Crizotinib is an oral inhibitor of receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK) and ROS1. It is indicated for the treatment of 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 relapsed or refractory, 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 with crizotinib therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Emetic Risk
-Moderate/High
-Administer routine antiemetic prophylaxis prior to treatment.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Take crizotinib orally with or without food; do not take with grapefruit or grapefruit juice.
-In addition to antiemetic prophylaxis, provide standard antidiarrheal agents to pediatric and young adult patients with anaplastic large-cell lymphoma (ALCL) and pediatric patients with inflammatory myofibroblastic tumor (IMT).
-If a dose is missed, it can be taken up to 6 hours before the next dose is due to maintain the twice daily regimen. Do not take both doses at the same time.
-If vomiting occurs after taking a dose, do not repeat the dose. Take the next dose at the regular time.
Oral Capsules:
-Swallow capsule whole; do not crush or chew.
-In patients with ALCL or IMT, different strength capsules may need to be combined to make up the desired dosage (e.g., 450 mg twice daily).
-Administer crizotinib capsules to pediatric patients under adult supervision.
Oral Pellets:
-Crizotinib pellets are encapsulated inside shells. Do not swallow crizotinib pellets encapsulated in the shells.
-Open the pellet shell and empty contents directly into the patient's mouth; alternatively, empty pellets into a consumer-supplied oral dosing aid (i.e., spoon, medicine cup) and then administer directly into the patient's mouth.
-Do not use more than 4 pellet shells for a single dose.
-Do not crush or chew crizotinib pellets.
-Give a sufficient amount of water to ensure that all medication is swallowed.
Interstitial lung disease (ILD) was reported in 2.9% (grade 3 or 4, 1%; grade 5, 0.5%) of patients with non-small cell lung cancer (NSCLC; n = 1,719) and 0.8% of patients aged 1 to 21 years with relapsed/refractory tumors including anaplastic large-cell lymphoma (ALCL; n = 121) who received crizotinib therapy in clinical trials. ILD/pneumonitis usually occurred within the first 3 months of treatment in patients with NSCLC. Monitor patients for pulmonary symptoms; if ILD/pneumonitis is suspected, exclude other causes. Permanently discontinue crizotinib in patients with confirmed treatment-related ILD/pneumonitis. ILD (including acute respiratory distress syndrome (ARDS) and pneumonitis) occurred in 1% to 4% of patients with NSCLC in 2 randomized trials. Dyspnea (2.3% to 4.1%) was among the most frequently reported serious adverse reactions reported in NSCLC patients treated with crizotinib in these trials. Cough occurred in 35% of patients aged 1 to 21 years with relapsed/refractory anaplastic large-cell lymphoma who received crizotinib therapy (n = 26) in a clinical trial.
Upper respiratory tract infection was reported in 26% to 32% of patients who received crizotinib in clinical trials. Additionally, pneumonia occurred in 4.2% of patients with non-small lung cancer (n = 172) in a randomized study; fatal cases of pneumonia and sepsis were reported. The term upper respiratory tract infection included laryngitis, nasopharyngitis, pharyngitis, sinusitis, and rhinitis. Additionally, allergic rhinitis occurred in 23% of patients aged 1 to 21 years with relapsed/refractory anaplastic large-cell lymphoma who received crizotinib (n = 26) in a clinical trial.
Fever was reported in 19% of patients with non-small cell lung cancer (n = 171) who received crizotinib in a randomized trial. Additionally, fever occurred in 38% of patients aged 1 to 21 years with relapsed/refractory anaplastic large-cell lymphoma (n = 26) who received crizotinib therapy in a clinical trial.
Pulmonary embolism (PE) (2.9%) and PE including pulmonary artery thrombosis (6%; grade 3 or 4, 5%) occurred in patients with non-small cell lung cancer who received crizotinib in a 2 randomized trials; fatal pulmonary embolism was also reported.
Hepatotoxicity has been reported with crizotinib therapy. Increased transaminase levels usually occurred within the first 3 months of treatment in patients with non-small cell lung cancer (NSCLC). Monitor liver function tests (LFTs), including AST, ALT, and bilirubin, every 2 weeks for the first 2 months of treatment, then monthly and as clinically indicated. More frequent testing is needed in patients who develop increased transaminase levels. An interruption of therapy, dose reduction, or permanent discontinuation of therapy may be needed for treatment-related increases in LFTs. Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of NSCLC patients who received crizotinib in clinical trials (n = 1,719). Elevated hepatic enzymes including ALT (76% to 81%; grade 3 or 4, 3.8% to 17%) and AST (55% to 65%; grade 3 or 4, 3.8% to 9%) levels were reported in patients with NSCLC and anaplastic large-cell lymphoma (ALCL) who received crizotinib in clinical trials. Hepatic failure was reported in 1% of patients with NSCLC who received crizotinib (n = 172) in a randomized trial. Hypoalbuminemia (54%), increased alkaline phosphatase level (19%), and increased gamma-glutamyl transferase level (8%) occurred in patients with ALCL (n = 26) who received crizotinib in a clinical trial.[45458
QT prolongation/prolongation of the QTc interval occurred in 2.1% of patients with non-small cell lung cancer (NSCLC; n = 1,616) and 4.1% of patients aged 1 to 21 years with relapsed/refractory tumors (n = 121), including 8% of patients with anaplastic large-cell lymphoma (ALCL; n = 26), who received crizotinib therapy in clinical trials. In patients with NSCLC, 2.1% of patients had a QTcF (corrected QT for heart rate by the Fridericia method) of 500 msec or more (n = 1,616) and 5% of patients had an increase from baseline QTcF of 60 msec or more by automated machine-read electrocardiogram (ECG; n = 1,582). Symptomatic bradycardia occurred in 13% of NSCLC patients (n = 1,719) and 14% (grade 3, 0.8%) of patients with relapsed/refractory tumors, including 19% of ALCL patients in clinical trials. QT prolongation on ECG (5% to 6%; grade 3 or 4, 2% to 3%) and bradycardia/sinus bradycardia (5% to 14%; grade 3 or 4, 1%) were reported in patients with metastatic NSCLC treated with crizotinib in 2 randomized trials. Fatal arrhythmia was reported with crizotinib therapy in one clinical trial of patients with metastatic NSCLC. Monitor heart rate and blood pressure regularly. Monitor ECG and electrolytes in patients with congestive heart failure, bradyarrhythmias (bradycardia), electrolyte imbalance (especially hypokalemia or hypomagnesemia), or in patients who are taking concomitant medications known to prolong the QT interval. Treatment interruption, dose reduction, or permanent discontinuation may be necessary for QT prolongation or bradycardia.
Dizziness was reported in 18% to 23% (grade 3 or 4, 1% or less) of patients with non-small lung cancer (NSCLC) and anaplastic large-cell lymphoma who received crizotinib in clinical trials. The term dizziness included balance disorder, postural dizziness, and presyncope. Grade 3 syncope was reported in 2.4% of NSCLC patients in clinical trials (n = 1,719). Additionally, syncope occurred in 1% and 3% (all grade 3 or 4) of patients with NSCLC who received crizotinib in 2 randomized trials.
Myelosuppression was reported with crizotinib therapy; patients with anaplastic large-cell lymphoma (ALCL) have the highest rate of myelosuppression. In patients with non-small cell lung cancer (NSCLC), monitor complete blood counts (CBC) monthly and as clinically indicated. In patients with ALCL, monitor CBC weekly for the first month and then at least monthly during therapy. Increase the frequency of CBC monitoring in patients who develop fever, infection, or grade 3 or 4 myelosuppression. Neutropenia (49% to 52%; grade 3 or 4, 11% to 12%) and lymphopenia (48% to 51%; grade 3 or 4, 7% to 9%) were reported in patients with NSCLC who received crizotinib in 2 randomized clinical trials. Neutropenia (100%; grade 3 or 4, 77%), febrile neutropenia (3.8%), lymphopenia (58%; grade 3 or 4, 38%), anemia (54%; grade 3 or 4, 3.8%), and thrombocytopenia (38%; grade 3 or 4, 19%) occurred in patients aged 1 to 21 years with relapsed/refractory ALCL who received crizotinib therapy (n = 26) in a clinical trial.
Visual disorder was reported in 46% to 92% of patients who received crizotinib in clinical trials. Patients with anaplastic large cell lymphoma (ALCL) should receive ophthalmological evaluations including a retinal exam at baseline, within 1 month of starting crizotinib, and every 3 months thereafter; monitor these patients for visual symptoms monthly during treatment. Additionally, perform an ophthalmological evaluation (e.g., best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography) in any crizotinib-treated patient who develops new onset visual symptoms or severe vision loss. An interruption of therapy or a dosage reduction may be needed in patients that develop visual symptoms. Discontinue crizotinib in patients with new onset of severe vision loss (best corrected vision less than 20/200 in one or both eyes); there is insufficient information regarding the resumption of crizotinib therapy in patients with a severe visual loss. Visual disorders (63%) and grade 4 visual field defects with visual loss (0.2%) occurred in non-small cell lung cancer (NSCLC) patients who received crizotinib in clinical trials (n = 1,719). Visual disorders included visual impairment, photopsia, blurred vision, or vitreous floaters. Grade 3 or 4 visual impairment occurred in 1% of NSCLC patients. Optic atrophy and optic nerve disorder (optic neuritis) were reported as potential causes of visual loss. The onset of vision disorder typically occurred within the first week of crizotinib therapy. Vision disorder occurred in 60% to 92% (grade 3 or 4, 1% or less) of patients with NSCLC who received crizotinib in 3 clinical trials. Additionally, vision disorders were reported in 46% of patients aged 1 to 21 years with relapsed/refractory tumors (n = 121) including 65% of patients with ALCL (n = 26) who received crizotinib in a clinical trial. In this trial, 1 patient (0.8%) developed grade 3 optic nerve disorder and the most common symptoms were blurred vision and visual impairment. The term vision disorder included diplopia, blurred vision, visual impairment, photophobia, photopsia, reduced visual acuity, vitreous floaters, cyanopsia, heterophoria, and visual field defect.
Gastrointestinal (GI) toxicity was reported with crizotinib therapy; the incidence of GI toxicity is higher in patients with anaplastic large-cell lymphoma (ALCL). In these patients, administer antiemetics prior to and during therapy. Consider intravenous or oral hydration in patients at risk of dehydration and replace electrolytes as clinically indicated. Provide nutritional support and antidiarrheal medications as necessary. Interruption of therapy and a dosage adjustment may be required in patients who have severe GI toxicity (e.g., grade 3 nausea lasting 3 days or grade 3 or 4 diarrhea or vomiting) despite maximum medical therapy. Diarrhea (60% to 61%; 2% or less), nausea (55% to 56%; grade 3 or 4, 1% or less), vomiting (46% to 47%; grade 3 or 4, 1% to 2%), constipation (42% to 43%; grade 3 or 4, 2%), decreased appetite/anorexia (27% to 30%), abdominal pain (26% or less), dyspepsia (8% to 14%), dysphagia (10% or less; grade 3 or 4, 1% or less), and esophagitis (2% to 6%; grade 3 or 4, 2% or less) were reported in patients with non-small cell lung cancer who received crizotinib in 2 randomized clinical trials. The term esophagitis included esophageal ulceration. Diarrhea (92%; grade 3 or 4, 12%), vomiting (92%; grade 3 or 4, 3.8%), nausea (77%; grade 3 or 4, 3.8%), abdominal pain (50%), stomatitis (46%; grade 3 or 4, 8%), decreased appetite (42%), constipation (31%), and esophagitis (8%) occurred in patients aged 1 to 21 years with relapsed/refractory ALCL who received crizotinib therapy (n = 26) in a clinical trial. The term stomatitis included oral pain and oropharyngeal pain.
Dysgeusia was reported in 23% to 26% of patients who received crizotinib in clinical trials.
Edema was reported in 27% to 49% (grade 3 or 4, 1% or less) of patients who received crizotinib in clinical trials. The term edema included peripheral edema, face edema, periorbital edema, and localized edema or swelling.
Weight loss was reported in 10% (grade 3 or 4, 1%) of patients with non-small cell lung cancer (NSCLC) who received crizotinib (n = 172) in a randomized trial. Weight gain occurred in 8% (grade 3 or 4, 1%) of patients with NSCLC (n = 171) in another randomized trial.
Neuropathy occurred in 25% of non-small cell lung cancer (NSCLC) patients who received crizotinib in clinical trials (n = 1,719). Additionally, neuropathy was reported in 19% to 21% of patients with NSCLC who received crizotinib in 2 randomized clinical trials. The term neuropathy included dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, paresthesias, polyneuropathy, burning sensation in skin, and sensory disturbance. Peripheral neuropathy (12%) and muscular weakness (8%) occurred in patients aged 1 to 21 years with relapsed/refractory anaplastic large-cell lymphoma who received crizotinib therapy (n = 26) in a clinical trial.
Rash was reported in 9% to 11% of patients with non-small cell lung cancer who received crizotinib in 2 randomized clinical trials; photosensitivity occurred in 0.3% to 0.4% of patients in these trials. Pruritus (35%) and rash (23%) occurred in patients aged 1 to 21 years with relapsed/refractory anaplastic large-cell lymphoma who received crizotinib therapy (n = 26) in a clinical trial; the term rash included maculopapular rash and pustular rash.
Hypophosphatemia (28% to 32%;grade 3 or 4, 5% to 10%) and hypokalemia (18% or less; grade 3 or 4, 4% or less) were reported in patients with non-small cell lung cancer who received crizotinib in 2 randomized clinical trials. Hypocalcemia (62%; grade 3 or 4, 3.8%), hypomagnesemia (46%), hypokalemia (31%; grade 3 or 4, 3.8%), hypermagnesemia (27%), hyperkalemia (23%), hypernatremia (19%), hyponatremia (12%), and hypophosphatemia (12%) occurred in patients aged 1 to 21 years with relapsed/refractory anaplastic large-cell lymphoma who received crizotinib therapy (n = 26) in a clinical trial.
Fatigue was reported in 27% to 46% of patients who received crizotinib in clinical trials.
