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Ceritinib
10:00 • Antineoplastic Agents (AHFS primary)
■ Ceritinib, an inhibitor of several receptor tyrosine ...
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or severe hepatic impairment has not been determined. (See Hepatic Impairment under
Warnings/Precautions: Spec...
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Renal Impairment.
Formal pharmacokinetic studies of ceritinib have not been conducted in patients
with renal i...
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(CYP) isoenzyme 3A4. The drug is 97% bound to plasma proteins. Following oral
administration of a single 750-m...
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Ahfs drug information monograph novabooks

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AHFS Drug Information

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Ahfs drug information monograph novabooks

  1. 1. Page 1 of 4 Ceritinib 10:00 • Antineoplastic Agents (AHFS primary) ■ Ceritinib, an inhibitor of several receptor tyrosine kinases including anaplastic lymphoma kinase (ALK), is an antineoplastic agent. Uses ■ Non-small Cell Lung Cancer Ceritinib is used for the treatment of adults with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) following failure (secondary to resistance or intolerance) of prior crizotinib therapy. The drug has been designated an orphan drug by the FDA for use in this condition. The accelerated approval of ceritinib for this indication is based on tumor response rate and duration of response; there currently are no clinical data demonstrating an improvement in survival or disease-related symptoms with the drug. Continued approval for this indication may be contingent on verification and description of clinical benefit of ceritinib in confirmatory studies. The results of several studies indicate that a relatively small subset of patients with NSCLC (approximately 1–7%) have ALK-positive disease, which indicates potential responsiveness to ALK inhibitor therapy (e.g., ceritinib, crizotinib). Patients with this form of lung cancer typically are nonsmokers or have a history of light smoking and often have adenocarcinoma. Patients with ALK-positive NSCLC usually are initially sensitive to crizotinib but eventually become resistant, limiting the drug's long-term therapeutic potential. (See Description.) The current indication for ceritinib is based principally on the results of a multicenter, single-arm, open-label study that enrolled 163 adult patients with metastatic ALK-positive NSCLC whose cancer had progressed with or who were intolerant of crizotinib. All patients in this study received an initial ceritinib dosage of 750 mg once daily. The primary efficacy end point was overall response rate (as evaluated by both investigators and a Blinded Independent Central Review Committee [BIRC]); an additional outcome measure was duration of response. The median age of patients enrolled in the study was 52 years; 91% of the patients had progressed during crizotinib therapy and 93% had adenocarcinoma histology. In the efficacy analysis, the BIRC-assessed overall response rate with ceritinib was 43.6%; partial responses were achieved in 41.1% of patients and 2.5% had a complete response. The investigator- assessed overall response rate with ceritinib was comparable (54.6%), with partial responses achieved in 53.4% of patients and complete responses achieved in 1.2% of patients. The median BIRC-assessed duration of response was 7.1 months, and the median investigator-assessed duration of response was similar (7.4 months). Phase 3 controlled trials comparing ceritinib as single-agent therapy with standard- of-care chemotherapy in patients with treatment-naive, or previously treated, ALK- positive NSCLC are underway. Ceritinib currently is not indicated for use in patients with treatment-naive ALK-positive NSCLC†. Dosage and Administration ■ General Because ceritinib may cause hepatotoxicity, the manufacturer states that liver function tests should be monitored monthly and as clinically indicated. More frequent repeat testing is recommended in patients who develop elevated serum transaminase concentrations during therapy. (See Hepatic Toxicity under Dosage: Dosage Modification, in Dosage and Administration.) Because ceritinib may cause hyperglycemia, the manufacturer states that serum glucose concentrations should be monitored during therapy as clinically indicated. (See Hyperglycemia under Dosage: Dosage Modification, in Dosage and Administration.) Restricted Distribution Program Ceritinib can only be obtained through a limited network of specialty pharmacies. Clinicians may contact the manufacturer (Novartis) by telephone at 888-669-6682 or consult the Zykadia® website for specific availability information (http:// www.zykadia.com/health-care-professional/pharmacy-network.jsp). ■ Administration Ceritinib is administered orally once daily on an empty stomach (i.e., the drug should be taken at least 2 hours before