ceritinib (Rx)

>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%)

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)

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.

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

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)