Dosing and uses of Zykadia (ceritinib)
Adult dosage forms and strengths
capsule
- 150mg
Non-Small Cell Lung Cancer
Indicated for anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer (NSCLC) in patients who have progressed on or are intolerant to crizotiniB
750 mg PO qDay
Continue until disease progression or unacceptable toxicity
Dosing Modifications
Coadministration with strong CYP3A inhibitors: Avoid if possible; iif concomitant use of a strong CYP3A inhibitor unavoidable, reduce dose by approximately one-third, rounded to nearest multiple of 150 mg dosage strength; after discontinuation of strong CYP3A inhibitor, resume dose that was taken prior to initiating strong CYP3A4 inhibitor
Severe/intolerable nausea, vomiting, or diarrhea despite optimal antiemetic or antidiarrheal therapy: Withhold until improved, and then resume ceritinib with 150-mg dose reduction
Any grade treatment-related interstitial lung disease/pneumonitis: Permanently discontinue therapy in patients diagnosed with treatment-related ILD/pneumonitis
Unable to tolerate ceritinib 300 mg/day: Discontinue
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 ceritinib 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
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
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 ceritinib 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 ceritinib with a 150-mg dose reduction, with frequent monitoring
Dosing Considerations
Indication for NSCLC was approved under accelerated approval based on tumor response rate and duration of response
Improvement in survival or disease-related symptoms has not been established
Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials
Administration
Take on empty stomach (ie, do not administer within 2 hr of a meal)
Pediatric dosage forms and strengths
Safety and efficacy not established
Zykadia (ceritinib) adverse (side) effects
>10%
Diarrhea (86%)
Decreased hemoglobin (84%)
Increased ALT (80%)
Increased AST (75%)
Nausea (80%)
Vomiting (60%)
Increased creatinine (58%)
Abdominal (54%)
Fatigue (52%)
Glucose increased (49%)
Phosphate decreased (36%)
Decreased appetite (34%)
Constipation (29%)
Lipase increased (28%)
Increased ALT, >5 x ULN (27%)
Neuropathy (17%)
Esophageal disorder (16%)
Rash (16%)
Bilirubin increased (15%)
Hyperglycemia, grade 3-4 (13%)
1-10%
Vision disorder (9%)
Interstitial lung disease/pneumonitis (4%)
Prolonged QT (4%)
Bradycardia (3%)
Warnings
Contraindications
None
Cautions
Also see Dosage modifications
Diarrhea, nausea, vomiting, or abdominal pain occurs in most patients, of which 14% have severe symptoms
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
Pregnancy and lactation
Pregnancy
Category: D; Advise women of reproductive potential to use effective contraception during treatment and for at least 2 weeks following therapy completion
In animal studies, administration of ceritinib to rats and rabbits during organogenesis at maternal plasma exposures below the recommended human dose caused increases in skeletal anomalies
Lactation
Unknown if distributed in human breast milk; because many drugs are present in human milk and because of the potential for serious adverse reactions in breastfeeding infants from ceritinib, advise mothers to discontinue breastfeeding
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.
Pharmacology of Zykadia (ceritinib)
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