or after a meal). Systemic exposure when the drug is administered with a meal may exceed that of a typical dose taken in a fasted state and result in increased adverse effects. (See Description.) ■ Dosage Non-small Cell Lung Cancer The recommended adult dosage of ceritinib for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) following failure (secondary to resistance or intolerance) of prior crizotinib therapy is 750 mg (five 150-mg capsules) once daily. Ceritinib therapy should be continued until disease progression or unacceptable toxicity occurs. Dosage Modification for Toxicity In the principal efficacy study, at least one dosage reduction from the recommended initial ceritinib dosage (750 mg once daily) was necessary in approximately 60% of patients (most commonly for GI toxicity); the median time to the first dosage reduction was 7 weeks. When dosage modification is necessary, the daily dosage of ceritinib should be reduced in decrements of 150 mg; however, if a dosage of 300 mg daily requires further reduction, ceritinib should be discontinued. Hepatic Toxicity. If an elevation in serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) concentrations exceeding 5 times the upper limit of normal (ULN) occurs with an elevation in total bilirubin concentrations no more than 2 times the ULN, ceritinib therapy should be withheld until the liver function test results return to baseline values or decrease to no more than 3 times the ULN. Ceritinib therapy may then be resumed with a 150-mg dosage reduction. If an elevation in ALT or AST concentrations exceeding 3 times the ULN occurs with an elevation in total bilirubin concentrations exceeding 2 times the ULN in the absence of cholestasis or hemolysis, therapy with ceritinib should be permanently discontinued. (See Hepatic Toxicity under Cautions: Warnings/Precautions.) Interstitial Lung Disease/Pneumonitis. If treatment-related interstitial lung disease/pneumonitis of any grade occurs, ceritinib therapy should be permanently discontinued. (See Interstitial Lung Disease/ Pneumonitis under Cautions: Warnings/Precautions.) Cardiovascular Toxicity. If corrected QT (QTc) interval exceeds 500 msec on at least 2 separate ECGs, ceritinib therapy should be withheld until the QTc interval is less than 481 msec or returns to baseline (if baseline QTc interval is 481 msec or more). Ceritinib therapy may then be resumed with a 150-mg dosage reduction. If QTc-interval prolongation occurs concurrently with torsades de pointes, polymorphic ventricular tachycardia, or signs and/or symptoms of serious arrhythmia, ceritinib therapy should be permanently discontinued. (See Prolongation of QT Interval under Cautions: Warnings/Precautions.) If symptomatic, but non-life-threatening, bradycardia occurs, therapy with ceritinib should be withheld until recovery to asymptomatic bradycardia or to a heart rate of 60 beats per minute or more occurs. Concomitant medications known to cause bradycardia should be evaluated, and the dosage of ceritinib should be adjusted. (See Drug Interactions: Drugs Associated with Bradycardia.) If clinically significant bradycardia requiring intervention or life-threatening bradycardia occurs in patients receiving concomitant medications known to cause bradycardia or hypotension, therapy with ceritinib should be withheld until recovery to asymptomatic bradycardia or to a heart rate of 60 or more beats per minute occurs. If therapy with the concomitant medication can be adjusted or discontinued, ceritinib therapy may then be resumed with a 150-mg dosage reduction and frequent monitoring. If life-threatening bradycardia occurs in patients not receiving concomitant medications known to cause bradycardia or hypotension, ceritinib therapy should be permanently discontinued. (See Bradycardia under Cautions: Warnings/Precautions.) GI Toxicity. In patients experiencing severe or intolerable nausea, vomiting, or diarrhea despite appropriate medical therapy (e.g., antiemetics, antidiarrhea agents), ceritinib therapy should be withheld until the GI symptoms have improved. Ceritinib may then be resumed with a 150-mg dosage reduction. (See Severe or Persistent GI Toxicity under Cautions: Warnings/Precautions.) Hyperglycemia. If persistent hyperglycemia with serum glucose concentrations exceeding 250 mg/dL occurs despite optimal antidiabetic agent therapy, ceritinib therapy should be withheld until adequate control of the hyperglycemia is achieved. Ceritinib therapy may then be resumed with a 150-mg dosage reduction. However, if hyperglycemia persists despite optimal medical management, ceritinib therapy should be discontinued. (See Hyperglycemia under Cautions: Warnings/Precautions.) Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes Concomitant use of ceritinib with drugs that are potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A should be avoided. If concomitant use of a potent CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the daily dosage of ceritinib by approximately 33% and rounding dosage to the nearest 150-mg strength of ceritinib capsules (e.g., from 750 mg daily to 450 mg daily). If concomitant use of the potent CYP3A inhibitor is discontinued, the ceritinib dosage should be returned to the dosage used prior to initiation of the potent CYP3A inhibitor. (See Inhibitors of CYP3A under Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.) ■ Special Populations Patients with hepatic impairment may have an increased exposure to ceritinib. No dosage adjustment is necessary in patients with mild hepatic impairment. The manufacturer states that the recommended dosage of ceritinib in patients with moderate
