ceritinib (Rx)

Brand and Other Names:Zykadia
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 150mg
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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 PO qDay with food

Continue until disease progression or unacceptable toxicity

Also see administration

Dosage Modifications

Dose reduction increments

  • Starting dose: 450 mg qDay
  • First dose reduction: 300 mg qDay
  • Second dose reduction: 150 mg qDay
  • 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 >5 x ULN with total bilirubin ≤2 x ULN: Withhold until recovery to baseline or ≤3 x ULN, then resume with 150-mg dose reduction
  • ALT/AST increase >3 x ULN with total bilirubin >2 x ULN in absence of cholestasis or hemolysis: Permanently discontinue

Gastrointestinal

  • Lipase or amylase increase ≥2 x ULN: Withhold and monitor serum lipase and amylase; resume with 150-mg dose reduction after recovery to < 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 >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 >500 msec (on at least 2 separate ECGs): Withhold until QTc interval <481 msec or recovery to baseline if baseline QTc ≥481 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; 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; if concomitant medication can be adjusted or discontinued, resume with a 150-mg dose reduction, with frequent monitoring
  • Life-threatening bradycardia in patient 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: http://www.fda.gov/CompanionDiagnostics

Safety and efficacy not established

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Interactions

Interaction Checker

and ceritinib

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10% (All grades)

            Increased alanine transaminase (ALT) (91%)

            Increased aspartate transaminase (AST) (86%)

            Diarrhea (85%)

            Increased gamma-glutamyl transpeptidase (GGT) (84%)

            Increased alkaline phosphatase (81%)

            Increased creatinine (77%)

            Nausea (69%)

            Vomiting (67%)

            Anemia (67%)

            Hyperglycemia (53%)

            Fatigue (45%)

            Abdominal pain (40%)

            Increased amylase (37%)

            Decreased phosphate (38%)

            Decreased appetite (34%)

            Neutropenia (27%)

            Cough (25%)

            Weight loss (24%)

            Constipation (20%)

            Non-cardiac chest pain (21%)

            Rash (21%)

            Back pain (19%)

            Pyrexia (19%)

            Headache (19%)

            Thrombocytopenia (16%)

            Esophageal disorder (15%)

            Increased total bilirubin (15%)

            Dizziness (12%)

            Prolonged QT interval (12%)

            Musculoskeletal pain (11%)

            Pruritus (11%)

            >10% (Grades 3-4)

            Increased gamma-glutamyl transpeptidase (GGT) (49%)

            Increased alanine transaminase (ALT) (34%)

            Increased aspartate transaminase (AST) (21%)

            Increased alkaline phosphatase (12%)

            1-10% (All Grades)

            Pericarditis (4.2%)

            1-10% (Grade 3-4)

            Hyperglycemia (10%)

            Increased amylase (8%)

            Fatigue (7%)

            Increased lipase (6%)

            Vomiting (5%)

            Diarrhea (4.8%)

            Increased creatinine (4.2%)

            Anemia (4.2%)

            Abdominal pain (3.7%)

            Weight loss (3.7%)

            Decreased phosphate (3.7%)

            Nausea (2.6%)

            Pericarditis (2.6%)

            Neutropenia (2.1%)

            Back pain (1.6%)

            Non-cardiac chest pain (1.6%)

            Decreased appetite (1.1%)

            Rash (1.1%)

            Dizziness (1.1%)

            Thrombocytopenia (1%)

            <1% (Grade 3-4)

            Esophageal disorder (0.5%)

            Musculoskeletal pain (0.5%)

            Increased bilirubin (0.5%)

            Pruritus (0.5%)

            Headache (0.5%)

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            Warnings

            Contraindications

            None

            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 prior to 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 prior to initiating therapy and periodically thereafter as clinically indicated; based on 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 (see Pregnancy)

            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 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 of ceritinib
            • Avoid grapefruit and grapefruit juice consumption; may inhibit CYP3A
            • Coadministration with a strong CYP3A4/P-gp inducer (rifampin) decreased systemic exposure of 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 use of these medications is unavoidable, consider dose reduction of CYP3A substrates with narrow therapeutic indexes (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) and CYP2C9 substrates with narrow therapeutic indexes (eg, phenytoin, warfarin)
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            Pregnancy & Lactation

            Pregnancy

            Based on animal studies and its mechanism of action, therapy can cause fetal harm when administered to a pregnant woman; limited data available on use of in pregnant women are insufficient to inform a risk; administration to rats and rabbits during period of organogenesis at maternal plasma exposures below the recommended human dose caused increases in skeletal anomalies in rats and rabbits; advise pregnant women of potential risk to fetus

            Advise females of reproductive potential to use effective contraception during treatment with and for 6 months following completion of therapy

            Based on potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment and for 3 months following completion of therapy

             Lactation

            There are no data regarding presence of ceritinib or metabolites in human milk; effects of ceritinib on breastfed infant, or effects on milk production; because of potential for serious adverse reactions including gastrointestinal toxicity, hepatotoxicity, pneumonitis, bradycardia and pancreatitis, advise a woman not to breastfeed during treatment and for 2 weeks following completion of therapy

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Tyrosine kinase inhibitor that targets anaplastic lymphoma kinase (ALK), insulinlike growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1

            Inhibits autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells (in vitro and in vivo assays)

            Absorption

            Peak plasma time: 4-6 hr

            High-fat meal increases AUC by 58% and Cmax by 43% compared with fasting (take on empty stomach 2 hr before or 2 hr after meals)

            Distribution

            Protein bound: 97%

            Vd: 4230 L

            Slight preferential distribution to RBCs, relative to plasma, with a mean in vitro blood-to-plasma ratio of 1.35

            Metabolism

            CYP3A (major enzymatic pathway)

            Following a single 750-mg radiolabeled ceritinib dose, ceritinib as the parent compound was the main circulating component (82%) in human plasma

            Elimination

            Half-life: 41 hr

            Clearance: 33.2 L/hr (steady-state); 88.5 L/hr (single dose)

            Excretion: 92.3% feces (68% as unchanged parent compound); 1.3% urine

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            Administration

            Oral Administration

            Take with food

            Missed dose: If a dose is missed, make up that dose unless the next dose is due within 12 hr

            Vomited dose: If vomiting occurs during the course of treatment, do not administer an additional dose; continue with the next scheduled dose

            Storage

            Tablets: Store at room temperature, 25°C (77°F); excursions permitted between 15-30°C (59-86°F)

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
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            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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