Fatal diabetic ketoacidosis was reported in patients with non-small cell lung cancer who received crizotinib (n = 171) in a randomized trial. Hyperglycemia occurred in 46% of patients aged 1 to 21 years with relapsed/refractory anaplastic large-cell lymphoma who received crizotinib therapy (n = 26) in a clinical trial.
Gonadal suppression (hypogonadism) resulting in decreased blood testosterone concentrations occurred in 1% of patients with ALK-positive metastatic NSCLC treated with crizotinib (n = 343) in 2 randomized clinical trials.
Extremity pain (16%) and muscle cramps/spasm (8%) were reported in patients with non-small cell lung cancer who received crizotinib (n = 171) in a randomized trial. Musculoskeletal pain occurred in 58% (grade 3 or 4, 12%) of patients aged 1 to 21 years with relapsed/refractory anaplastic large-cell lymphoma who received crizotinib therapy (n = 26) in a clinical trial. The term musculoskeletal pain included arthralgia, back pain, myalgia, non-cardiac chest pain, and extremity pain. Increased blood creatine phosphokinase level was reported in postmarketing surveillance of crizotinib.
Nephrotoxicity, specifically increased serum creatinine level, was reported in 96% to 99% (grade 3 or 4, 2% or less) of patients who received crizotinib in clinical trials. Renal cysts occurred in 3% of non-small cell lung cancer (NSCLC) patients who received crizotinib in clinical trials (n = 1,719); most cyst were complex. In some cases, imaging characteristics were suggestive of abscess formation; however, no renal abscesses were confirmed by microbiology tests. Across clinical trials in NSCLC patients, a decrease of estimated glomerular filtration rate (eGFR) to less than 90 mL/min/1.73 m2 occurred in 76% of patients, to less than 60 mL/min/1.73 m2 occurred in 38% of patients, and to less than 30 mL/min/1.73 m2 occurred in 3.6% of patients. Acute renal injury occurred in 8% of patients aged 1 to 21 years with relapsed/refractory anaplastic large-cell lymphoma who received crizotinib (n = 26) in a clinical trial.
Headache was reported in 22% (grade 3 or 4, 1%) of patients with non-small cell lung cancer who received crizotinib (n = 171) in a randomized trial. Additionally, headache occurred in 58% (grade 3 or 4, 3.8%) of patients aged 1 to 21 years with relapsed/refractory anaplastic large-cell lymphoma who received crizotinib therapy (n = 26) in a clinical trial.
Hypertension (31%) and hypotension (19%; grade 3 or 4, 8%) occurred in patients aged 1 to 21 years with relapsed/refractory anaplastic large-cell lymphoma who received crizotinib (n = 26) in a clinical trial.
Hyperuricemia occurred in 12% of patients aged 1 to 21 years with relapsed/refractory anaplastic large-cell lymphoma who received crizotinib therapy (n = 26) in a clinical trial.
Hypoglycemia occurred in 35% of patients aged 1 to 21 years with relapsed/refractory anaplastic large-cell lymphoma who received crizotinib (n = 26) in a clinical trial.
Severe and life-threatening interstitial lung disease (ILD)/pneumonitis has been reported with crizotinib therapy; some cases were fatal. ILD/pneumonitis usually occurred within the first 3 months of treatment. Patients with a history of pulmonary disease may be at increased risk for ILD/pneumonitis. Monitor patients for pulmonary symptoms; if ILD/pneumonitis is suspected, exclude other causes. Permanently discontinue crizotinib in patients with confirmed treatment-related ILD/pneumonitis.
Use crizotinib with caution in patients with pre-existing hepatic disease; fatal drug-induced hepatotoxicity has been reported with crizotinib use. A lower starting dose of crizotinib is recommended for patients with moderate to severe hepatic impairment at baseline. During therapy, increased transaminases generally occurred within the first 2 months of treatment. Monitor liver function tests (LFTs), including AST, ALT, and bilirubin, every 2 weeks for the first 2 months of treatment, then monthly and as clinically indicated. More frequent testing is needed in patients who develop increased transaminases. An interruption of therapy, dose reduction, or permanent discontinuation of therapy may be needed for treatment-related increases in LFTs.
QT prolongation has been reported with the use of crizotinib; avoid use in patients who have congenital long QT syndrome. Symptomatic bradycardia has also been reported; if possible, do not use crizotinib in combination with other agents known to cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin). Monitor heart rate and blood pressure regularly. Monitor ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias (bradycardia), electrolyte imbalance (especially hypokalemia or hypomagnesemia), or in patients who are taking concomitant medications known to prolong the QT interval. Treatment interruption, dose reduction, or permanent discontinuation may be necessary for QT prolongation or bradycardia. Use crizotinib with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.
Use crizotinib with caution in patients with pre-existing ocular disease. Serious visual disorders/visual impairment including vision loss have occurred with crizotinib therapy. The onset of vision disorder typically occurred within the first week of crizotinib therapy. Pediatric patients with anaplastic large cell lymphoma (ALCL) or inflammatory myofibroblastic tumor and young adults with ALCL should receive ophthalmological evaluations including a retinal exam at baseline, within 1 month of starting crizotinib, and every 3 months thereafter; monitor all patients for visual symptoms monthly during treatment. Additionally, perform an ophthalmological evaluation (e.g., best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography) in any crizotinib-treated patient who develops new onset visual symptoms or severe vision loss. An interruption of therapy or a dosage reduction may be needed in patients that develop visual symptoms. Permanently discontinue crizotinib in patients with new onset of severe vision loss (best corrected vision less than 20/200 in one or both eyes) unless another cause is identified; there is insufficient information regarding the resumption of crizotinib therapy in patients with a severe visual loss. Caution should be used when driving or operating machinery in patients who experience changes in vision.
Pediatric and young adult patients with anaplastic large-cell lymphoma (ALCL) and pediatric patients with inflammatory myofibroblastic tumor (IMT) who received crizotinib experienced a high rate of gastrointestinal (GI) toxicity, including diarrhea, nausea/vomiting, and stomatitis; provide these patients with standard antiemetic and antidiarrheal agents. Administer antiemetics prior to and during therapy. Consider intravenous or oral hydration in patients at risk of dehydration and replace electrolytes as clinically indicated if an electrolyte imbalance occurs. Provide nutritional support as necessary. Interruption of therapy and a dosage adjustment may be required in patients who have severe GI toxicity (e.g., grade 3 nausea lasting 3 days or grade 3 or 4 diarrhea or vomiting) despite maximum medical therapy.
Myelosuppression (e.g., neutropenia and thrombocytopenia) has been reported with crizotinib therapy; the incidence of myelosuppression is higher in patients with anaplastic large-cell lymphoma (ALCL). Monitor complete blood counts (CBC) weekly for the first month of therapy and then at least monthly, with more frequent monitoring if grade 3 or 4 abnormalities, fever, or infection occur.
Children may be at risk of growth inhibition with crizotinib therapy based on data from animal studies. Decreased bone formation in growing long bones was observed in immature rats with dosing that exceeded the human adult dose by approximately 5.4 times the recommended human dose based on AUC. Other toxicities have not been evaluated in juvenile animals.
Crizotinib may cause fetal harm based on its mechanism of action and animal studies showing potential for maternal-fetal transmission; however, there are no well-controlled studies in pregnant women. In animal studies, crizotinib was embryotoxic and fetotoxic at exposures similar to those observed in humans at the maximum recommended doses. Women of childbearing potential should be advised to avoid becoming pregnant while receiving crizotinib and for 45 days after the last dose. When administered to pregnant rats during organogenesis, postimplantation loss was increased at approximately 0.6 times the recommended human dose based on AUC. No teratogenic effects were observed in rats or rabbits at doses up to 2.7 and 1.6 times the recommended human dose based on AUC, respectively; fetal body weights were reduced at both dose levels. If this drug is used during pregnancy, or if the patient or their partner becomes pregnant while taking this drug, the patient should be cautioned of the potential hazard to the fetus.
Counsel patients about the reproductive risk and contraception requirements during crizotinib treatment. Crizotinib can cause fetal harm if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for 45 days after the last dose of crizotinib. Men with female partners of reproductive potential should use condoms during treatment with crizotinib and for 90 days after the last dose due to a potential for male-mediated teratogenicity. Females of reproductive potential should undergo pregnancy testing prior to initiation of therapy. Women who become pregnant while receiving treatment should be apprised of the potential hazard to the fetus. In addition, based on animal data, crizotinib may cause infertility in females and males; it is not known whether these effects on fertility are reversible.
It is not known whether crizotinib or its metabolites are excreted into human milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in a nursing infant, advise women to discontinue breast-feeding during treatment with crizotinib and for 45 days after the last dose.
For the treatment of non-small cell lung cancer (NSCLC):
-for the treatment of patients with metastatic NSCLC that is anaplastic lymphoma kinase (ALK)- or ROS1- positive as detected by an FDA-approved test:
NOTE: Information on FDA-approved tests for the detection of ALK and ROS1 rearrangements in NSCLC is available at www.fda.gov/companiondiagnostics.
Oral dosage:
Adults: 250 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with crizotinib monotherapy significantly improved the primary outcome of progression-free survival (PFS) compared with chemotherapy (pemetrexed or docetaxel) in a randomized, open-label trial of patients with ALK-positive metastatic NSCLC previously treated with platinum-based therapy (7.7 vs. 3 months); additionally, the objective response rate (ORR) was 65% vs. 20%, and duration of response was 7.4 vs. 5.6 months. Overall survival was not improved (20.3 vs. 22.8 months) at an interim analysis; however, 64% of patients randomized to chemotherapy had crossed over to receive crizotinib after disease progression. Crizotinib also significantly improved median PFS compared with chemotherapy (pemetrexed plus cisplatin or carboplatin) in a separate multicenter, randomized, open-label, phase 3 study of previously untreated patients with ALK-positive locally advanced, recurrent, or metastatic non-squamous NSCLC (10.9 vs. 7 months); ORR was also significantly improved (74% vs. 45%), and the median duration of response was 11.3 months versus 5.3 months, respectively. Overall survival, possibly confounded by a crossover rate of 70% from chemotherapy to crizotinib, was not significantly improved. Finally, treatment with crizotinib resulted in an ORR of 66% for a median duration of 18.3 months by independent radiology review in a multicenter, single-arm clinical trial in patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC); most responses were partial responses.
For the treatment of systemic anaplastic large-cell lymphoma (ALCL):
NOTE: Crizotinib has been designated as an orphan drug by the FDA for the treatment of ALCL.
-for the treatment of relapsed or refractory, ALK-positive, systemic ALCL:
Oral dosage:
Adults 21 years and younger, BSA 1.7 m2 or greater: 500 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer antiemetics prior to and during therapy. Consider intravenous or oral hydration in patients at risk of dehydration. The objective response rate was 88% (complete response rate, 81%) in patients aged 1 to 21 years of age with relapsed or refractory, systemic ALK-positive ALCL who received crizotinib in a multicenter, single-arm trial (n = 26). The response was maintained in 57%, 39%, and 22% of responding patients at 3, 6, and 12 months, respectively. In this trial, patients (median age, 11 years; range, 3 to 20 years) had received at least 3 prior therapies; 2 patients (8%) had received a prior hematopoietic stem-cell transplant.
Children and Adolescents, BSA 1.7 m2 or greater: 500 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer antiemetics prior to and during therapy. Consider intravenous or oral hydration in patients at risk of dehydration. The objective response rate was 88% (complete response rate, 81%) in patients aged 1 to 21 years of age with relapsed or refractory, systemic ALK-positive ALCL who received crizotinib in a multicenter, single-arm trial (n = 26). The response was maintained in 57%, 39%, and 22% of responding patients at 3, 6, and 12 months, respectively. In this trial, patients (median age, 11 years; range, 3 to 20 years) had received at least 3 prior therapies; 2 patients (8%) had received a prior hematopoietic stem-cell transplant.
Adults 21 years and younger, BSA 1.52 to 1.69 m2: 450 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer antiemetics prior to and during therapy. Consider intravenous or oral hydration in patients at risk of dehydration. The objective response rate was 88% (complete response rate, 81%) in patients aged 1 to 21 years of age with relapsed or refractory, systemic ALK-positive ALCL who received crizotinib in a multicenter, single-arm trial (n = 26). The response was maintained in 57%, 39%, and 22% of responding patients at 3, 6, and 12 months, respectively. In this trial, patients (median age, 11 years; range, 3 to 20 years) had received at least 3 prior therapies; 2 patients (8%) had received a prior hematopoietic stem-cell transplant.
Children and Adolescents, BSA 1.52 to 1.69 m2: 450 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer antiemetics prior to and during therapy. Consider intravenous or oral hydration in patients at risk of dehydration. The objective response rate was 88% (complete response rate, 81%) in patients aged 1 to 21 years of age with relapsed or refractory, systemic ALK-positive ALCL who received crizotinib in a multicenter, single-arm trial (n = 26). The response was maintained in 57%, 39%, and 22% of responding patients at 3, 6, and 12 months, respectively. In this trial, patients (median age, 11 years; range, 3 to 20 years) had received at least 3 prior therapies; 2 patients (8%) had received a prior hematopoietic stem-cell transplant.
Adults 21 years and younger, BSA 1.34 to 1.51 m2: 400 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer antiemetics prior to and during therapy. Consider intravenous or oral hydration in patients at risk of dehydration. The objective response rate was 88% (complete response rate, 81%) in patients aged 1 to 21 years of age with relapsed or refractory, systemic ALK-positive ALCL who received crizotinib in a multicenter, single-arm trial (n = 26). The response was maintained in 57%, 39%, and 22% of responding patients at 3, 6, and 12 months, respectively. In this trial, patients (median age, 11 years; range, 3 to 20 years) had received at least 3 prior therapies; 2 patients (8%) had received a prior hematopoietic stem-cell transplant.