  2. 2. Page 2 of 4 or severe hepatic impairment has not been determined. (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.) There are currently no special dosage recommendations for geriatric patients or patients with renal impairment. (See Geriatric Use and also see Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.) Cautions ■ Contraindications The manufacturer states that there are no known contraindications to the use of ceritinib. ■ Warnings/Precautions Severe or Persistent GI Toxicity Diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of patients receiving the recommended dosage of ceritinib (750 mg once daily) in the principal efficacy study, with severe cases reported in 14% of the patients. Over one-third (38%) of patients in this study required dosage modification. Patients receiving ceritinib should be monitored for development of GI toxicity and treated as necessary with appropriate therapy (e.g., antidiarrhea agents, antiemetics, fluid replacement). Temporary interruption, followed by dosage reduction or discontinuance of ceritinib may be necessary depending on the severity of the GI toxicity. (See GI Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.) Hepatic Toxicity Drug-induced hepatotoxicity has occurred in patients receiving ceritinib. Elevations in alanine aminotransferase (ALT) exceeding 5 times the upper limit of normal (ULN) were reported in 27% of ceritinib-treated patients in the primary efficacy study; permanent discontinuance of the drug due to transaminase elevations and jaundice was necessary in 1 of 255 patients (0.4%) in this study. The manufacturer states that liver function tests, including ALT, aspartate aminotransferase (AST), and total bilirubin, should be monitored once every month and as clinically indicated during ceritinib therapy, with more frequent testing in patients who develop transaminase elevations during therapy. Temporary interruption, followed by dosage reduction or permanent discontinuance of ceritinib may be necessary depending on the severity of the hepatic toxicity. (See Hepatic Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.) Interstitial Lung Disease/Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis may occur in patients receiving ceritinib. In the primary efficacy study, pneumonitis occurred in 4% of ceritinib-treated patients, grade 3 or 4 ILD or pneumonitis occurred in 3% of patients, and fatal ILD/pneumonitis was reported in one patient (0.4%). Discontinuance of ceritinib due to ILD or pneumonitis occurred in 1% of ceritinib- treated patients. Patients receiving ceritinib should be monitored for pulmonary symptoms indicative of ILD or pneumonitis (see Advice to Patients), and other potential causes of ILD or pneumonitis should be excluded. Ceritinib should be permanently discontinued in patients who are diagnosed with treatment-related ILD or pneumonitis. (See Interstitial Lung Disease/Pneumonitis under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.) Prolongation of QT Interval Prolongation of the corrected QT (QTc) interval has been reported in patients receiving ceritinib. The prolongation appears to occur in a plasma concentration- dependent manner. An increase in the QTc interval exceeding 60 msec from baseline occurred in 3% of patients receiving ceritinib in the primary efficacy study. In the clinical development program, a QTc interval exceeding 500 msec occurred in one of 304 ceritinib-treated patients (less than 1%) and 3% of ceritinib-treated patients had an increase exceeding 60 msec from baseline; dosages in these studies ranged from 50– 750 mg daily. Ceritinib should be avoided in patients with congenital long QT syndrome, if possible. The manufacturer recommends periodic monitoring of ECGs and serum electrolytes during ceritinib therapy in patients with congestive heart failure, bradyarrhythmias, or electrolyte abnormalities and in those who are receiving drugs known to prolong the QT interval. (See Drug Interactions: Drugs that Prolong the QT Interval.) Temporary interruption, followed by dosage reduction of ceritinib is necessary when the QTc interval exceeds 500 msec on at least 2 separate ECGs. When QTc- interval prolongation occurs concurrently with torsades de pointes, polymorphic ventricular tachycardia, or signs and/or symptoms of serious arrhythmia, ceritinib therapy should be permanently discontinued. (See