crizotinib (Rx)

>10%

ALK- or ROS1-positive metastatic NSCLC

• Vision disorders (≥25%)
• Nausea (≥25%)
• Diarrhea (≥25%)
• Vomiting (≥25%)
• Edema (≥25%)
• Constipation (≥25%)
• Elevated transaminases (≥25%)
• Fatigue (≥25%)
• Decreased appetite (≥25%)
• Upper respiratory infection (≥25%)
• Dizziness (≥25%)
• Neuropathy (≥25%)

ALK-positive metastatic NSCLC

• All grades

  • Increased ALT (76-79%)
  • Vision disorder (60-71%)
  • Increased AST (61-66%)
  • Diarrhea (60-61%)
  • Nausea (55-56%)
  • Neutropenia (49-52%)
  • Lymphopenia (48-51%)
  • Edema (31-49%)
  • Vomiting (46-47%)
  • Constipation (42-43%)
  • Upper respiratory tract infection (26-32%)
  • Hypophosphatemia (28-32%)
  • Decreased appetite (27-30%)
  • Fatigue (27-29%)
  • Abdominal pain (26%)
  • Dysgeusia (26%)
  • Headache (22%)
  • Dizziness (18-22%)
  • Neuropathy (19-21%)
  • Pyrexia (19%)
  • Hypokalemia (18%)
  • Pain in extremity (16%)
  • Bradycardia (5-14%)
  • Dyspepsia (8-14%)
  • Rash (9-11%)

• Grade 3-4

  • Increased ALT (15-17%)
  • Neutropenia (11-12%)

ALCL

• All grades

  • Neutropenia (100%)
  • Blood creatinine increased (100%)
  • Diarrhea (92%)
  • Vomiting (92%)
  • ALT increased (81%)
  • Nausea (77%)
  • AST increased (65%)
  • Vision disorders (65%)
  • Hypocalcemia (62%)
  • Lymphopenia (58%)
  • Headache (58%)
  • Musculoskeletal pain (58%)
  • Hypoalbuminemia (54%)
  • Anemia (54%)
  • Abdominal pain (50%)
  • Stomatitis (46%)
  • Hyperglycemia (46%)
  • Hypomagnesemia (46%)
  • Fatigue (46%)
  • Decreased appetite (42%)
  • Thrombocytopenia (38%)
  • Pyrexia (38%)
  • Hypoglycemia (35%)
  • Pruritus (35%)
  • Cough (35%)
  • Hypokalemia (31%)
  • Constipation (31%)
  • Upper respiratory tract infection (31%)
  • Hypertension (31%)
  • Hypermagnesemia (27%)
  • Edema (27%)
  • Chills (27%)
  • Hyperkalemia (23%)
  • Dysgeusia (23%)
  • Dizziness (23%)
  • Rash (23%)
  • Rhinitis allergic (23%)
  • Bradycardia (19%)
  • Hypotension (19%)
  • Alkaline phosphatase increase (19%)
  • Hypernatremia (19%)
  • Hyponatremia (12%)
  • Hyperuricemia (12%)
  • Hypophosphatemia (12%)
  • Peripheral neuropathy (12%)

• Grade 3-4

  • Neutropenia (77%)
  • Lymphopenia (38%)
  • Thrombocytopenia (19%)
  • Diarrhea (12%)
  • Musculoskeletal pain (12%)

1-10%

ALK-positive metastatic NSCLC

• All grades

  • Dysphagia (10%)
  • Decreased weight (10%)
  • Increased weight (8%)
  • Esophagitis (2-6%)
  • Pulmonary embolism (6%)
  • QT prolonged (5-6%)
  • Renal cyst (4-5%)
  • ILD/pneumonitis (1-4%)
  • Syncope (1-3%)
  • Decreased blood testosterone (1%)
  • Hepatic failure (1%)

• Grade 3-4

  • Hypophosphatemia (5-10%)
  • Increased AST (8-9%)
  • Lymphopenia (7-9%)
  • Pulmonary embolism (5%)
  • Hypokalemia (4%)
  • Syncope (3%)
  • QT prolonged (2-3%)
  • Diarrhea (2%)
  • Vomiting (1-2%)
  • Constipation (2%)
  • Esophagitis (2%)
  • Bradycardia (1%)
  • Vision disorder (1%)
  • Dysphagia (1%)
  • Edema (1%)
  • Increased weight (1%)
  • Headache (1%)
  • Dizziness (1%)
  • Decreased weight (1%)
  • Nausea (1%)

ALCL

• Grade 3-4

  • Stomatitis (8%)
  • QT prolonged (8%)
  • GGT increase (8%)
  • Esophagitis (8%)
  • Muscular weakness (8%)
  • Acute renal injury (8%)
  • Febrile neutropenia (3.8%)
  • Vomiting (3.8%)
  • Nausea (3.8%)
  • Anemia (3.8%)
  • ALT increased (3.8%)
  • AST increased (3.8%)
  • Hypocalcemia (3.8%)
  • Hypokalemia (3.8%)

Postmarketing Reports

Increased blood creatine phosphokinase

Contraindications

None

Cautions

Severe, including fatal, treatment-related ILD/pneumonitis reported; monitor for pulmonary symptoms indicative of pneumonitis; generally occurred within 3 months after initiation

Drug-induced hepatoxicity reported; monitor liver function tests every 2 weeks during the first 2 months of treatment, then monthly, and as clinically needed; more frequently in patients who develop increased transaminases; withhold, reduce dose, or permanently discontinue for hepatotoxicity as recommended

Symptomatic bradycardia reported, including syncope; monitor HR and blood pressure regularly

Caution when driving or operating machinery because of vision disorder, dizziness, or fatigue associated with treatment