Children and Adolescents, BSA 1.34 to 1.51 m2: 400 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer antiemetics prior to and during therapy. Consider intravenous or oral hydration in patients at risk of dehydration. The objective response rate was 88% (complete response rate, 81%) in patients aged 1 to 21 years of age with relapsed or refractory, systemic ALK-positive ALCL who received crizotinib in a multicenter, single-arm trial (n = 26). The response was maintained in 57%, 39%, and 22% of responding patients at 3, 6, and 12 months, respectively. In this trial, patients (median age, 11 years; range, 3 to 20 years) had received at least 3 prior therapies; 2 patients (8%) had received a prior hematopoietic stem-cell transplant.
Oral dosage:
Children and Adolescents, BSA 1.17 to 1.33 m2: 350 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer antiemetics prior to and during therapy. Consider intravenous or oral hydration in patients at risk of dehydration. The objective response rate was 88% (complete response rate, 81%) in patients aged 1 to 21 years of age with relapsed or refractory, systemic ALK-positive ALCL who received crizotinib in a multicenter, single-arm trial (n = 26). The response was maintained in 57%, 39%, and 22% of responding patients at 3, 6, and 12 months, respectively. In this trial, patients (median age, 11 years; range, 3 to 20 years) had received at least 3 prior therapies; 2 patients (8%) had received a prior hematopoietic stem-cell transplant.
Children and Adolescents, BSA 0.98 to 1.16 m2: 300 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer antiemetics prior to and during therapy. Consider intravenous or oral hydration in patients at risk of dehydration. The objective response rate was 88% (complete response rate, 81%) in patients aged 1 to 21 years of age with relapsed or refractory, systemic ALK-positive ALCL who received crizotinib in a multicenter, single-arm trial (n = 26). The response was maintained in 57%, 39%, and 22% of responding patients at 3, 6, and 12 months, respectively. In this trial, patients (median age, 11 years; range, 3 to 20 years) had received at least 3 prior therapies; 2 patients (8%) had received a prior hematopoietic stem-cell transplant.
Children and Adolescents, BSA 0.81 to 0.97 m2: 250 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer antiemetics prior to and during therapy. Consider intravenous or oral hydration in patients at risk of dehydration. The objective response rate was 88% (complete response rate, 81%) in patients aged 1 to 21 years of age with relapsed or refractory, systemic ALK-positive ALCL who received crizotinib in a multicenter, single-arm trial (n = 26). The response was maintained in 57%, 39%, and 22% of responding patients at 3, 6, and 12 months, respectively. In this trial, patients (median age, 11 years; range, 3 to 20 years) had received at least 3 prior therapies; 2 patients (8%) had received a prior hematopoietic stem-cell transplant.
Infants and Children, BSA 0.62 to 0.8 m2: 200 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer antiemetics prior to and during therapy. Consider intravenous or oral hydration in patients at risk of dehydration. The objective response rate was 88% (complete response rate, 81%) in patients aged 1 to 21 years of age with relapsed or refractory, systemic ALK-positive ALCL who received crizotinib in a multicenter, single-arm trial (n = 26). The response was maintained in 57%, 39%, and 22% of responding patients at 3, 6, and 12 months, respectively. In this trial, patients (median age, 11 years; range, 3 to 20 years) had received at least 3 prior therapies; 2 patients (8%) had received a prior hematopoietic stem-cell transplant.
Infants and Children, BSA 0.52 to 0.61 m2: 150 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer antiemetics prior to and during therapy. Consider intravenous or oral hydration in patients at risk of dehydration. The objective response rate was 88% (complete response rate, 81%) in patients aged 1 to 21 years of age with relapsed or refractory, systemic ALK-positive ALCL who received crizotinib in a multicenter, single-arm trial (n = 26). The response was maintained in 57%, 39%, and 22% of responding patients at 3, 6, and 12 months, respectively. In this trial, patients (median age, 11 years; range, 3 to 20 years) had received at least 3 prior therapies; 2 patients (8%) had received a prior hematopoietic stem-cell transplant.
Infants and Children, BSA 0.47 to 0.51 m2: 140 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer antiemetics prior to and during therapy. Consider intravenous or oral hydration in patients at risk of dehydration. The objective response rate was 88% (complete response rate, 81%) in patients aged 1 to 21 years of age with relapsed or refractory, systemic ALK-positive ALCL who received crizotinib in a multicenter, single-arm trial (n = 26). The response was maintained in 57%, 39%, and 22% of responding patients at 3, 6, and 12 months, respectively. In this trial, patients (median age, 11 years; range, 3 to 20 years) had received at least 3 prior therapies; 2 patients (8%) had received a prior hematopoietic stem-cell transplant.
Infants and Children, BSA 0.38 to 0.46 m2: 120 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Administer antiemetics prior to and during therapy. Consider intravenous or oral hydration in patients at risk of dehydration. The objective response rate was 88% (complete response rate, 81%) in patients aged 1 to 21 years of age with relapsed or refractory, systemic ALK-positive ALCL who received crizotinib in a multicenter, single-arm trial (n = 26). The response was maintained in 57%, 39%, and 22% of responding patients at 3, 6, and 12 months, respectively. In this trial, patients (median age, 11 years; range, 3 to 20 years) had received at least 3 prior therapies; 2 patients (8%) had received a prior hematopoietic stem-cell transplant.
For the treatment of inflammatory myofibroblastic tumor (IMT):
NOTE: Crizotinib has been designated as an orphan drug by the FDA for the treatment of inflammatory myofibroblastic tumor.
-for the treatment of unresectable, recurrent, or refractory ALK-positive inflammatory myofibroblastic tumor (IMT):
Oral dosage:
Adults: 250 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A multicenter, single-arm, open-label phase IB study (Study A8081013) included 7 adult patients with unresectable, recurrent, or refractory ALK-positive IMT who were treated with crizotinib. Of these patients, 5 experienced a response per investigator assessment, including 1 complete response. The duration of response was at least 6 months for all 5 patients and at least 1 year for 2 patients.
Children and Adolescents, BSA 1.7 m2 or greater: 500 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A multicenter, single-arm, open-label phase 1/2 study (Study ADVL0912) included 14 pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT who were treated with crizotinib. Of these patients, 12 experienced a response per an independent review committee, including 5 complete responses. The duration of response was at least 6 months for 7 patients, all of whom continued to maintain their response for at least 12 months.
Children and Adolescents, BSA 1.52 to 1.69 m2: 450 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A multicenter, single-arm, open-label phase 1/2 study (Study ADVL0912) included 14 pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT who were treated with crizotinib. Of these patients, 12 experienced a response per an independent review committee, including 5 complete responses. The duration of response was at least 6 months for 7 patients, all of whom continued to maintain their response for at least 12 months.
Children and Adolescents, BSA 1.34 to 1.51 m2: 400 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A multicenter, single-arm, open-label phase 1/2 study (Study ADVL0912) included 14 pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT who were treated with crizotinib. Of these patients, 12 experienced a response per an independent review committee, including 5 complete responses. The duration of response was at least 6 months for 7 patients, all of whom continued to maintain their response for at least 12 months.
Oral dosage:
Children and Adolescents, BSA 1.17 to 1.33 m2: 350 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A multicenter, single-arm, open-label phase 1/2 study (Study ADVL0912) included 14 pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT who were treated with crizotinib. Of these patients, 12 experienced a response per an independent review committee, including 5 complete responses. The duration of response was at least 6 months for 7 patients, all of whom continued to maintain their response for at least 12 months.
Children and Adolescents, BSA 0.98 to 1.16 m2: 300 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A multicenter, single-arm, open-label phase 1/2 study (Study ADVL0912) included 14 pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT who were treated with crizotinib. Of these patients, 12 experienced a response per an independent review committee, including 5 complete responses. The duration of response was at least 6 months for 7 patients, all of whom continued to maintain their response for at least 12 months.
Children and Adolescents, BSA 0.81 to 0.97 m2: 250 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A multicenter, single-arm, open-label phase 1/2 study (Study ADVL0912) included 14 pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT who were treated with crizotinib. Of these patients, 12 experienced a response per an independent review committee, including 5 complete responses. The duration of response was at least 6 months for 7 patients, all of whom continued to maintain their response for at least 12 months.
Infants and Children, BSA 0.62 to 0.8 m2: 200 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A multicenter, single-arm, open-label phase 1/2 study (Study ADVL0912) included 14 pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT who were treated with crizotinib. Of these patients, 12 experienced a response per an independent review committee, including 5 complete responses. The duration of response was at least 6 months for 7 patients, all of whom continued to maintain their response for at least 12 months.
Infants and Children, BSA 0.52 to 0.61 m2: 150 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A multicenter, single-arm, open-label phase 1/2 study (Study ADVL0912) included 14 pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT who were treated with crizotinib. Of these patients, 12 experienced a response per an independent review committee, including 5 complete responses. The duration of response was at least 6 months for 7 patients, all of whom continued to maintain their response for at least 12 months.
Infants and Children, BSA 0.47 to 0.51 m2: 140 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A multicenter, single-arm, open-label phase 1/2 study (Study ADVL0912) included 14 pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT who were treated with crizotinib. Of these patients, 12 experienced a response per an independent review committee, including 5 complete responses. The duration of response was at least 6 months for 7 patients, all of whom continued to maintain their response for at least 12 months.
Infants and Children, BSA 0.38 to 0.46 m2: 120 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A multicenter, single-arm, open-label phase 1/2 study (Study ADVL0912) included 14 pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT who were treated with crizotinib. Of these patients, 12 experienced a response per an independent review committee, including 5 complete responses. The duration of response was at least 6 months for 7 patients, all of whom continued to maintain their response for at least 12 months.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Recommended Dosage Reductions
Adults with Non-Small Cell Lung Cancer (NSCLC) or Inflammatory Myofibroblastic Tumor (IMT)
-First dose reduction: 200 mg PO twice daily.
-Second dose reduction: 250 mg PO once daily. Permanently discontinue crizotinib if unable to tolerate 250 mg once daily.
Pediatric patients and young adults with Anaplastic Large Cell Lymphoma (ALCL) and pediatric patients with IMT
BSA 0.38 to 0.46 m2
-First dose reduction: 90 mg PO twice daily (pellets).
-Second dose reduction: 70 mg PO twice daily (pellets). Permanently discontinue crizotinib if unable to tolerate this dose.
BSA 0.47 to 0.51 m2
-First dose reduction: 100 mg PO twice daily (pellets)
-Second dose reduction: 80 mg PO twice daily (pellets). Permanently discontinue crizotinib if unable to tolerate this dose.
BSA 0.52 to 0.61 m2
-First dose reduction: 120 mg PO twice daily (pellets).
-Second dose reduction: 90 mg PO twice daily (pellets). Permanently discontinue crizotinib if unable to tolerate this dose.
BSA 0.62 to 0.8 m2
-First dose reduction: 150 mg PO twice daily (pellets).
-Second dose reduction: 120 mg PO twice daily (pellets). Permanently discontinue crizotinib if unable to tolerate this dose.
BSA 0.81 to 0.97 m2
-First dose reduction: 200 mg PO twice daily (pellets).
-Second dose reduction: 150 mg PO twice daily (pellets). Permanently discontinue crizotinib if unable to tolerate this dose.
BSA 0.98 to 1.16 m2
-First dose reduction: 220 mg PO twice daily (pellets).
-Second dose reduction: 170 mg PO twice daily (pellets). Permanently discontinue crizotinib if unable to tolerate this dose.
BSA 1.17 to 1.69 m2
-First dose reduction: 250 mg PO twice daily (BSA 1.17 to 1.33 m2, pellets; BSA 1.34 to 1.69 m2, pellets or capsules).
-Second dose reduction: 200 mg PO twice daily (BSA 1.17 to 1.33 m2, pellets; BSA 1.34 to 1.69 m2, pellets or capsules). Permanently discontinue crizotinib if unable to tolerate this dose.
BSA 1.7 to m2 or greater
-First dose reduction: 400 mg PO twice daily (pellets or capsules).
-Second dose reduction: 250 mg PO twice daily (pellets or capsules). Permanently discontinue crizotinib if unable to tolerate this dose.
Cardiotoxicity
Bradycardia (heart rate less than 60 beats per minute (bpm) for adult and pediatric patients older than 8 years of age; less than 64 bpm for patients 6 to 8 years of age; less than 72 bpm for patients 4 to 5 years of age; less than 82 bpm for patients 2 to 3 years of age; less than 91 bpm for patients 1 to less than 2 years of age)
-Symptomatic, may be severe and medically significant, medical intervention indicated: Hold crizotinib therapy. Evaluate concomitant medications known to cause bradycardia as well as antihypertensive medications. If a contributing medication is identified and either discontinued or dose-adjusted, resume crizotinib at the previous dose when bradycardia is asymptomatic or the heart rate returns to the age-specific heart rate provided above. If no contributing medication is identified or if a contributing medication is continued without dose reduction, resume crizotinib at a reduced dose when bradycardia is asymptomatic or the heart rate returns to the age-specific heart rate provided above.
-Life-threatening bradycardia that requires urgent intervention: If a contributing medication is identified and either discontinued or dose-adjusted, resume crizotinib at the 2nd level of dose reduction when bradycardia is asymptomatic or the heart rate returns to the age-specific heart rate provided above. Frequently monitor the heart rate. If no contributing medication is identified or if life-threatening bradycardia recurs, permanently discontinue crizotinib.
QT Interval Prolongation
-QT interval corrected for heart rate (QTc) greater than 500 milliseconds (msec) on at least 2 separate electrocardiograms (ECGs): Hold crizotinib therapy. When the QTc is less than 481 msec or at baseline, resume treatment at the next lower dosage.
-QTc greater than 500 msec; QTc change of 60 msec or more from baseline with Torsade de pointes; polymorphic ventricular tachycardia; or signs or symptoms of serious arrhythmia: Permanently discontinue crizotinib.
Gastrointestinal Toxicity (for pediatric patients and young adults with ALCL and pediatric patients with IMT ONLY)
-Grade 3 nausea (oral intake inadequate for more than 3 days despite maximum medical therapy; or medical intervention required): Hold crizotinib therapy. When nausea resolves, resume therapy at the next lower dose level.