Cardiovascular Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.) Hyperglycemia Hyperglycemia has been reported in patients receiving ceritinib. In the primary efficacy study, grade 3 or 4 hyperglycemia occurred in 13% of ceritinib-treated patients. The risk of grade 3 or 4 hyperglycemia was increased by sixfold in patients with diabetes or glucose intolerance and by twofold in those concurrently receiving corticosteroids. Serum glucose concentrations should be monitored in patients receiving ceritinib as clinically indicated. Antidiabetic agents should be initiated or optimized as necessary. Temporary interruption, followed by dosage reduction or discontinuance of ceritinib may be necessary depending on the severity of the hyperglycemia. (See Hyperglycemia under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.) Bradycardia Ceritinib may cause bradycardia. In the primary efficacy study, sinus bradycardia (defined as a heart rate of less than 50 beats per minute) was reported as a new finding in 1% of ceritinib-treated patients; bradycardia was reported as an adverse drug reaction in 3% of patients in this study. Ceritinib should be avoided in patients who are receiving other drugs known to cause bradycardia when possible. (See Drug Interactions: Drugs associated with Bradycardia.) Heart rate and blood pressure should be monitored regularly in all patients receiving ceritinib. Temporary interruption, followed by dosage reduction is necessary if non-life- threatening, symptomatic bradycardia occurs. If life-threatening bradycardia occurs in patients who are not concomitantly receiving medications known to cause bradycardia or hypotension, ceritinib therapy should be permanently discontinued. However, if associated with a concomitant medication known to cause bradycardia or hypotension, ceritinib should be withheld until recovery to asymptomatic bradycardia or to a heart rate of 60 beats per minute or more occurs. If the concomitant medication can be adjusted or discontinued, ceritinib therapy can be resumed at a reduced dosage upon recovery to asymptomatic bradycardia or to a heart rate of 60 beats per minute or more occurs; such patients should be monitored frequently. (See Cardiovascular Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.) Fetal/Neonatal Morbidity and Mortality Based on its mechanism of action, ceritinib may cause fetal harm if administered to pregnant women. Ceritinib produced developmental toxicity, including dose-related skeletal abnormalities (e.g., delayed or incomplete ossification, skeletal variations) and a low incidence of visceral abnormalities, when administered to pregnant animals in dosages associated with exposure levels lower than those associated with the recommended human dosage; maternal toxicity, abortion, and embryolethality also were observed. Pregnancy should be avoided during therapy. Women of childbearing potential should use effective methods of contraception while receiving the drug and for at least 2 weeks after the drug is discontinued. If ceritinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard. (See Advice to Patients.) Specific Populations Pregnancy. Category D. (See Users Guide and also see Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.) Lactation. It is not known whether ceritinib or its metabolites are distributed into human milk. Because many drugs are distributed into human milk and because of the potential for serious adverse reactions to ceritinib in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. Pediatric Use. Safety, efficacy, and pharmacokinetics of ceritinib have not been established in pediatric patients. Geriatric Use. Clinical studies of ceritinib did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults. In the primary efficacy trial evaluating ceritinib in patients with metastatic anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), 16% of patients receiving ceritinib at the recommended dosage were 65 years of age or older. In pharmacokinetic population analyses, age did not have a clinically important effect on the systemic exposure of ceritinib in adults. Hepatic Impairment. Formal pharmacokinetic studies of ceritinib have not been conducted in patients with hepatic impairment. However, ceritinib is eliminated principally by the liver and increased exposure to the drug may occur in patients with hepatic impairment. In a population pharmacokinetic analysis, the systemic exposure to ceritinib was similar in patients with mild hepatic impairment (total bilirubin concentration no more than the ULN with AST concentration exceeding the ULN or total bilirubin concentration exceeding 1–1.5 times the ULN with any AST concentration) and those with normal hepatic function. Ceritinib dosage adjustment is not recommended in patients with mild hepatic impairment. Because the pharmacokinetics of ceritinib have not been studied in patients with moderate to severe hepatic impairment, the recommended dosage of the drug has not yet been determined in such patients.