May cause fetal harm when administered to pregnant females

Interstitial lung disease (ILD)/Pneumonitis reported; permanently discontinue in patients with ILD/pneumonitis

Visual loss

• Visual field defect with vision loss reported; optic atrophy and optic nerve disorder have been reported as potential causes of vision loss; most common visual symptoms were blurred vision and visual impairment in ALCL patients
• There is insufficient information to characterize risks of resumption of drug in patients who develop visual symptoms or visual loss; a decision to resume therapy should consider potential benefits versus risks to patient
• Perform an ophthalmological evaluation consisting of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT), and other evaluations as appropriate for new onset of visual loss and for other visual symptoms as clinically warranted

Gastrointestinal toxicity

• Severe gastrointestinal toxicities (eg, diarrhea, nausea, vomiting, stomatitis) can occur in ALCL patients; provide standard antiemetic and antidiarrheal agents for gastrointestinal toxicities in patients with ALCL; antiemetics are recommended prior to and during treatment with drug to prevent nausea and vomiting; if patients develop Grade 3 nausea lasting 3 days or Grade 3 or 4 diarrhea or vomiting despite maximum medical therapy, withhold therapy until resolved, and then resume at next lower dose level; consider supportive care such as hydration, electrolyte supplementation, and nutritional support as clinically indicated

QT interval prolongation

• QTc prolongation reported
• Avoid use with congenital long QT syndrome
• Consider periodic ECG and electrolyte monitoring in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or taking medications known to prolong QT interval

Drug interaction overview

• CYP3A4/5 and P-gp substrate; CYP3A4 inhibitor

• Strong or moderate CYP3A inhibitors

  • Avoid coadministration
  • Strong CYP3A inhibitors increases crizotinib plasma concentration and risk of adverse reactions of crizotinib
  • If unavoidable, reduce crizotinib dosage
  • Avoid grapefruit or grapefruit
  • Use caution with concomitant use of moderate CYP3A4 inhibitors

• Strong CYP3A inducers

  • Avoid coadministration
  • Strong CYP3A inducers decreases crizotinib plasma concentrations and efficacy of crizotinib

• CYP3A substrates

  • Avoid coadministration
  • Crizotinib may increases plasma concentrations and rise of adverse effects of CYP3A substrates
  • If unavoidable, decrease CYP3A substrate dosage according to prescribing information

• Drugs that prolong the QT interval

  • Avoid coadministration

• Drugs that cause bradycardia

  • Avoid coadministration
  • Drugs include beta-blockers, nondihydropyridine calcium channel blockers, clonidine, and digoxin

Pregnancy

Based on its mechanism of action, can cause fetal harm when administered to a pregnant woman

Verify pregnancy status of females of reproductive potential before initiation

Animal data

• Oral administration in pregnant rats during organogenesis at exposures similar to those observed with maximum recommended human dose resulted in embryotoxicity and fetotoxicity

Contraception

• Females of reproductive potential: Use effective contraception during treatment and for at least 45 days following the final dose
• Males with female partners of reproductive potential: Use condoms during treatment and for at least 90 days after final dose

Infertility

• Based on reproductive organ findings in animals, reduced fertility in females and males of reproductive potential may occur
• Unknown whether these effects on fertility are reversible

Lactation

No information available on drug presence in human milk, effects on the breastfed infants, or effects on milk production

Do not breastfeed during treatment and for 45 days after final dose

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

Inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), and Recepteur d’Origine Nantais (RON)

ALK gene expression and signaling that contribute to increased cell proliferation and survival of the tumors become activated following formation of ALK oncogenic fusion proteins

Inhibits signaling that promotes the expression of these oncogenic fusion proteins, thereby inhibiting tumor cell proliferation

Absorption

Adults

• Bioavailability: 43% (mean absolute bioavailability)
• Mean accumulation ratio: 4.8
• Peak plasma time: 4-6 hr
• Steady-state reached at 15 days (250 mg PO BID)

• Effect of food

  • High-fat meal reduced AUC and peak plasma concentration by ~14%

Children and young adults

• Peak plasma concentration: 621 ng/mL
• AUC: 6530 ng⋅hr/mL

Distribution

Protein Bound: 91% to human plasma proteins, independent of drug concentration

Vd (steady-state): 1772 L (50-mg IV dose)

Blood-to-plasma ratio: 1

P-glycoprotein (P-gp) substrate and inhibitor

Metabolism

Predominantly metabolized by CYP3A4/5

Time-dependent inhibitor of CYP3A

Primary metabolic pathways in humans were oxidation of the piperidine ring to crizotinib lactam and O-dealkylation, with subsequent Phase 2 conjugation of O-dealkylated metabolites

Elimination

Half-life: 42 hr

Total body clearance: 60 L/hr (250 mg PO q12hr at steady-state); 100 L/hr (250 mg PO qDay)

Excretion: Feces 63%; urine 22%

Pharmacogenomics

Patient selection for treatment is based on presence of ALK fusion gene

Verify presence of ALK fusion gene by using the diagnostic test, Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit

Oral Administration

Take with or without food

Swallow capsules whole

ALCL

• Administer under adult supervision
• May combine different strengths capsules if necessary

Before and during treatment

• Provide standard antiemetic and antidiarrheal agents before and during treatment
• Consider IV or oral hydration and replace electrolytes as clinically indicated

Missed dose

• Next dose >6 hr: Take as soon as possible
• Next dose <6 hr: Skip missed dose; do NOT double dose to make up for missed dose
• Vomited dose after administration: Do NOT take extra dose; take next dose at regularly scheduled time

Storage

Capsules: Store at room temperature (20-25ºC [68-77ºF]); excursions permitted to 15-30ºC (59-86ºF)