-Grade 3 or 4 vomiting (more than 6 episodes in 24 hours for more than 3 days despite maximum medical therapy; medical intervention required [i.e., tube feeding or hospitalization]; life-threatening consequences; or urgent intervention required): Hold crizotinib therapy. When vomiting resolves, resume therapy at the next lower dose level.
-Grade 3 or 4 diarrhea (increase of 7 or more stools per day over baseline despite maximum medical therapy; incontinence; hospitalization indicated; life-threatening consequences; or urgent intervention required): Hold crizotinib therapy. When diarrhea resolves, resume therapy at the next lower dose level.
Hematologic Toxicity (adults with NSCLC or IMT) (does not include lymphopenia unless associated with clinical events such as opportunistic infections)
-Grade 3 toxicity: Hold crizotinib therapy. When toxicity resolves to grade 2 or less, resume treatment at the same dosage.
-Grade 4 toxicity: Hold crizotinib therapy. When toxicity resolves to grade 2 or less, resume treatment at the next lower dosage.
Hematologic Toxicity (pediatric patients and young adults with ALCL and pediatric patients with IMT)
Anemia
-Hemoglobin less than 8 g/dL: Hold crizotinib therapy. When the hemoglobin recovers to 8 g/dL or higher, resume crizotinib at the same dose.
-Life-threatening anemia, urgent intervention required: Hold crizotinib therapy. When the hemoglobin recovers to 8 g/dL or higher, resume crizotinib at the next lower dose. Permanently discontinue crizotinib for a recurrence.
Neutropenia
-ANC less than 500 cells/mm3: Hold crizotinib therapy. When ANC recovers to greater than 1,000 cells/mm3, resume crizotinib at the next lower dose. If the ANC falls below 500 cells/mm3 for a second time and is complicated by neutropenic fever, permanently discontinue crizotinib. If the ANC falls below 500 cells/mm3 for a second time and is not complicated by neutropenic fever, either hold crizotinib until the ANC recovers to 1,000 cells/mm3 or higher and resume therapy at the next lower dose, or permanently discontinue therapy.
Thrombocytopenia
-Platelets 25,000 to 50,000 cells/mm3 with concurrent bleeding: Hold crizotinib therapy. When the platelet count recovers to greater than 50,000 cells/mm3 and the bleeding resolves, resume crizotinib at the same dose.
-Platelets less than 25,000 cells/mm3: Hold crizotinib therapy. When the platelet count recovers to greater than 50,000 cells/mm3, resume crizotinib at the next lower dose. Permanently discontinue crizotinib for a second occurrence of platelet counts less than 25,000 cells/mm3.
Interstitial Lung Disease or Pneumonitis
-Any grade toxicity: Permanently discontinue crizotinib.
Ocular Toxicity, including Visual Loss
-Grade 1 or 2 (mild symptoms, or moderate symptoms affecting the ability to perform age-appropriate activities of daily living): Report any symptoms to an eye specialist. Consider a dose reduction for grade 2 ocular toxicity.
-Grade 3 or 4 (marked decrease in vision): Discontinue crizotinib during evaluation; permanently discontinue crizotinib therapy if no other cause is found on evaluation.
Maximum Dosage Limits:
-Adults
Non-Small Cell Lung Cancer (NSCLC) and Inflammatory Myofibroblastic Tumor (IMT): 250 mg PO twice daily.
Anaplastic Large-Cell Lymphoma (ALCL):
18 to 21 years of age:
-BSA of 1.7 m2 or more: 500 mg PO twice daily.
-BSA of 1.52 to 1.69 m2: 450 mg PO twice daily.
-BSA of 1.34 to 1.51 m2: 400 mg PO twice daily.
-BSA of 1.17 to 1.33 m2: 350 mg PO twice daily.
Older than 21 years:
-Safety and efficacy not established.
-Geriatric
NSCLC: 250 mg PO twice daily.
IMT and ALCL: Safety and efficacy not established.
-Adolescents
NSCLC: Safety and efficacy not established.
ALCL and IMT:
-BSA of 1.7 m2 or more: 500 mg PO twice daily.
-BSA of 1.52 to 1.69 m2: 450 mg PO twice daily.
-BSA of 1.34 to 1.51 m2: 400 mg PO twice daily.
-BSA of 1.17 to 1.33 m2: 350 mg PO twice daily.
-BSA of 0.98 to 1.16 m2: 300 mg PO twice daily.
-BSA of 0.81 to 0.97 m2: 250 mg PO twice daily.
-Children
NSCLC: Safety and efficacy not established.
ALCL and IMT:
-BSA of 1.7 m2 or more: 500 mg PO twice daily.
-BSA of 1.52 to 1.69 m2: 450 mg PO twice daily.
-BSA of 1.34 to 1.51 m2: 400 mg PO twice daily.
-BSA of 1.17 to 1.33 m2: 350 mg PO twice daily.
-BSA of 0.98 to 1.16 m2: 300 mg PO twice daily.
-BSA of 0.81 to 0.97 m2: 250 mg PO twice daily.
-BSA of 0.62 to 0.8 m2: 200 mg PO twice daily.
-BSA of 0.52 to 0.61 m2: 150 mg PO twice daily.
-BSA of 0.47 to 0.51 m2: 140 mg PO twice daily.
-BSA of 0.38 to 0.46 m2: 120 mg PO twice daily.
-Infants
Safety and efficacy not established.
-Neonates
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment
-Mild hepatic impairment (AST greater than the upper limit of normal (ULN) and total bilirubin less than or equal to ULN OR total bilirubin more than 1 to 1.5 times ULN with any AST): No dosage adjustment is necessary.
-Moderate hepatic impairment (total bilirubin 1.6 to 3 times ULN with any AST): Reduce the dose of crizotinib to the first dose reduction, provided above.
-Severe hepatic impairment (total bilirubin greater than 3 times ULN with any AST): Reduce the dose of crizotinib to the second dose reduction, provided above.
Treatment-Related Hepatotoxicity
-ALT or AST greater than 5 times ULN with a total bilirubin 1.5 times ULN or less: Hold crizotinib therapy. When the ALT or AST recovers to 3 times ULN or less or to baseline, resume treatment at the next lower dosage.
-ALT or AST greater than 3 times ULN with a total bilirubin greater than 1.5 times ULN (in the absence of cholestasis or hemolysis): Permanently discontinue crizotinib.
Patients with Renal Impairment Dosing
Baseline Renal Impairment
-Mild to moderate renal impairment (creatinine clearance (CrCl) 30 to 89 mL/min): No dosage adjustment is recommended.
-Severe renal impairment (CrCl of less than 30 mL/min, not requiring dialysis: Reduce the dose of crizotinib to the second dose reduction, provided above.
*non-FDA-approved indication
Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with crizotinib is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with moderate CYP3A4 inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with crizotinib. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; crizotinib is a moderate CYP3A inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
Acebutolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with crizotinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Crizotinib is a moderate inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. If crizotinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like crizotinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If crizotinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Major) Avoid concomitant use of crizotinib and adagrasib due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de points (TdP). If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Albuterol; Budesonide: (Moderate) Avoid coadministration of systemic budesonide with crizotinib due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. If crizotinib is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A inhibitors like crizotinib can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If crizotinib is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alfuzosin: (Major) Avoid coadministration of crizotinib with alfuzosin due to the risk of QT prolongation; increased alfuzosin exposure may also occur. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Also monitor for evidence of alfuzosin-related adverse effects (e.g., hypotension). Alfuzosin is a CYP3A4 substrate that, based on electrophysiology studies performed by the manufacturer, may prolong the QT interval in a dose-dependent manner. Crizotinib is a moderate CYP3A inhibitor that has also been associated with concentration-dependent QT prolongation. Coadministration with a moderate CYP3A4 inhibitor increased the alfuzosin AUC by 1.3-fold.
Alprazolam: (Major) Avoid coadministration of alprazolam and crizotinib due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with crizotinib, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased alprazolam exposure by 1.6- to 1.98-fold.
Amiodarone: (Major) Concomitant use of amiodarone and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase amiodarone exposure and the risk for other adverse effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Amiodarone is a CYP3A substrate, crizotinib is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Avoid coadministration of crizotinib with amisulpride due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Amisulpride causes dose- and concentration- dependent QT prolongation.
Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Atorvastatin: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Celecoxib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of crizotinib and clarithromycin due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de points (TdP). If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Anagrelide: (Major) According to the manufacturer of anagrelide, coadministration with other medications that prolong the QT interval should be avoided. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide; in addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Crizotinib has also been associated with QT prolongation.
Apalutamide: (Major) Avoid coadministration of crizotinib with apalutamide due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and apalutamide is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
Apomorphine: (Major) Avoid coadministration of crizotinib with apomorphine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aprepitant, Fosaprepitant: (Major) Avoid coadministration of crizotinib and aprepitant/fosaprepitant due to substantially increased exposure of aprepitant. Fosaprepitant is rapidly converted to aprepitant; therefore, a similar interaction is likely. Increased crizotinib exposure may also occur with multi-day regimens of oral aprepitant, resulting in increased crizotinib-related adverse reactions, including QT prolongation. Crizotinib is a CYP3A substrate and a moderate CYP3A inhibitor. Aprepitant is also a CYP3A4 substrate and, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate. Administration with another moderate CYP3A4 inhibitor increased the aprepitant AUC by 2-fold.
Aripiprazole: (Major) Avoid concomitant use aripiprazole and crizotinib, if possible, especially in patients with risk factors for torsade de pointes (TdP). If concomitant use is necessary, patients receiving both a CYP2D6 inhibitor plus crizotinib may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use increases the risk for QT/QTc prolongation and TdP and may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate, crizotinib is a moderate CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Arsenic Trioxide: (Major) Avoid concomitant use of arsenic trioxide with crizotinib due to the risk of QT prolongation; discontinue crizotinib or select an alternative drug that does not prolong the QT interval prior to starting arsenic trioxide therapy. If concomitant use is unavoidable, frequently monitor electrocardiograms and electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Crizotinib has also been associated with concentration-dependent QT prolongation.
Artemether; Lumefantrine: (Major) Avoid coadministration of lumefantrine with crizotinib if possible due to the risk of QT prolongation; an increase in lumefantrine-related adverse reactions may also occur. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs have been associated with QT prolongation. Additionally, crizotinib is a moderate CYP3A inhibitor and lumefantrine is a CYP3A4 substrate. The potential for increased lumefantrine concentrations when administered with CYP3A inhibitors could further increase the risk of QT prolongation. (Major) Because both drugs have been associated with QT prolongation, avoid coadministration of artemether with crizotinib if possible; an increase in artemether-related adverse reactions may also occur. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; a dose reduction, interruption of therapy, or discontinuation of therapy may be needed for crizotinib patients if QT prolongation occurs. Crizotinib is a moderate CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Artemether is a CYP3A4 substrate that is also associated with QT prolongation.
Asenapine: (Major) Avoid coadministration of crizotinib with asenapine due to the risk of QT prolongation. Crizotinib has been associated with concentration-dependent QT prolongation. Asenapine has also been associated with QT prolongation.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. If crizotinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like crizotinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If crizotinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Major) Avoid concomitant use of crizotinib and atazanavir due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Atazanavir; Cobicistat: (Major) Avoid concomitant use of crizotinib and atazanavir due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%. (Major) Avoid concomitant use of crizotinib and cobicistat due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects; exposure to cobicistat may also increase. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Atenolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Atenolol; Chlorthalidone: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Atomoxetine: (Major) Avoid coadministration of crizotinib with atomoxetine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval has also occurred during therapeutic use of atomoxetine as well as following overdose.
Avanafil: (Major) Do not exceed an avanafil dose of 50 mg once every 24 hours in patients receiving crizotinib. Coadministration may increase avanafil exposure. Avanafil is a sensitive CYP3A4 substrate; crizotinib is a moderate CYP3A inhibitor. Administration of another moderate CYP3A4 inhibitor increased the avanafil AUC by 3-fold and prolonged the half-life to approximately 8 hours.
Avapritinib: (Major) Avoid coadministration of avapritinib with crizotinib due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Azithromycin: (Major) Avoid coadministration of crizotinib with azithromycin due to the risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance.
Bedaquiline: (Major) Avoid coadministration of crizotinib with bedaquiline due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Bedaquiline has also been reported to prolong the QT interval.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with crizotinib may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of crizotinib in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Crizotinib is a moderate inhibitor of CYP3A.
Berotralstat: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with berotralstat is necessary; crizotinib exposure may increase. Crizotinib is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Beta-adrenergic blockers: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Betaxolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bisoprolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Bosentan: (Moderate) Use caution if coadministration of crizotinib with bosentan is necessary, as the systemic exposure of bosentan may be increased resulting in an increase in treatment-related adverse reactions; however, a bosentan dose adjustment is not necessary. Administration of bosentan with both crizotinib and a strong or moderate CYP2C9 inhibitor is not recommended. Bosentan is a CYP3A and CYP2C9 substrate; crizotinib is a moderate CYP3A inhibitor.
Bosutinib: (Major) Avoid concomitant use of bosutinib and crizotinib as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Brexpiprazole: (Moderate) Use caution if coadministration of crizotinib with brexpiprazole is necessary, as the systemic exposure of brexpiprazole may be increased resulting in an increase in brexpiprazole-related adverse reactions. Reduce the dose of brexpiprazole to one-quarter (25%) of the usual dose if brexpiprazole and crizotinib are coadministered with a moderate to strong inhibitor of CYP2D6 or if the patient is a poor metabolizer of CYP2D6. If crizotinib is discontinued, adjust the brexpiprazole dosage to its original level. Crizotinib is a moderate CYP3A inhibitor. Brexpiprazole is a CYP3A4 and CYP2D6 substrate. Concomitant use of moderate CYP3A4 inhibitors with a strong or moderate CYP2D6 inhibitor increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
Brigatinib: (Major) Avoid coadministration of brigatinib with crizotinib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of crizotinib, resume the brigatinib dose that was tolerated prior to initiation of crizotinib. Brigatinib is a CYP3A4 substrate; crizotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
Brimonidine; Timolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of crizotinib. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; crizotinib is a moderate inhibitor of CYP3A4. Coadministration with another moderate CYP3A4 inhibitor increased bromocriptine exposure by 2.8-fold.