  3. 3. Page 3 of 4 Renal Impairment. Formal pharmacokinetic studies of ceritinib have not been conducted in patients with renal impairment. In a population pharmacokinetic analysis, the pharmacokinetics of ceritinib were similar in patients with mild (creatinine clearance of 60–89 mL/ minute) or moderate (creatinine clearance of 30–59 mL/minute) renal impairment compared with patients with normal renal function. Patients with severe renal impairment (creatinine clearance less than 30 mL/minute) were not included in the clinical trials. ■ Common Adverse Effects Adverse effects reported in more than 10% of patients receiving ceritinib in the main efficacy trial include diarrhea, nausea, vomiting, abdominal pain, constipation, esophageal disorder (including dyspepsia, gastroesophageal reflux disease, and dysphagia), fatigue, decreased appetite, neuropathy (including paresthesia, muscular weakness, gait disturbance, peripheral neuropathy, hypoesthesia, peripheral sensory neuropathy, dysesthesia, neuralgia, peripheral motor neuropathy, hypotonia, and polyneuropathy), and rash. Laboratory abnormalities reported in more than 10% of patients receiving ceritinib in the main efficacy trial include anemia, elevated concentrations of transaminases (i.e., ALT, AST), elevated concentrations of serum creatinine, hyperglycemia, hypophosphatemia, increased lipase concentrations, and hyperbilirubinemia. Drug Interactions Ceritinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4. In vitro, ceritinib is a substrate of CYP3A and P-glycoprotein (P-gp). In vitro studies also indicate that ceritinib may inhibit CYP isoenzymes 3A and 2C9 at clinically relevant concentrations. In vitro, ceritinib induces CYP3A4, but does not induce CYP isoenzymes 1A2, 2B6, or 2C9. In vitro, ceritinib is 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. Ceritinib also 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. ■ Drugs Affecting Hepatic Microsomal Enzymes Inhibitors of CYP3A Concomitant use of ceritinib with potent inhibitors of CYP3A is likely to increase systemic exposure of ceritinib. When the potent CYP3A inhibitor ketoconazole (200 mg twice daily for 14 days) was administered concomitantly with ceritinib (as a single 450-mg dose) in healthy individuals, AUC and peak plasma concentrations of ceritinib increased by 2.9-fold and 22%, respectively. The steady-state AUC of ceritinib following concurrent administration of ketoconazole (200 mg twice daily for 14 days) with reduced dosages of ceritinib is expected to be similar to the steady-state AUC of ceritinib alone. Concomitant use of potent CYP3A inhibitors, including certain antivirals (e.g., ritonavir), macrolide antibiotics (e.g., telithromycin), antifungals (e.g., ketoconazole), and nefazodone, should be avoided during ceritinib therapy. If concomitant use of a potent CYP3A inhibitor cannot be avoided, the manufacturer recommends reducing the daily dosage of ceritinib by approximately 33% and rounding to the nearest 150-mg strength of ceritinib capsules (e.g., from 750 mg daily to 450 mg daily). If concomitant use of the potent CYP3A inhibitor is discontinued, the ceritinib dosage should be returned to the dosage used prior to initiation of the potent CYP3A4 inhibitor. Inducers of CYP3A Concomitant use of ceritinib with potent inducers of CYP3A (e.g., carbamazepine, phenytoin, rifampin) may result in decreased systemic exposure of ceritinib and should be avoided. When the potent CYP3A4 inducer rifampin (600 mg daily for 14 days) was administered concomitantly with ceritinib (as a single 750-mg dose) in healthy individuals, AUC and peak plasma concentrations of ceritinib decreased by 70 and 44%, respectively. Use of St. John's wort (Hypericum perforatum), a potent CYP3A inducer, also should be avoided during ceritinib therapy. ■ Drugs Metabolized by Hepatic Microsomal Enzymes Substrates of CYP3A Ceritinib may inhibit CYP3A at clinically relevant concentrations and potentially can increase plasma concentrations of other drugs metabolized by CYP3A. Concomitant use of ceritinib with CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) or substrates primarily metabolized by CYP3A should be avoided. If concomitant use of CYP3A substrates with a narrow therapeutic index cannot be avoided, a dosage reduction of the CYP3A substrate should be considered. Substrates of CYP2C9 Ceritinib may inhibit CYP2C9 at clinically relevant concentrations and potentially can increase plasma concentrations of other drugs metabolized by CYP2C9. Concomitant use of ceritinib with CYP2C9 substrates that have a narrow therapeutic index (e.g., phenytoin, warfarin) or substrates principally metabolized by CYP2C9 should be avoided. If concomitant use of CYP2C9 substrates with a narrow therapeutic index cannot be avoided, a dosage reduction of the CYP2C9 