obtain ceritinib through a limited network of specialty pharmacies.5

  Contact manufacturer at 888-669-6682 or consult the Zykadia website () for specific availability information.1 5

Administration

Oral Administration

Administer orally once daily on an empty stomach (i.e., ≥2 hours before or after a meal).1 Systemic exposure when administered with a meal may exceed that of a typical dose taken in a fasted state, resulting in increased adverse effects.1 (See Food under Pharmacokinetics.)

If a dose of ceritinib is missed, do not take the missed dose within 12 hours of the next dose.1 (See Advice to Patients.)

Dosage

Adults

750 mg (five 150-mg capsules) once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

In the principal efficacy study, ≥1 dosage reduction was required in approximately 60% of patients (most commonly for GI toxicity); median time to first dosage reduction was 7 weeks.1 3

When dosage reduction is necessary, reduce daily dosage in decrements of 150 mg.1

If a dosage of 300 mg daily requires further reduction, discontinue the drug.1

If ALT or AST concentrations >5 times ULN with total bilirubin concentrations ≤2 times ULN occur, interrupt therapy.1 When liver function tests return to baseline or ≤3 times ULN, may resume ceritinib with a 150-mg dosage reduction.1

If ALT or AST concentrations >3 times ULN with total bilirubin concentrations >2 times ULN occur without cholestasis or hemolysis, permanently discontinue drug.1

If treatment-related interstitial lung disease/pneumonitis of any grade occurs, permanently discontinue drug.1 (See Interstitial Lung Disease (ILD)/Pneumonitis under Cautions.)

If QTc-interval prolongation >500 msec on ≥2 separate ECGs occurs, interrupt ceritinib therapy.1 Once QTc-interval prolongation improves to <481 msec or returns to baseline (if baseline QTc interval ≥481 msec), may resume ceritinib with a 150-mg dosage reduction.1

If QTc-interval prolongation occurs concurrently with torsades de pointes, polymorphic ventricular tachycardia, or signs and/or symptoms of serious arrhythmia, permanently discontinue drug.1 (See Prolongation of QT Interval under Cautions.)

If symptomatic, but non-life-threatening, bradycardia occurs, interrupt ceritinib therapy until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats per minute occurs.1 Evaluate concomitant medications known to cause bradycardia, and adjust dosage of ceritinib.1 (See Interactions.)

If clinically significant bradycardia requiring intervention or life-threatening bradycardia occurs in patients receiving concomitant medications known to cause bradycardia or hypotension, interrupt ceritinib therapy until recovery to asymptomatic bradycardia or to a heart rate of ≥60 beats per minute occurs.1 If therapy with the concomitant medication can be adjusted or discontinued, may resume ceritinib with a 150-mg dosage reduction and frequent monitoring.1

If life-threatening bradycardia occurs in patients not receiving concomitant medications known to cause bradycardia or hypotension, permanently discontinue drug.1 (See Bradycardia under Cautions.)

If severe or intolerable nausea, vomiting, or diarrhea occurs despite appropriate medical therapy (e.g., antiemetics, antidiarrhea agents), interrupt therapy.1 Once GI toxicity improves, may resume ceritinib with a 150-mg dosage reduction.1 (See Severe or Persistent GI Toxicity under Cautions.)

If persistent hyperglycemia with serum glucose concentrations >250 mg/dL occurs despite optimal antidiabetic agent therapy, interrupt therapy.1 Once adequate control of hyperglycemia is achieved, may resume ceritinib with a 150-mg dosage reduction.1 However, if hyperglycemia persists despite optimal medical management, discontinue ceritinib.1 (See Hyperglycemia under Cautions.)

Special Populations

Hepatic Impairment

Possible increased exposure to ceritinib.1

Moderate or severe hepatic impairment: Recommended dosage not determined.1 (See Hepatic Impairment under Cautions.)

Mild hepatic impairment: Dosage adjustment not necessary.1

Renal Impairment

No specific dosage recommendations.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations.1 (See Geriatric Use under Cautions.)