Budesonide: (Moderate) Avoid coadministration of systemic budesonide with crizotinib due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Budesonide; Formoterol: (Moderate) Avoid coadministration of systemic budesonide with crizotinib due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of systemic budesonide with crizotinib due to increased budesonide exposure; use caution with inhaled budesonide, as systemic exposure may increase. Budesonide is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine-related adverse reactions and toxicities if coadministration with crizotinib is necessary. Lidocaine is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Buprenorphine: (Major) Avoid coadministration of crizotinib with buprenorphine due to the risk of QT prolongation. Buprenorphine exposure may also increase, resulting in increased or prolonged opioid effects, particularly when crizotinib is added after a stable dose of buprenorphine has been achieved. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Consider a dosage reduction of buprenorphine until stable drug effects are achieved; monitor for respiratory depression and sedation at frequent intervals. When stopping crizotinib, the buprenorphine concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If crizotinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Buprenorphine is a CYP3A4 substrate that has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
Buprenorphine; Naloxone: (Major) Avoid coadministration of crizotinib with buprenorphine due to the risk of QT prolongation. Buprenorphine exposure may also increase, resulting in increased or prolonged opioid effects, particularly when crizotinib is added after a stable dose of buprenorphine has been achieved. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Consider a dosage reduction of buprenorphine until stable drug effects are achieved; monitor for respiratory depression and sedation at frequent intervals. When stopping crizotinib, the buprenorphine concentration will decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If crizotinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Buprenorphine is a CYP3A4 substrate that has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval.
Buspirone: (Moderate) Monitor for an increase in buspirone-related adverse reactions if coadministration with crizotinib is necessary; the effect may be more pronounced if the patient has been titrated to a stable dose of buspirone and crizotinib is added or removed from therapy. Buspirone is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased buspirone exposure by 3.4 to 6-fold and was accompanied by increased buspirone-related adverse reactions.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
Cabotegravir; Rilpivirine: (Major) Avoid coadministration of crizotinib with rilpivirine due to the risk of QT prolongation; exposure to rilpivirine may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation; rilpivirine is also a CYP3A4 substrate.
Capivasertib: (Major) Reduce the dose of capivasertib to 320 mg PO twice daily for 4 days followed by 3 days off if coadministration with crizotinib is necessary; monitor for adverse reactions. Concomitant use may increase capivasertib exposure which may increase the risk for capivasertib-related adverse effects. Capivasertib is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor is predicted to increase the overall exposure of capivasertib by up to 1.5-fold.
Carbamazepine: (Major) Avoid coadministration of crizotinib with carbamazepine due to decreased crizotinib exposure; increased carbamazepine exposure may also occur. Both drugs are CYP3A substrates. Crizotinib is also a moderate CYP3A inhibitor and carbamazepine is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the AUC of crizotinib at steady-state by 84%.
Carteolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Carvedilol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with crizotinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of crizotinib, a moderate CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Ceritinib: (Major) Avoid concomitant use of crizotinib and ceritinib due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de points (TdP). If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate, ceritinib is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Chloramphenicol: (Major) Avoid concomitant use of crizotinib and chloramphenicol due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Chloroquine: (Major) Avoid coadministration of chloroquine with crizotinib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpromazine: (Major) Avoid coadministration of crizotinib with chlorpromazine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Chlorpromazine, a phenothiazine, is also associated with an established risk of QT prolongation and torsade de pointes (TdP).
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with crizotinib and monitor for an increase in cilostazol-related adverse reactions. Cilostazol is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased the Cmax and AUC of cilostazol (single dose) by 47% and 73%, respectively; the AUC of 4-trans-hydroxycilostazol increased by 141%.
Ciprofloxacin: (Major) Avoid coadministration of crizotinib with ciprofloxacin due to the risk of QT prolongation; crizotinib exposure may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Also monitor for an increase in crizotinib-related adverse reactions. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Ciprofloxacin is a moderate CYP3A4 inhibitor that has had rare cases of QT prolongation and torsade de pointes (TdP) reported during postmarketing surveillance.
Cisapride: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of crizotinib with cisapride is contraindicated. QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride; crizotinib is also associated with QT prolongation.
Citalopram: (Major) Coadministration of crizotinib with citalopram is not recommended due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs have been associated with concentration-dependent QT prolongation.
Clarithromycin: (Major) Avoid concomitant use of crizotinib and clarithromycin due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de points (TdP). If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Clofazimine: (Major) Concomitant use of clofazimine and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clonazepam: (Moderate) Monitor for an increase in clonazepam-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary; adjust the dose of clonazepam if necessary. Crizotinib is a moderate CYP3A inhibitor and clonazepam is a CYP3A substrate. Although clinical studies have not been performed, based on the involvement of CYP3A in clonazepam metabolism, inhibitors of this enzyme system may increase clonazepam exposure and should be used cautiously.
Clonidine: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as clonidine, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Clozapine: (Major) Avoid coadministration of crizotinib with clozapine due to the risk of QT prolongation; exposure to clozapine may also increase. If concomitant use is unavoidable, consider a clozapine dose reduction. Monitor ECGs for QT prolongation and monitor electrolytes; also monitor for clozapine-related adverse reactions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. If crizotinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Clozapine is partially metabolized by CYP3A4, and has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Cobicistat: (Major) Avoid concomitant use of crizotinib and cobicistat due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects; exposure to cobicistat may also increase. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with cobimetinib due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate and cobimetinib is a moderate inhibitor of CYP3A. Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone.
Codeine: (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of promethazine and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
Codeine; Promethazine: (Major) Concomitant use of promethazine and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Concomitant use of codeine with crizotinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of crizotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If crizotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Crizotinib is a moderate inhibitor of CYP3A.
Colchicine: (Major) Avoid concomitant use of colchicine and crizotinib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. If concomitant use is necessary, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce a dose of 0.6 mg twice daily to 0.3 mg twice daily or 0.6 mg once daily; reduce a dose of 0.6 mg once daily to 0.3 mg once daily. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 1.2 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 1.2 mg. Colchicine is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors increased colchicine overall exposure by 1.4- to 1.9-fold.
Conivaptan: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with conivaptan is necessary; crizotinib exposure may increase. Crizotinib is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor.
Conjugated Estrogens; Medroxyprogesterone: (Moderate) Use caution if concomitant of crizotinib and medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Crizotinib is a moderate CYP3A4 inhibitor. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4.
Cyclosporine: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with crizotinib; additionally, monitor for an increase in crizotinib-related adverse reactions. Use of these medications together may result in elevated serum concentrations of both drugs, causing an increased risk for treatment-related adverse events. Crizotinib Is a CYP3A substrate and moderate inhibitor. Cyclosporine is a CYP3A4 substrate with a narrow therapeutic index and is also a moderate CYP3A4 inhibitor.
Danazol: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with danazol is necessary. Crizotinib is a CYP3A substrate and danazol is a moderate CYP3A inhibitor.
Daridorexant: (Major) Limit the daridorexant dose to 25 mg if coadministered with crizotinib. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Darunavir: (Major) Avoid concomitant use of crizotinib and darunavir due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects; exposure to darunavir may also increase. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor; darunavir is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Darunavir; Cobicistat: (Major) Avoid concomitant use of crizotinib and cobicistat due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects; exposure to cobicistat may also increase. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%. (Major) Avoid concomitant use of crizotinib and darunavir due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects; exposure to darunavir may also increase. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor; darunavir is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant use of crizotinib and cobicistat due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects; exposure to cobicistat may also increase. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%. (Major) Avoid concomitant use of crizotinib and darunavir due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects; exposure to darunavir may also increase. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor; darunavir is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Dasatinib: (Major) Avoid coadministration of crizotinib with dasatinib due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. In vitro studies have shown that dasatinib also has the potential to prolong the QT interval.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with crizotinib. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; crizotinib is a moderate inhibitor of CYP3A4.
Degarelix: (Major) Avoid coadministration of crizotinib with degarelix due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
Delavirdine: (Major) Avoid concomitant use of crizotinib and delavirdine due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Desflurane: (Major) Avoid coadministration of crizotinib with halogenated anesthetics due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Halogenated anesthetics can also prolong the QT interval.
Deutetrabenazine: (Major) Avoid coadministration of crizotinib with deutetrabenazine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextromethorphan; Quinidine: (Major) Avoid coadministration of crizotinib with quinidine due to the risk of QT prolongation; exposure to quinidine may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Quinidine administration is also associated with QT prolongation and torsade de pointes (TdP).
Diazepam: (Moderate) Monitor for increased diazepam-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary. Diazepam is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation.
Digoxin: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as digoxin, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor for heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Dihydroergotamine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions including cerebral and peripheral ischemia during concomitant use of ergotamine and crizotinib. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor.
Diltiazem: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as diltiazem, to the extent possible due to the risk of additive bradycardia; increased exposure to both drugs may also occur. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly, and watch for an increase in crizotinib-related adverse reactions. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs. Crizotinib and diltiazem are both CYP3A substrates and moderate inhibitors.
Disopyramide: (Major) Avoid coadministration of crizotinib with disopyramide due to the risk of QT prolongation; disopyramide exposure may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; also monitor for an increase in disopyramide-related adverse reactions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Disopyramide is a CYP3A4 substrate that is also associated with QT prolongation and torsade de pointes (TdP). Cases of life-threatening interactions have been reported when disopyramide was coadministered with moderate CYP3A4 inhibitors.
Dofetilide: (Major) Avoid coadministration of crizotinib with dofetilide due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
Dolasetron: (Major) Avoid coadministration of crizotinib with dolasetron due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Dolasetron has also been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir; Rilpivirine: (Major) Avoid coadministration of crizotinib with rilpivirine due to the risk of QT prolongation; exposure to rilpivirine may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation; rilpivirine is also a CYP3A4 substrate.
Donepezil: (Major) Avoid coadministration of crizotinib with donepezil due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
Donepezil; Memantine: (Major) Avoid coadministration of crizotinib with donepezil due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
Dorzolamide; Timolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Doxorubicin Liposomal: (Major) Avoid coadministration of crizotinib with doxorubicin due to the risk of increased doxorubicin exposure resulting in increased treatment-related adverse reactions. Crizotinib is a moderate CYP3A inhibitor and doxorubicin is a major substrate of CYP3A4; clinically significant interactions have been reported with other CYP3A4 inhibitors, resulting in increased concentration and clinical effect of doxorubicin.
Doxorubicin: (Major) Avoid coadministration of crizotinib with doxorubicin due to the risk of increased doxorubicin exposure resulting in increased treatment-related adverse reactions. Crizotinib is a moderate CYP3A inhibitor and doxorubicin is a major substrate of CYP3A4; clinically significant interactions have been reported with other CYP3A4 inhibitors, resulting in increased concentration and clinical effect of doxorubicin.
Dronabinol: (Moderate) Monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence) if coadministration with crizotinib is necessary. Crizotinib is a moderate CYP3A inhibitor and dronabinol is a CYP3A substrate.
Dronedarone: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of crizotinib with dronedarone is contraindicated. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Crizotinib has also been associated with concentration-dependent QT prolongation. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Major) Droperidol should not be used in combination with any drug known to have potential to prolong the QT interval, such as crizotinib. If concomitant use is unavoidable, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. Crizotinib is also associated with concentration-dependent QT prolongation.
Dutasteride; Tamsulosin: (Moderate) Use caution if coadministration of crizotinib with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. The effects of concomitant administration of a moderate CYP3A4 inhibitor on the pharmacokinetics of tamsulosin have not been evaluated, but tamsulosin exposure may increase based on the effects of strong CYP3A4 inhibition.
Duvelisib: (Moderate) Monitor for increased toxicity of duvelisib and crizotinib during coadministration. Coadministration may increase the exposure of both drugs. Duvelisib is a substrate and moderate inhibitor of CYP3A; crizotinib is also a substrate and moderate inhibitor of CYP3A.
Efavirenz: (Major) Avoid concomitant use of crizotinib and efavirenz due to the risk of QT prolongation. Crizotinib can cause concentration-dependent QT prolongation. QTc prolongation has also been observed with the use of efavirenz.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of crizotinib and efavirenz due to the risk of QT prolongation. Crizotinib can cause concentration-dependent QT prolongation. QTc prolongation has also been observed with the use of efavirenz.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of crizotinib and efavirenz due to the risk of QT prolongation. Crizotinib can cause concentration-dependent QT prolongation. QTc prolongation has also been observed with the use of efavirenz.
Elacestrant: (Major) Avoid concomitant use of elacestrant and crizotinib due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased elacestrant overall exposure by 2.3-fold.
Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with crizotinib. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A4, and crizotinib is a moderate CYP3A inhibitor. Coadministration of other moderate CYP3A4 inhibitors increased the eletriptan AUC by 2 to 4-fold.
Elexacaftor; tezacaftor; ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with crizotinib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); crizotinib is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If crizotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to every other day in the morning when coadministered with crizotinib; omit the ivacaftor evening dose and administer in the morning every other day alternating with elexacaftor; tezacaftor; ivacaftor (i.e., recommended dose of elexacaftor; tezacaftor; ivacaftor on day 1 in the morning and recommended dose of ivacaftor on day 2 in the morning). Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; crizotinib is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure by 2.9-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2.1-fold, respectively.
Eliglustat: (Major) Avoid coadministration of crizotinib with eliglustat in all patients due to the risk of QT prolongation. If concomitant use is unavoidable in extensive CYP2D6 metabolizers (EMs), reduce the dose of eliglustat to 84 mg PO once daily; monitor ECGs for QT prolongation and monitor electrolytes. In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of crizotinib and eliglustat is not recommended. The coadministration of eliglustat with both crizotinib and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Both eliglustat and crizotinib can independently prolong the QT interval, and coadministration increases this risk. Crizotinib is a moderate CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors, such as crizotinib, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant use of crizotinib and cobicistat due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects; exposure to cobicistat may also increase. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of crizotinib and cobicistat due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects; exposure to cobicistat may also increase. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of crizotinib with rilpivirine due to the risk of QT prolongation; exposure to rilpivirine may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation; rilpivirine is also a CYP3A4 substrate.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of crizotinib with rilpivirine due to the risk of QT prolongation; exposure to rilpivirine may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation; rilpivirine is also a CYP3A4 substrate.