substrate should be considered. ■ Drugs Affecting the P-glycoprotein Transport System Ceritinib is a substrate of the efflux transporter P-glycoprotein (P-gp). If ceritinib is administered with drugs that inhibit P-gp (e.g., ketoconazole), increased concentrations of ceritinib may occur. ■ Drugs that Prolong the QT Interval Because ceritinib has been associated with QT-interval prolongation, the manufacturer recommends periodic monitoring of ECGs and electrolytes in ceritinib- treated patients concurrently receiving other drugs known to prolong the QT interval, including class IA antiarrhythmics (e.g., quinidine, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), some antipsychotic agents (e.g., chlorpromazine, haloperidol, pimozide, thioridazine), citalopram, and clarithromycin. (See Prolongation of QT Interval under Cautions: Warnings/Precautions.) ■ Drugs Associated with Bradycardia Because ceritinib has been associated with bradycardia, the manufacturer recommends that concurrent use with other drugs known to cause bradycardia (e.g., β- adrenergic blocking agents, nondihydropyridine calcium-channel blocking agents [e.g., diltiazem, verapamil], clonidine, digoxin) be avoided, if possible. (See Bradycardia under Cautions: Warnings/Precautions.) ■ Drugs Affecting Gastric Acidity Although formal studies with ceritinib have not been conducted to date, the possibility exists that drugs that increase gastric pH (e.g., antacids, histamine H2- receptor antagonists, proton-pump inhibitors) may decrease the solubility of ceritinib and subsequently reduce its bioavailability. ■ Grapefruit Grapefruit products are CYP3A inhibitors and should be avoided because of the potential for increased plasma ceritinib concentrations during concurrent use. Description Ceritinib, an inhibitor of receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK), insulin-like growth factor receptor-1 (IGFR-1), insulin receptor, and c-ros oncogene-1 (ROS-1), is an antineoplastic agent. Among these tyrosine kinases, ceritinib is most active against ALK. Activating mutations or translocations of the ALK gene have been identified in several malignancies and can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 [EML4]-ALK). Such ALK gene rearrangements have been identified in approximately 1–7% of patients with NSCLC. Formation of ALK fusion proteins such as EML4-ALK results in activation and dysregulation of the gene's expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins. In vitro and in vivo, ceritinib has demonstrated inhibition of ALK phosphorylation, ALK- mediated phosphorylation of the downstream signaling protein signal transducer and activator of transcription-3 (STAT-3), and proliferation of ALK-dependent cancer cells. In vitro, ceritinib inhibited proliferation of cell lines that expressed EML4-ALK and nucleophosmin (NPM)-ALK fusion proteins. The drug also has demonstrated dose- dependent inhibition of EML4-ALK in mice and rats bearing NSCLC tumor xenografts that expressed EML4-ALK. In vitro, ceritinib is approximately 20-fold more potent than crizotinib in its activity against ALK. At clinically relevant concentrations, ceritinib has demonstrated dose-dependent antitumor activity in mice bearing NSCLC tumor xenografts that expressed EML4- ALK with demonstrated resistance to crizotinib. Clinical resistance to crizotinib has been attributed to several possible resistance mechanisms. Limited data to date suggest that secondary mutations of ALK (e.g., L1196M, G1269A) are responsible for only about 30% of cases of acquired crizotinib resistance. The remaining cases appear to be due to several other resistance mechanisms, such as activation of alternate signaling pathways, expression of another oncogenic fusion protein, or gene amplification. In preclinical studies in cell-line models, ceritinib inhibited several crizotinib-resistant ALK kinase domain mutant forms. The absolute bioavailability of ceritinib has not been established. Peak plasma concentrations of ceritinib are achieved about 4–6 hours following single-dose, oral administration of the drug. Following repeated administration of ceritinib 50– 750 mg once daily, systemic exposure increases in a greater than dose-proportional manner. Following multiple-dose administration of ceritinib 750 mg daily, steady-state concentrations of the drug were achieved in approximately 15 days. Systemic exposure to ceritinib is increased when the drug is administered with food. Oral administration of a single 500-mg dose of ceritinib with a low-fat (approximately 330 calories and 9 g of fat) or high-fat meal (approximately 1000 calories and 58 g of fat) resulted in increases in systemic exposure of 58 or 73%, respectively, and increases in peak plasma concentrations by 43 or 41%, respectively, compared with the fasted state. Administration of a 600 mg or higher dose of ceritinib with a meal is expected to result in an increase in systemic exposure exceeding that of a 750-mg dose taken in a fasted state. Ceritinib is predominantly metabolized by the cytochrome P-450