Metabolized principally by CYP3A4.1 Substrate of CYP3A and P-glycoprotein (P-gp) in vitro.1

May inhibit CYP isoenzymes 3A and 2C9 at clinically relevant concentrations; does not induce CYP isoenzymes 1A2, 2B6, or 2C9.1 6 Induces CYP3A4 in vitro.6

In vitro, not a substrate or inhibitor of breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) 2, organic cation transporter (OCT) 1, organic anion transporter (OAT) 2, or organic anion transport protein (OATP) 1B1.1 Does not inhibit apical efflux transporters, P-gp, OATP1B3, renal organic anion transporters (OAT) 1 and OAT3, or OCT2 in vitro at clinically relevant concentrations.1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased systemic exposure of ceritinib).1 Avoid concomitant use.1 If concomitant use cannot be avoided, reduce daily dosage of ceritinib by approximately 33% and round to the nearest 150-mg strength (e.g., from 750 mg daily to 450 mg daily).1 If the potent CYP3A inhibitor is discontinued, resume ceritinib therapy at the dosage used prior to initiation of the potent CYP3A inhibitor.1

Potent CYP3A inducers: Possible pharmacokinetic interaction (decreased systemic exposure of ceritinib).1 Avoid concomitant use.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A: Possible pharmacokinetic interaction (increased plasma concentrations of CYP3A substrate).1 Avoid concomitant use of ceritinib and CYP3A substrates that have a narrow therapeutic index or substrates primarily metabolized by CYP3A.1 If concomitant use of CYP3A substrates with a narrow therapeutic index cannot be avoided, consider dosage reduction of the CYP3A substrate.1

Substrates of CYP2C9: Possible pharmacokinetic interaction (increased plasma concentrations of CYP2C9 substrate).1 Avoid concomitant use of ceritinib and CYP2C9 substrates that have a narrow therapeutic index or substrates primarily metabolized by CYP2C9.1 If concomitant use of CYP2C9 substrates with a narrow therapeutic index cannot be avoided, consider dosage reduction of the CYP2C9 substrate.1

Inhibitors of P-gp

P-gp inhibitors: Potential pharmacokinetic interaction (increased plasma ceritinib concentrations).1

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT-interval prolongation).1 Periodically monitor ECGs and electrolytes during concomitant use.1 (See Prolongation of QT Interval under Cautions.)

Drugs associated with Bradycardia

Potential pharmacologic interaction (increased risk of bradycardia).1 Avoid concomitant use, if possible.1 (See Bradycardia under Cautions.)

Drugs Affecting Gastric Acidity

Potential pharmacokinetic interaction (decreased solubility and reduced oral bioavailability of ceritinib) with drugs that increase gastric pH.1 6

Specific Drugs and Foods

(se RI ti nib)

Preexisting mild impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST): No dosage adjustment is necessary.

Preexisting moderate or severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Ceritinib is primarily metabolized and eliminated hepatically; exposure is likely increased in patients with hepatic impairment.

Hepatotoxicity during treatment:

ALT or AST >5 times ULN with total bilirubin ≤2 times ULN: Interrupt therapy until recovery to baseline or ALT/AST ≤3 times ULN, then resume with a 150 mg dose reduction.

ALT or AST >3 times ULN with total bilirubin >2 times ULN in the absence of cholestasis or hemolysis: Permanently discontinue therapy.

Commonly reported side effects of ceritinib include: abdominal pain, diarrhea, hyperglycemia, increased serum alanine aminotransferase, nausea, and vomiting. Other side effects include: interstitial pulmonary disease, pneumonitis, and prolonged qt interval on ecg. See below for a comprehensive list of adverse effects.

Mild to moderate renal impairment (CrCl 30 to less than 90 mL/min): No adjustment recommended.
Severe renal impairment (CrCl less than 30 mL/min): Data not available

May cause fetal harm. US FDA pregnancy category: D Comments: Advise females of reproductive potential to use effective contraception during treatment and for at least 2 weeks following completion of therapy.

Animal studies during organogenesis at levels less than the recommended human dose showed increased skeletal anomalies including incomplete ossification and skeletal variations; low incidence of visceral anomalies, including absent or malpositioned gallbladder and retroesophageal subclavian cardiac artery were also seen. Maternal toxicity and abortion occurred in rabbits at doses of 35 mg/kg or higher; embryolethality was observed at a dose of 50 mg/kg. There is no controlled data in human pregnancy. US FDA pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.