Encorafenib: (Major) Avoid concomitant use of encorafenib and crizotinib due to the risk for decreased crizotinib exposure, increased encorafenib exposure, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 225 mg, reduce a daily dose of 300 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another moderate CYP3A inhibitor increased encorafenib overall exposure by 2-fold. Coadministration with another strong CYP3A inducer decreased the crizotinib AUC at steady state by 84%.
Entrectinib: (Major) Avoid concomitant use of entrectinib with crizotinib due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day or 400 mg/day to 200 mg/day; 300 mg/day to 100 mg/day; 200 mg/day to 50 mg/day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, crizotinib is a moderate CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of a moderate CYP3A inhibitor is predicted to increase the overall exposure of entrectinib by 3-fold.
Enzalutamide: (Major) Avoid coadministration of crizotinib with enzalutamide due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with crizotinib in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving concurrent crizotinib, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. Measure serum creatinine and serum potassium within 3 to 7 days of initiating crizotinib and periodically thereafter. Eplerenone is a CYP3A4 substrate. Crizotinib is a moderate CYP3A inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Ergotamine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions including cerebral and peripheral ischemia during concomitant use of ergotamine and crizotinib. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor.
Ergotamine; Caffeine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions including cerebral and peripheral ischemia during concomitant use of ergotamine and crizotinib. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor.
Eribulin: (Major) Avoid coadministration of crizotinib with eribulin due to the risk of QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Eribulin has also been associated with QT prolongation.
Erythromycin: (Major) Avoid coadministration of crizotinib with erythromycin due to the risk of QT prolongation; crizotinib exposure may also increase. If concomitant use is unavoidable, monitor for an increase in crizotinib-related adverse reactions, monitor ECGs for QT prolongation, and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Erythromycin is a moderate CYP3A4 inhibitor that is also associated with QT prolongation and torsade de pointes (TdP).
Escitalopram: (Major) Avoid coadministration of crizotinib with escitalopram due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Escitalopram has also been associated with a risk of QT prolongation and torsade de pointes (TdP).
Esmolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Etrasimod: (Major) Avoid concomitant use of etrasimod and crizotinib in CYP2C9 poor metabolizers due to the risk for increased etrasimod exposure which may increase the risk for adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de pointes (TdP). Etrasimod is a CYP2C9 and CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Etravirine: (Minor) Monitor for an increase in etravirine-related adverse reactions if coadministration with crizotinib is necessary. Etravirine is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with crizotinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Crizotinib is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with crizotinib is necessary. Simvastatin is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Fedratinib: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with fedratinib is necessary; crizotinib exposure may increase. Crizotinib is a CYP3A substrate and fedratinib is a moderate CYP3A inhibitor.
Felodipine: (Moderate) Concurrent use of felodipine and crizotinib should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Concurrent use of another moderate CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 2.5-fold and 2-fold, respectively.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. If crizotinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A inhibitors like crizotinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If crizotinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Fexinidazole: (Major) Avoid concomitant use of fexinidazole and medications that cause bradycardia, such as crizotinib, especially in patients with additional risk factors for torsade de pointes (TdP). Coadministration may increase the risk of QT/QTc prolongation and TdP. Fexinidazole is known to prolong the QT interval and medications that may cause bradycardia can increase the risk for TdP in patients with a prolonged QT/QTc interval. Concomitant use may also limit conversion of fexinidazole to its active metabolites, reducing its efficacy. Fexinidazole is converted to its active metabolites via CYP3A and crizotinib is a moderate CYP3A inhibitor.
Finasteride; Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with crizotinib is necessary. Tadalafil is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or crizotinib; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased overall exposure to finerenone by 248%.
Fingolimod: (Major) Avoid coadministration of crizotinib with fingolimod due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP). An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flecainide: (Major) Avoid coadministration of crizotinib with flecainide due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and crizotinib is contraindicated due to increased flibanserin exposure, which can result in severe hypotension and syncope. If initiating flibanserin following use of crizotinib, start flibanserin at least 2 weeks after the last dose of crizotinib. If initiating crizotinib following flibanserin use, start crizotinib at least 2 days after the last dose of flibanserin. Flibanserin is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
Fluconazole: (Contraindicated) The concurrent use of fluconazole with crizotinib is contraindicated due to the risk of QT prolongation; increased crizotinib exposure may also occur. Both fluconazole and crizotinib have been associated with QT prolongation; fluconazole has also been associated with rare cases of torsade de pointes (TdP). Additionally, fluconazole is a moderate inhibitor of CYP3A4 and crizotinib is a CYP3A4 substrate. Fluconazole is contraindicated for coadministration with drugs that are associated with QT prolongation and are also CYP3A4 substrates.
Fluoxetine: (Major) Avoid coadministration of crizotinib with fluoxetine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine.
Fluphenazine: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with fluphenazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs have been associated with QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Fluvoxamine: (Major) Avoid coadministration of crizotinib with fluvoxamine due to the risk of QT prolongation; crizotinib exposure may also increase. If concomitant use is unavoidable, monitor for an increase in crizotinib-related adverse reactions; also, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Fluvoxamine is a moderate CYP3A4 inhibitor that has had postmarketing reports of QT prolongation and torsade de pointes (TdP).
Fosamprenavir: (Moderate) Monitor for an increase in adverse reactions from both drugs if crizotinib is coadministered with fosamprenavir. Concomitant use may increase the exposure of both drugs. Crizotinib and fosamprenavir are both CYP3A substrates and moderate CYP3A inhibitors.
Foscarnet: (Major) Avoid coadministration of crizotinib with foscarnet due to the risk of QT prolongation. Crizotinib has been associated with concentration-dependent QT prolongation. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
Fosphenytoin: (Major) Avoid coadministration of crizotinib with fosphenytoin due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
Fostemsavir: (Major) Avoid coadministration of crizotinib with fostemsavir due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause dose-dependent QT prolongation. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, 4 times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gemifloxacin: (Major) Avoid coadministration of crizotinib with gemifloxacin due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Gemifloxacin may also prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Major) Avoid coadministration of crizotinib with gemtuzumab due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes at baseline and during treatment. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
Gilteritinib: (Major) Avoid coadministration of crizotinib with gilteritinib due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Gilteritinib has been associated with QT prolongation.
Glasdegib: (Major) Avoid coadministration of glasdegib with crizotinib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; monitor with increased frequency in patients at increased risk for QT prolongation. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Crizotinib has also been associated with concentration-dependent QT prolongation.
Goserelin: (Major) Avoid coadministration of crizotinib with goserelin due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Androgen deprivation therapy (e.g., goserelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
Granisetron: (Major) Avoid coadministration of crizotinib with granisetron due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Granisetron has also been associated with QT prolongation.
Grapefruit juice: (Major) Due to the potential for increased crizotinib exposure and side effects, patients should be advised to avoid intake of grapefruit or grapefruit juice during crizotinib therapy. Crizotinib is a CYP3A substrate and grapefruit juice is a strong CYP3A inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC and Cmax of single-dose crizotinib by 216% and 44%, respectively. Concomitant use with another strong CYP3A4 inhibitor increased the steady-state AUC and Cmax of crizotinib by 57% and 33%, respectively, compared to crizotinib alone.
Guanfacine: (Major) Reduce the extended-release (ER) guanfacine dosage to half of the recommended dose if coadministration with crizotinib is necessary. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If crizotinib is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Crizotinib may significantly increase guanfacine plasma concentrations.
Halogenated Anesthetics: (Major) Avoid coadministration of crizotinib with halogenated anesthetics due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Halogenated anesthetics can also prolong the QT interval.
Haloperidol: (Major) Avoid coadministration of crizotinib with haloperidol due to the risk of QT prolongation; haloperidol plasma concentrations may also increase. If concomitant use is unavoidable, monitor for an increase in haloperidol-related adverse reactions; also monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Haloperidol is a CYP3A4 substrate that has had reports of QT prolongation and torsade de pointes (TdP) during treatment; excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk. In clinical trials, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with CYP3A4 inhibitors.
Histrelin: (Major) Avoid coadministration of crizotinib with histrelin due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like crizotinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If crizotinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydroxychloroquine: (Major) Avoid coadministration of crizotinib and hydroxychloroquine due to the risk of increased QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Hydroxychloroquine also prolongs the QT interval.
Hydroxyzine: (Major) Avoid coadministration of crizotinib with hydroxyzine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Postmarketing data indicate that hydroxyzine also causes QT prolongation and torsade de pointes (TdP).
Ibrutinib: (Major) If ibrutinib is coadministered with crizotinib, reduce the ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if crizotinib is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A substrate; crizotinib is a moderate CYP3A inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. If crizotinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like crizotinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If crizotinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ibutilide: (Major) Avoid coadministration of crizotinib with ibutilide due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Ibutilide administration can also cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
Idelalisib: (Major) Avoid concomitant use of crizotinib and idelalisib due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with crizotinib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Crizotinib is a moderate CYP3A inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Major) Avoid coadministration of crizotinib with iloperidone due to the risk of QT prolongation. Crizotinib has been associated with concentration-dependent QT prolongation. Iloperidone has also been associated with QT prolongation.
Imatinib: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with imatinib is necessary. Crizotinib is a CYP3A substrate and imatinib is a moderate CYP3A inhibitor.
Indinavir: (Major) Avoid concomitant use of crizotinib and indinavir due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and indinavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Infigratinib: (Major) Avoid concomitant use of infigratinib and crizotinib. Coadministration may increase infigratinib exposure, increasing the risk of adverse effects. Infigratinib is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with crizotinib due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for QT prolongation. Inotuzumab has been associated with QT interval prolongation. Crizotinib has also been associated with concentration-dependent QT prolongation.
Isavuconazonium: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with isavuconazonium is necessary. Crizotinib is a CYP3A substrate and isavuconazonium is a moderate CYP3A inhibitor.
Isoflurane: (Major) Avoid coadministration of crizotinib with halogenated anesthetics due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Halogenated anesthetics can also prolong the QT interval.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of crizotinib with rifampin due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of crizotinib with rifampin due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
Isradipine: (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with crizotinib is necessary. Isradipine is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor.
Itraconazole: (Contraindicated) Itraconazole use is contraindicated with medications that may prolong the QT/QTc interval that are also CYP3A substrates, such as crizotinib, due to the risk for increase crizotinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). While coadministration is not recommended, if use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate, itraconazole is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use has been observed to increase crizotinib overall exposure by 57%.
Ivabradine: (Major) Avoid coadministration of ivabradine and crizotinib as increased concentrations of ivabradine are possible, which may result in bradycardia exacerbation and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4 and crizotinib is a moderate CYP3A inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased the AUC of ivabradine by 2- to 3-fold.
Ivacaftor: (Major) If crizotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with crizotinib due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of crizotinib is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor.
Ketoconazole: (Contraindicated) Ketoconazole use is contraindicated with medications that may prolong the QT/QTc interval that are also CYP3A substrates, such as crizotinib, due to the risk for increase crizotinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). While coadministration is not recommended, if use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate, ketoconazole is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use has been observed to increase crizotinib overall exposure by 216%.
Labetalol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of crizotinib and clarithromycin due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de points (TdP). If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Lapatinib: (Major) Avoid coadministration of crizotinib with lapatinib due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Both drugs have been associated with concentration-dependent QT prolongation. Ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
Larotrectinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with crizotinib is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Lefamulin: (Major) Avoid coadministration of lefamulin with crizotinib as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. If coadministration cannot be avoided, monitor ECG and electrolytes during treatment; additionally, monitor for lefamulin-related adverse effects if oral lefamulin is administered. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Crizotinib is a moderate CYP3A4 that can cause concentration-dependent QT prolongation.
Lemborexant: (Major) Avoid coadministration of lemborexant and crizotinib as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; crizotinib is a moderate CYP3A4 inhibitor. Coadministration of lemborexant with another moderate CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Lenacapavir: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with lenacapavir is necessary; crizotinib exposure may increase. Crizotinib is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with crizotinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Crizotinib has been associated with concentration-dependent QT prolongation.
Letermovir: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with letermovir is necessary; concomitant use may increase crizotinib exposure and the risk for crizotinib-related adverse effects. Avoid concomitant use of crizotinib and letermovir plus cyclosporine as use may further increase crizotinib overall exposure. If concomitant use of letermovir plus cyclosporine is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate. Letermovir is a moderate CYP3A inhibitor; the combined effect of letermovir plus cyclosporine on CYP3A substrates is similar to a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Leuprolide: (Major) Avoid coadministration of crizotinib with leuprolide due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Androgen deprivation therapy (e.g., leuprolide) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
Leuprolide; Norethindrone: (Major) Avoid coadministration of crizotinib with leuprolide due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Androgen deprivation therapy (e.g., leuprolide) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Levobunolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Levofloxacin: (Major) Concomitant use of levofloxacin and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Ketoconazole use is contraindicated with medications that may prolong the QT/QTc interval that are also CYP3A substrates, such as crizotinib, due to the risk for increase crizotinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). While coadministration is not recommended, if use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate, ketoconazole is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use has been observed to increase crizotinib overall exposure by 216%.
Lidocaine: (Moderate) Monitor for lidocaine-related adverse reactions and toxicities if coadministration with crizotinib is necessary. Lidocaine is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine-related adverse reactions and toxicities if coadministration with crizotinib is necessary. Lidocaine is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine-related adverse reactions and toxicities if coadministration with crizotinib is necessary. Lidocaine is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Lithium: (Major) Avoid coadministration of crizotinib with lithium due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Lithium has also been associated with QT prolongation.
