Crizotinib

DAE Class; Rx

Common Brand Names; Xalkori

• Antineoplastics, Tyrosine Kinase Inhibitors; 
• Antineoplastics, Anaplastic Lymphoma Kinase Inhibitors

Oral inhibitor of receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK) and ROS1
Used in adult patients with ALK-positive or ROS1-positive metastatic non-small cell lung cancer; pediatric patients 1 year of age and older and young adults with ALK-positive systemic anaplastic large-cell lymphoma; and adult and pediatric patients with inflammatory myofibroblastic tumor
Hepatotoxicity, interstitial lung disease, QT interval prolongation, bradycardia, and severe visual loss have been reported

Indicated for metastatic non-small cell lung cancer (NSCLC) in adults whose tumors are anaplastic lymphoma kinase (ALK)- or ROS1-positive

Indicated for unresectable, recurrent, or refractory inflammatory myofibroblastic tumors (IMT) in adults who are ALK-positive

None

>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%)

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
• For pediatric and young adult patients with ALCL or pediatric patients with IMT, obtain baseline and follow-up ophthalmologic examinations including retinal examination within 1 month of initiating therapy and every 3 months thereafter
• 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
• Permanently discontinue therapy for Grade 3 or 4 ocular disorders or severe visual loss (best-corrected vision less than 20/200 in one or both eyes) unless another cause is identified

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

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

Adults

Non-small cell lung cancer: 500 mg/day PO.
Anaplastic large-cell lymphoma (dosage based on body surface area (BSA))
21 years or younger: BSA of 1.7 m2 or more: 1,000 mg/day PO.BSA of 1.52 to 1.69 m2: 900 mg/day PO. BSA of 1.17 to 1.51 m2: 800 mg/day PO.
Older than 21 years: Safety and efficacy not established.

Geriatric

Non-small cell lung cancer: 500 mg/day PO.Anaplastic large-cell lymphoma: Safety and efficacy not established.

Adolescents

Anaplastic large-cell lymphoma (dosage based on BSA)
BSA of 1.7 m2 or more: 1,000 mg/day PO.BSA of 1.52 to 1.69 m2: 900 mg/day PO. BSA of 1.17 to 1.51 m2: 800 mg/day PO.

Children

Anaplastic large-cell lymphoma (dosage based on BSA), ages 1 to 12
BSA of 1.52 to 1.69 m2: 900 mg/day PO.BSA of 1.17 to 1.51 m2: 800 mg/day PO.BSA of 0.81 to 1.16 m2: 500 mg/day PO.BSA of 0.6 to 0.8 m2: 400 mg/day PO.BSA less than 0.6 m2: Dosage not established.
 
Less than 1 year of age: Dosage not established.

Infants

Safety and efficacy not established.

Neonates

Safety and efficacy not established.

Crizotinib