Ceritinib

Ceritinibis used to treat metastaticnon-small cell lung cancer(NSCLC).

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

Dosages of Ceritinib:

Adult Dosage Forms and Strengths

Capsule

• 150mg

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 anaplasticlymphomakinase (ALK)-positive as detected by anFDA-approved test
• 450 mg orally once daily withfood
• Continue untildiseaseprogression or unacceptabletoxicity
• 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/ASTelevation

• ALT/AST increase greater than 5 x ULN with totalbilirubinup to 2 x ULN: Withhold until recovery tobaselineor 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 ULNinabsence ofcholestasisorhemolysis: Permanently discontinue

Gastrointestinal

• Lipase oramylaseincrease 2 x ULN or greater: Withhold and monitorserumlipase and amylase; resume with 150-mg dose reduction after recovery to less than 1.5 times ULN
• Severe or intolerablenausea, vomiting, ordiarrheadespite optimal antiemetictherapy: 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 hyperglycemiccontrolcannot 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 orpolymorphicventricular tachycardiaor signs/symptoms of seriousarrhythmia: Permanently discontinueBradycardia
• Symptomatic(not life-threatening): Withhold until recovery toasymptomaticbradycardia or aheart rateof 60 bpm or greater; evaluate concomitant medications known to cause bradycardia, and adjust the dose
• Clinically significant requiringinterventionor life-threatening in patients taking the concomitant drug also known to cause bradycardia: Withhold until recovery to asymptomatic bradycardia or aheartrate of 60 bpm or greater; if the concomitantmedicationcan 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 causehypotension: Permanently discontinue

Hepaticimpairment

• Mild-to-moderate (Child-Pugh A to B): No dosage adjustment is necessary
• Severe (Child-Pugh C): Reduce dose by approximately one-third,roundto the nearest multiple of 150 mg dosage strength

Dosing Considerations

• Selection for ceritinib treatment is based on the presence of ALK positivity intumorspecimens
• 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 inpediatricpatients

常见的副作用Ceritinib include:

• Increasedalaninetransaminase (ALT)
• Increased aspartate transaminase (AST)
• Diarrhea
• Increased gamma-glutamyl transpeptidase (GGT)
• Increasedalkaline phosphatase
• Increasedcreatinine
• Nausea
• Vomiting
• Anemia
• High blood sugar(hyperglycemia)
• Fatigue
• Abdominal pain
• Increased amylase
• Decreasedphosphate
• Decreased appetite
• Lowwhite blood cell count(neutropenia)
• Cough
• Weight loss
• Constipation
• Non-cardiacchest pain
• Rash
• Back pain
• Fever
• Headache
• Lowplatelet count(thrombocytopenia)
• Esophagealdisorder
• Increased total bilirubin
• Dizziness
• Prolonged QT interval
• Musculoskeletalpain
• 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 yourphysicianfor additional information about side effects.

If yourdoctorhas directed you to use this medication, your doctor orpharmacistmay 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,healthcare 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:
  • estradiolvaginal

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 aPoison Control Centerimmediately.

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 fatalinterstitiallung disease/pneumonitis
• May prolong QT interval; when possible, avoid use in patients withcongenitallong QT syndrome; periodically monitorECGand electrolytes in patients withcongestive heart failure, bradyarrhythmias,electrolyteabnormalities, or those who are taking medications known to prolong the QTc interval
• Hyperglycemia reported; monitorfastingglucosebefore treatment and periodically thereafter as clinically indicated; initiate or optimizeanti-hyperglycemic medications as indicated; withhold then dose reduce, or permanently discontinue therapy
• Pancreatitisreported 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 oflaboratoryabnormalities, 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 apregnantwoman
• Severe, life-threatening, or fatal ILD/pneumonitis occurred; monitor forpulmonarysymptoms 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, orabdominal疼痛发生在大多数患者,其中14% severe symptoms; monitor and manage patients using standards of care, including antidiarrheals,antiemetics, or fluid replacement, as indicated; based on the severity ofadverse drug reaction, withhold therapy with resumption at reduced dose
• Datain 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 sevenclinicalstudies atsystemicexposures 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 theincidenceof 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
• Avoidgrapefruitand grapefruit juiceconsumption; 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 narrowtherapeuticindexes 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 atmaternalplasmaexposures below the recommended human dose caused increases inskeletalanomalies in rats and rabbits. Pregnant women should be advised of the potential risk to thefetus.
• 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 withfemalepartners of reproductive potential are advised to use condoms during treatment with ceritinib and for 3 months following completion of therapy.
• 没有数据关于ceriti的存在nib 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,breastfeedingis not recommended during treatment with ceritinib and for 2 weeks following completion of therapy.