Lofexidine: (Major) Avoid coadministration of crizotinib with lofexidine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Lofexidine also prolongs the QT interval.
Lomitapide: (Contraindicated) Concomitant use of crizotinib and lomitapide is contraindicated due to increased lomitapide exposure. If treatment with crizotinib is unavoidable, lomitapide should be stopped during the course of treatment. Lomitapide is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Although concomitant use of moderate CYP3A4 inhibitors with lomitapide has not been studied, a significant increase in lomitapide exposure is likely during concurrent use based on the 27-fold increase in exposure observed with coadministration of a strong CYP3A4 inhibitor.
Lonafarnib: (Contraindicated) Concomitant use of lonafarnib and crizotinib is contraindicated and may increase the exposure and risk of adverse effects from both drugs. While coadministration is not recommended, if use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Lonafarnib is a CYP3A substrate and strong CYP3A inhibitor; crizotinib is a CYP3A substrate and moderate CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Loperamide: (Major) Avoid concomitant use of crizotinib and loperamide due to the risk of additive QT prolongation. If concomitant use is necessary, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is has been associated with concentration-dependent QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Loperamide; Simethicone: (Major) Avoid concomitant use of crizotinib and loperamide due to the risk of additive QT prolongation. If concomitant use is necessary, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is has been associated with concentration-dependent QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with crizotinib due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Interrupt, dose reduce, or discontinue crizotinib therapy if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Lopinavir is associated with QT prolongation. (Major) Avoid concomitant use of crizotinib and ritonavir due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with crizotinib is necessary. Lovastatin is a sensitive substrate of CYP3A4 and crizotinib is a moderate CYP3A inhibitor.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of crizotinib with lumacaftor; ivacaftor due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively. (Major) If crizotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of crizotinib with lumacaftor; ivacaftor due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
Lumateperone: (Major) Reduce the dose of lumateperone to 21 mg once daily if concomitant use of crizotinib is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; crizotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased lumateperone exposure by approximately 2-fold.
Lurasidone: (Major) The recommended starting dose of lurasidone is 20 mg daily (maximum, 80 mg daily) if coadministration with crizotinib is necessary. Reduce the lurasidone dose to half of its original dose level if crizotinib is added to existing lurasidone therapy. Lurasidone is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased lurasidone exposure by 116%.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and crizotinib due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. If concomitant use is unavoidable, consider reducing the dose of lurbinectedin if clinically indicated. Lurbinectedin is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as crizotinib. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Crizotinib has been associated with concentration-dependent QT prolongation.
Macitentan; Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with crizotinib is necessary. Tadalafil is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Maprotiline: (Major) Avoid coadministration of crizotinib with maprotiline due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if concomitant use with crizotinib is necessary. Maraviroc is a sensitive CYP3A substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors may result in increased maraviroc concentrations.
Mavacamten: (Major) Reduce the mavacamten dose by 1 level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients receiving mavacamten and starting crizotinib therapy. Avoid initiation of crizotinib in patients who are on stable treatment with mavacamten 2.5 mg per day because a lower dose of mavacamten is not available. Initiate mavacamten at the recommended starting dose of 5 mg PO once daily in patients who are on stable crizotinib therapy. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions. Mavacamten is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. The impact that a CYP3A inhibitor may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of a moderate CYP3A inhibitor increased mavacamten overall exposure by 15% in CYP2C19 normal and intermediate metabolizers; concomitant use in poor metabolizers is predicted to increase mavacamten exposure by up to 55%.
Medroxyprogesterone: (Moderate) Use caution if concomitant of crizotinib and medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Crizotinib is a moderate CYP3A4 inhibitor. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4.
Mefloquine: (Major) Avoid coadministration of crizotinib with mefloquine due to the risk of QT prolongation; exposure to mefloquine may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; also monitor for an increase in mefloquine-related adverse reactions. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Mefloquine is a CYP3A4 substrate. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
Metformin; Repaglinide: (Moderate) Monitor blood sugar if coadministration of repaglinide with crizotinib is necessary; an increase in repaglinide-related adverse reactions may occur. Repaglinide is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Methadone: (Major) Avoid coadministration of crizotinib with methadone due to the risk of QT prolongation; exposure to methadone may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. If crizotinib is discontinued, consider increasing the methadone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Methadone is a CYP3A4 substrate considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (greater than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Crizotinib is a moderate CYP3A inhibitor that has also been associated with concentration-dependent QT prolongation. Coadministration can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone. If crizotinib is discontinued, methadone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
Methylergonovine: (Moderate) Monitor for an increase in the incidence and severity of vasospastic adverse reactions, including cerebral and peripheral ischemia, during concomitant use of methylergonovine and crizotinib. Concomitant use may increase methylergonovine exposure. Methylergonovine is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor.
Metoprolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Metoprolol; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Metronidazole: (Major) Concomitant use of metronidazole and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Midazolam: (Moderate) Monitor for an increase in midazolam-related adverse reactions (e.g., sedation, respiratory depression) if coadministration with crizotinib is necessary. Midazolam is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with crizotinib increased midazolam exposure by 3.7-fold.
Midostaurin: (Major) Avoid coadministration of crizotinib with midostaurin due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval was also reported in patients who received midostaurin in clinical trials.
Mifepristone: (Major) Avoid concomitant use of crizotinib and mifepristone due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de points (TdP). If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate, mifepristone is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Mirtazapine: (Major) Concomitant use of crizotinib and mirtazapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mitapivat: (Moderate) Do not exceed mitapivat 20 mg PO twice daily during coadministration with crizotinib and monitor hemoglobin and for adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased mitapivat overall exposure by 2.6-fold.
Mitotane: (Major) Avoid coadministration of crizotinib with mitotane due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and crizotinib; reduce the dose of mobocertinib by approximately 50% and monitor the QT interval more frequently if use is necessary. Concomitant use increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may increase mobocertinib exposure and the risk for mobocertinib-related adverse reactions. Mobocertinib is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Use of a moderate CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 100% to 200%.
Moxifloxacin: (Major) Avoid coadministration of crizotinib with moxifloxacin due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Quinolones have also been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (TdP) has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
Nadolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with crizotinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; crizotinib is a moderate CYP3A inhibitor.
Naloxegol: (Major) Avoid concomitant administration of naloxegol and crizotinib due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with crizotinib is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of crizotinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor.
Nebivolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Nebivolol; Valsartan: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Nefazodone: (Major) Avoid concomitant use of crizotinib and nefazodone due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Nelfinavir: (Major) Avoid concomitant use of crizotinib and nelfinavir due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects; exposure to nelfinavir may also increase. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor; nelfinavir is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Neratinib: (Major) Avoid concomitant use of crizotinib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with netupitant is necessary. Crizotinib is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor.
NIFEdipine: (Moderate) Monitor for an increase in nifedipine-related adverse reactions, including hypotension, if coadministration with crizotinib is necessary. Nifedipine is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor.
Nilotinib: (Major) Avoid coadministration of crizotinib with nilotinib due to the risk of QT prolongation; exposure to crizotinib may also increase. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy; nilotinib is also a moderate CYP3A4 inhibitor. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation.
Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with crizotinib is necessary. Nimodipine is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of crizotinib and ritonavir due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Nirogacestat: (Major) Avoid concomitant use of nirogacestat and crizotinib due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase crizotinib exposure and the risk for crizotinib-related adverse effects. Both medications are CYP3A substrates and moderate CYP3A inhibitors. Concomitant use with other moderate CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 2.73- to 3.18-fold.
Nisoldipine: (Major) In general, coadministration of nisoldipine with crizotinib should be avoided due to increased nisoldipine exposure. Crizotinib is a moderate CYP3A inhibitor and nisoldipine is a CYP3A substrate.
Ofloxacin: (Major) Concomitant use of ofloxacin and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) Avoid coadministration of crizotinib with olanzapine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Olanzapine; Fluoxetine: (Major) Avoid coadministration of crizotinib with fluoxetine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine. (Major) Avoid coadministration of crizotinib with olanzapine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Olanzapine; Samidorphan: (Major) Avoid coadministration of crizotinib with olanzapine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Olaparib: (Major) Avoid coadministration of olaparib with crizotinib due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 150 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after crizotinib is discontinued. Olaparib is a CYP3A substrate and crizotinib is a moderate CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with a moderate CYP3A inhibitor is predicted to increase the olaparib Cmax by 14% and the AUC by 121%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and crizotinib is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and crizotinib may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If crizotinib is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and crizotinib. If concomitant use is necessary, decrease omaveloxolone dose to 100 mg once daily; additional dosage reductions may be necessary. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased omaveloxolone overall exposure by 1.25-fold.
Ondansetron: (Major) Concomitant use of ondansetron and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Osilodrostat: (Major) Avoid coadministration of crizotinib with osilodrostat due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Osilodrostat is associated with dose-dependent QT prolongation.
Osimertinib: (Major) Avoid coadministration of crizotinib with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib; crizotinib has been associated with concentration-dependent QT prolongation.
Oxaliplatin: (Major) Avoid coadministration of crizotinib with oxaliplatin due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval and ventricular arrhythmias including fatal torsade de pointes (TdP) have been reported with oxaliplatin in postmarketing experience.
Oxybutynin: (Minor) Monitor for oxybutynin-related adverse reactions if coadministration with crizotinib is necessary. Oxybutynin is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Concomitant use with moderate CYP3A4 inhibitors may alter the mean pharmacokinetic parameters of oxybutynin, although the clinical relevance of these potential interactions is unknown. The manufacturer of oxybutynin recommends administering with caution.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. If crizotinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like crizotinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If crizotinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ozanimod: (Major) Avoid coadministration of crizotinib with ozanimod due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with torsade de pointes in patients with bradycardia.
Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration with crizotinib is necessary. Paclitaxel is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with crizotinib is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de pointes (TdP). Pacritinib is a CYP3A substrate and crizotinib is a strong CYP3A inhibitor.
Paliperidone: (Major) Avoid coadministration of crizotinib with paliperidone if possible due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Paliperidone has also been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose.
Palovarotene: (Major) Avoid concomitant use of palovarotene and crizotinib due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. If concomitant use is necessary, decrease the palovarotene dose by half. Palovarotene is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased palovarotene overall exposure by 2.5-fold.
Panobinostat: (Major) Coadministration of crizotinib with panobinostat is not recommended due to the risk of QT prolongation. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval has also been reported with panobinostat.
Pasireotide: (Major) Avoid coadministration of crizotinib with pasireotide due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval has occurred with pasireotide at therapeutic and supra-therapeutic doses.
Pazopanib: (Major) Avoid coadministration of crizotinib with pazopanib due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Pazopanib has also been reported to prolong the QT interval.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and crizotinib due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If crizotinib is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of crizotinib. Pemigatinib is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase pemigatinib exposure by approximately 50% to 80%.
Pentamidine: (Major) Avoid coadministration of crizotinib with systemic pentamidine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Systemic pentamidine has also been associated with QT prolongation.
Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Perphenazine: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with perphenazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Perphenazine is also associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Perphenazine; Amitriptyline: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with perphenazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Perphenazine is also associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and crizotinib due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If crizotinib is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of crizotinib. Pexidartinib is a CYP3A substrate; crizotinib is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased pexidartinib overall exposure by 67%.
Phenobarbital: (Major) Avoid coadministration of crizotinib with phenobarbital due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of crizotinib with phenobarbital due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
Phenytoin: (Major) Avoid coadministration of crizotinib with phenytoin due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
Pimavanserin: (Major) Avoid coadministration of crizotinib with pimavanserin due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Pimavanserin may also cause QT prolongation.
Pimozide: (Contraindicated) Because of the potential for TdP, use of crizotinib with pimozide is contraindicated. Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP), and crizotinib has also been associated with QT prolongation. Additionally, pimozide is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
Pindolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Pitolisant: (Major) Avoid coadministration of crizotinib with pitolisant due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Pitolisant also prolongs the QT interval.
Ponesimod: (Major) Avoid concomitant use of ponesimod and crizotinib due to the risk of severe bradycardia and heart block, QT prolongation, and torsade de pointes (TdP); additive immunosuppression may also occur which may extend the duration or severity of immune suppression. If concomitant use is unavoidable, monitor ECGs, electrolytes, and for signs and symptoms of infection; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia.
Posaconazole: (Contraindicated) Posaconazole use is contraindicated with medications that may prolong the QT/QTc interval that are also CYP3A substrates, such as crizotinib, due to the risk for increase crizotinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). While coadministration is not recommended, if use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate, posaconazole is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Pralsetinib: (Major) Avoid concomitant use of crizotinib with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of pralsetinib by 71%.
Primaquine: (Major) Avoid coadministration of crizotinib with primaquine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Primaquine may also cause QT interval prolongation.
Primidone: (Major) Avoid coadministration of crizotinib with primidone due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and crizotinib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. If concomitant use is necessary, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce a dose of 0.6 mg twice daily to 0.3 mg twice daily or 0.6 mg once daily; reduce a dose of 0.6 mg once daily to 0.3 mg once daily. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 1.2 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 1.2 mg. Colchicine is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors increased colchicine overall exposure by 1.4- to 1.9-fold.
Procainamide: (Major) Avoid coadministration of crizotinib with procainamide due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Procainamide is also associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
Prochlorperazine: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with prochlorperazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation. Crizotinib has been associated with concentration-dependent QT prolongation. Prochlorperazine is also associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Promethazine: (Major) Concomitant use of promethazine and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Dextromethorphan: (Major) Concomitant use of promethazine and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Phenylephrine: (Major) Concomitant use of promethazine and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propafenone: (Major) Concomitant use of propafenone and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propranolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Quetiapine: (Major) Concomitant use of quetiapine and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Quinidine: (Major) Avoid coadministration of crizotinib with quinidine due to the risk of QT prolongation; exposure to quinidine may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Quinidine administration is also associated with QT prolongation and torsade de pointes (TdP).