  4. 4. Page 4 of 4 (CYP) isoenzyme 3A4. The drug is 97% bound to plasma proteins. Following oral administration of a single 750-mg radiolabeled dose of ceritinib, 92.3% of the dose was recovered in feces and 1.3% was recovered in urine; unchanged drug accounted for 68% of the dose recovered in feces. The mean terminal half-life of ceritinib is 41 hours. Advice to Patients Importance of instructing patients to read the manufacturer's patient information. If a dose is missed, importance of advising patients to take it as soon as they remember unless it is less than 12 hours before the next dose, in which case they should not take the missed dose. Importance of informing patients that ceritinib should be taken on an empty stomach since taking the drug with food may increase blood concentrations and the risk of adverse effects; importance of instructing patients not to eat for at least 2 hours before and after taking the drug. Importance of also advising patients to avoid grapefruit and grapefruit juice while taking ceritinib. Importance of informing patients that nausea, vomiting, diarrhea, and abdominal pain are the most common adverse effects associated with ceritinib therapy, as well as supportive treatment options (e.g., antiemetic and/or antidiarrhea agents). Importance of contacting clinician if severe or persistent adverse GI effects occur. Risk of hepatotoxicity; importance of liver function test monitoring. Importance of informing patients of the signs and symptoms of hepatotoxicity (e.g., fatigue, anorexia, nausea, vomiting, abdominal pain [especially right upper quadrant pain], jaundice, dark or “tea-colored” urine, generalized pruritus, unusual bleeding or bruising) and advising them to immediately report possible symptoms of hepatotoxicity to their clinician. Risk of severe or fatal interstitial lung disease/pneumonitis. Importance of advising patients that pneumonitis symptoms may be similar to those of lung cancer and to contact their clinician immediately if they experience any new or worsening pulmonary symptoms (e.g., dyspnea, shortness of breath, cough with or without mucus, chest pain, fever). Risk of QTc-interval prolongation and bradycardia. Importance of informing clinicians immediately if new chest pain or discomfort, changes in heartbeat, palpitations, dizziness, lightheadedness, faintness, or changes in or new use of cardiovascular or antihypertensive therapy occurs. Risk of hyperglycemia, particularly in patients with diabetes or glucose intolerance and in those receiving corticosteroid medications. Importance of informing patients of the signs and symptoms of hyperglycemia (e.g., increased thirst, increased urination, increased appetite, fatigue, blurred vision, headache, difficulty thinking or concentrating, breath that smells like fruit) and advising patients to immediately contact their clinician if they experience such signs and symptoms. Risk of fetal harm. Necessity of advising women of childbearing potential that they should use effective methods of contraception while receiving ceritinib and for at least 2 weeks after discontinuance of therapy. Importance of patients informing their clinicians if they are pregnant or plan to become pregnant. If pregnancy occurs, advise patient of potential risk to the fetus. Importance of advising women to avoid breast-feeding while receiving ceritinib therapy. Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses (e.g., hepatic impairment, cardiovascular disease [including congenital long QT syndrome], diabetes mellitus or hyperglycemia). Importance of informing patients of other important precautionary information. (See Cautions.) Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer’s labeling should be consulted. It is essential that the manufacturer’s labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the pharmacology of antineoplastic agents, resistance, and general principles in cancer chemotherapy, see the Antineoplastic Agents General Statement 10:00 at http:// www.ahfsdruginformation.com. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at http://www.ahfsdruginformation.com. Preparations Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. Distribution of ceritinib is restricted. (See Restricted Distribution under Dosage and Administration: General.) Ceritinib Oral Ceritinib Capsules 150 mg Zykadia ® , Novartis † Use is not currently included in the labeling approved by the US Food and Drug Administration. © Copyright, October 31, 2014, American Society of Health-System Pharmacists, Inc.

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