Quinine: (Major) Avoid coadministration of crizotinib with quinine due to the risk of QT prolongation; exposure to quinine drugs may also increase. Crizotinib is a CYP3A substrate and moderate inhibitor that has been associated with concentration-dependent QT prolongation. Quinine is a CYP3A4 substrate that has also been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Quizartinib: (Major) Concomitant use of quizartinib and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ranolazine: (Major) Avoid coadministration of crizotinib with ranolazine due to the risk of QT prolongation. If concomitant use is unavoidable, limit the dose of ranolazine to 500 mg twice daily and monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Ranolazine is a CYP3A4 substrate that is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Coadministration with other moderate CYP3A4 inhibitors increased ranolazine exposure by 50% to 130%.
Relugolix: (Major) Avoid coadministration of crizotinib with relugolix due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of crizotinib with relugolix due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Repaglinide: (Moderate) Monitor blood sugar if coadministration of repaglinide with crizotinib is necessary; an increase in repaglinide-related adverse reactions may occur. Repaglinide is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with crizotinib due to increased repotrectinib exposure which may increase the risk for repotrectinib-related adverse effects. Repotrectinib is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor.
Ribociclib: (Major) Avoid concomitant use of crizotinib and ribociclib due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de points (TdP). If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate, ribociclib is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Ribociclib; Letrozole: (Major) Avoid concomitant use of crizotinib and ribociclib due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de points (TdP). If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate, ribociclib is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Rifampin: (Major) Avoid coadministration of crizotinib with rifampin due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
Rifapentine: (Major) Avoid coadministration of crizotinib with rifapentine as concurrent use may decrease crizotinib exposure, which may reduce its efficacy. Crizotinib is primarily metabolized by CYP3A4 and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
Rilpivirine: (Major) Avoid coadministration of crizotinib with rilpivirine due to the risk of QT prolongation; exposure to rilpivirine may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation; rilpivirine is also a CYP3A4 substrate.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with crizotinib; concurrent use may increase rimegepant exposure. Rimegepant is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor.
Risperidone: (Major) Avoid coadministration of crizotinib with risperidone due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Risperidone has also been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP), primarily in the overdose setting.
Ritlecitinib: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with ritlecitinib is necessary; crizotinib exposure may increase. Crizotinib is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor.
Ritonavir: (Major) Avoid concomitant use of crizotinib and ritonavir due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Roflumilast: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if coadministration with crizotinib is necessary; carefully weigh the risks and benefits of treatment. Roflumilast is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of roflumilast by 70%.
Romidepsin: (Moderate) Avoid coadministration of crizotinib with romidepsin due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Romidepsin has also been reported to prolong the QT interval.
Saquinavir: (Contraindicated) Saquinavir use is contraindicated with medications that may prolong the QT/QTc interval and increase saquinavir concentrations, such as crizotinib, due to the increased risk for saquinavir-related adverse effects and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Use may also increase crizotinib exposure. While coadministration is not recommended, if use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor, saquinavir is a CYP3A substrate and strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and crizotinib due to the risk of additive QT prolongation and increased selpercatinib exposure resulting in increased treatment-related adverse effects. If coadministration is unavoidable, reduce the dose of selpercatinib to 80 mg PO twice daily if original dose was 120 mg twice daily, and to 120 mg PO twice daily if original dose was 160 mg twice daily. Monitor electrolytes and ECGs for QT prolongation more frequently. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. If crizotinib is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of crizotinib. Selpercatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; crizotinib is a moderate CYP3A4 inhibitor that can cause concentration-dependent QT prolongation. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase selpercatinib exposure by 60% to 99%.
Selumetinib: (Major) Avoid coadministration of selumetinib and crizotinib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If crizotinib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of crizotinib. Selumetinib is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Sertraline: (Major) Concomitant use of sertraline and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Avoid coadministration of crizotinib with halogenated anesthetics due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Halogenated anesthetics can also prolong the QT interval.
Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with crizotinib is necessary; consider a starting dose of 25 mg of sildenafil when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. In a drug interaction study, coadministration with a moderate CYP3A4 inhibitor increased the Cmax and AUC of sildenafil by 160% and 182%, respectively. Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A inhibitors will be less for sildenafil injection than those observed after oral sildenafil administration.
Silodosin: (Moderate) Monitor for silodosin-related adverse reactions if coadministration with crizotinib is necessary. Silodosin is a substrate of CYP3A4. Crizotinib is a moderate CYP3A inhibitor. The effect of moderate CYP3A4 inhibitors has not been evaluated; however, plasma concentrations of silodosin may increase based on its interaction with strong CYP3A4 inhibitors.
Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with crizotinib is necessary. Simvastatin is a sensitive CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving crizotinib due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Crizotinib has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and crizotinib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; crizotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of crizotinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Solifenacin: (Major) Avoid coadministration of crizotinib with solifenacin due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Solifenacin has also been associated with dose-dependent prolongation of the QT interval; torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined.
Sonidegib: (Major) Avoid coadministration of sonidegib with crizotinib due to increased plasma concentrations of sonidegib, with may result in increased adverse reactions including musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Sorafenib: (Major) Avoid coadministration of crizotinib with sorafenib due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Crizotinib can cause concentration-dependent QT prolongation. Sorafenib is also associated with QTc prolongation.
Sotalol: (Major) Concomitant use of sotalol and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sparsentan: (Moderate) Monitor for an increase in sparsentan-related adverse effects if concomitant use with crizotinib is necessary. Concomitant use may increase sparsentan exposure. Sparsentan is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sparsentan overall exposure by 70%.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of crizotinib with St. John's Wort due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if crizotinib must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of crizotinib is necessary. If crizotinib is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a moderate CYP3A4 inhibitor like crizotinib can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If crizotinib is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sunitinib: (Major) Avoid coadministration of crizotinib with sunitinib due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Sunitinib can also prolong the QT interval.
Suvorexant: (Major) A dose reduction to 5 mg of suvorexant is recommended during concurrent use with crizotinib. The suvorexant dose may be increased to 10 mg if needed for efficacy. Suvorexant is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased the suvorexant AUC by 2-fold.
Tacrolimus: (Major) Avoid coadministration of crizotinib with tacrolimus due to the risk of QT prolongation; exposure to tacrolimus may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. Frequently monitor tacrolimus whole blood concentrations; adjust the dose of tacrolimus as clinically appropriate. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Tacrolimus is a sensitive CYP3A4 substrate that also causes QT prolongation.
Tadalafil: (Moderate) Monitor for an increase in tadalafil-related adverse reactions if coadministration with crizotinib is necessary. Tadalafil is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Although specific interactions have not been studied, moderate CYP3A4 inhibitors would likely increase tadalafil exposure.
Tamoxifen: (Major) Concomitant use of tamoxifen and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tamsulosin: (Moderate) Use caution if coadministration of crizotinib with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. The effects of concomitant administration of a moderate CYP3A4 inhibitor on the pharmacokinetics of tamsulosin have not been evaluated, but tamsulosin exposure may increase based on the effects of strong CYP3A4 inhibition.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with crizotinib as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. If concomitant use is unavoidable, decrease current tazemetostat daily dosage by 50% (e.g., decrease 800 mg PO twice daily to 400 mg PO twice daily; 600 mg PO twice daily to 400 mg PO for first dose and 200 mg PO for second dose; 400 mg PO twice daily to 200 mg PO twice daily). If crizotinib is discontinued, wait at least 3 half-lives of crizotinib before increasing the dose of tazemetostat to the previous tolerated dose. Tazemetostat is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telavancin: (Major) Avoid coadministration of crizotinib with telavancin due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Telavancin has also been associated with QT prolongation.
Telmisartan; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Tetrabenazine: (Major) Avoid coadministration of crizotinib with tetrabenazine due to the risk of QT prolongation. Crizotinib has been associated with concentration-dependent QT prolongation. Tetrabenazine also causes a small increase in the corrected QT interval (QTc).
Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with crizotinib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); crizotinib is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If crizotinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Thioridazine: (Contraindicated) Because of the potential for torsade de pointes (TdP), use of crizotinib with thioridazine is contraindicated. Thioridazine is associated with a well-established risk of QT prolongation and TdP. Crizotinib has also been associated with concentration-dependent QT prolongation.
Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with crizotinib. Coadministration may increase the exposure of ticagrelor. Ticagrelor is a sensitive substrate of CYP3A; crizotinib is a moderate inhibitor of CYP3A.
Timolol: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as beta-blockers, to the extent possible due to the risk of additive bradycardia. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs.
Tinidazole: (Moderate) Monitor for an increase in tinidazole-related adverse reactions if coadministration with crizotinib is necessary. Tinidazole is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Inhibitors of CYP3A4 inhibitors may prolong the half-life and decrease the plasma clearance of tinidazole, increasing the plasma concentrations of tinidazole.
Tipranavir: (Major) Avoid concomitant use of crizotinib and tipranavir due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects; exposure to tipranavir may also increase. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor; tipranavir is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Tolterodine: (Major) Avoid coadministration of crizotinib with tolterodine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Tolvaptan: (Major) Avoid coadministration of crizotinib when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with crizotinib. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; crizotinib is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
Toremifene: (Major) Avoid coadministration of crizotinib with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. An interruption of therapy, dose reduction, or discontinuation of crizotinib therapy may be necessary if QT prolongation occurs. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Crizotinib has also been associated with concentration-dependent QT prolongation.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with crizotinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of crizotinib, a moderate CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with crizotinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of crizotinib, a moderate CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Trandolapril; Verapamil: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as verapamil, to the extent possible due to the risk of additive bradycardia; increased exposure to both drugs may also occur. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly, and watch for an increase in crizotinib-related adverse reactions. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs. Crizotinib and verapamil are both CYP3A substrates and moderate inhibitors.
Trazodone: (Major) Concomitant use of trazodone and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with crizotinib and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and crizotinib is a moderate CYP3A inhibitor.
Triclabendazole: (Major) Concomitant use of triclabendazole and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Trifluoperazine: (Minor) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with trifluoperazine. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Triptorelin: (Major) Avoid coadministration of crizotinib with triptorelin due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Androgen deprivation therapy (e.g., triptorelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
Tucatinib: (Major) Avoid concomitant use of crizotinib and tucatinib due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with crizotinib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; crizotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor resulted in a 3.5-fold increase in the exposure of ubrogepant.
Vandetanib: (Major) Avoid coadministration of vandetanib with crizotinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for both drugs if QT prolongation occurs. Both drugs can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have also been reported in patients receiving vandetanib.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with crizotinib due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; crizotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold. In addition, vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil may produce an increase in QTc interval. Crizotinib has also been associated with concentration-dependent QT prolongation. Monitor ECGs and electrolytes if crizotinib and vardenafil oral tablets are used together.
Vemurafenib: (Major) Avoid coadministration of crizotinib with vemurafenib due to the risk of QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Vemurafenib has also been associated with QT prolongation.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with crizotinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of crizotinib. Venetoclax is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Venlafaxine: (Major) Concomitant use of venlafaxine and crizotinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Verapamil: (Major) Avoid coadministration of crizotinib with agents known to cause bradycardia, such as verapamil, to the extent possible due to the risk of additive bradycardia; increased exposure to both drugs may also occur. If concomitant use is unavoidable, monitor heart rate and blood pressure regularly, and watch for an increase in crizotinib-related adverse reactions. An interruption of crizotinib therapy or dose adjustment may be necessary if bradycardia occurs. Crizotinib and verapamil are both CYP3A substrates and moderate inhibitors.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with crizotinib is necessary. Vinblastine is a CYP3A4 substrate and crizotinib is a moderate CYP3A4 inhibitor. Enhanced vinblastine toxicity was reported with coadministration of another moderate CYP3A4 inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with crizotinib is necessary. Vinorelbine is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor.
Voclosporin: (Major) Avoid coadministration of crizotinib and voclosporin due to the risk of QT prolongation. Voclosporin exposure and the risk for voclosporin-related adverse effects may also be increased. If concomitant use is unavoidable, monitor ECGs and electrolytes and reduce voclosporin dosage to 15.8 mg PO in the morning and 7.9 mg PO in the evening. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Voclosporin is a sensitive CYP3A4 substrate that is associated with QT prolongation at supratherapeutic doses. Crizotinib is a moderate CYP3A4 inhibitor that can cause concentration-dependent QT prolongation. Coadministration with moderate CYP3A4 inhibitors is predicted to increase voclosporin exposure by 3-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of crizotinib and clarithromycin due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de points (TdP). If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Voriconazole: (Major) Avoid concomitant use of crizotinib and voriconazole due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. Concomitant use may also increase voriconazole exposure and result in additive risk for QT/QTc prolongation and torsade de points (TdP). If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor, voriconazole is a CYP3A substrate and strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%. Coadministration with another moderate CYP3A inhibitor increased voriconazole exposure by 79%.
Vorinostat: (Major) Avoid coadministration of crizotinib with vorinostat due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Vorinostat therapy is also associated with a risk of QT prolongation.
Voxelotor: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with voxelotor is necessary; crizotinib exposure may increase. Crizotinib is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with crizotinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Crizotinib is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO twice daily if coadministered with crizotinib. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Further decrease the zanubrutinib dose as recommended if adverse reactions occur. After discontinuation of crizotinib, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; crizotinib is a moderate CYP3A4 inhibitor. The AUC of zanubrutinib is predicted to increase by 157% to 317% when coadministered with other moderate CYP3A4 inhibitors.
Ziprasidone: (Major) Concomitant use of ziprasidone and crizotinib should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Crizotinib has been associated with concentration-dependent QT prolongation. Monitor ECGs and electrolytes in patients receiving crizotinib concomitantly with other drugs known to prolong the QT interval. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary.
Crizotinib is an inhibitor of receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK), Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins, including the chinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene. The formation of ALK fusion proteins results in the activation and dysregulation of the gene's expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed EML4- or NPM-ALK fusion proteins or c-Met. The EML4-ALK fusion gene occurs in 2% to 7% of all non-small cell lung cancers (NSCLC) and is more prevalent in nonsmokers, in patients with a history of light smoking, and in patients with adenocarcinomas.
Crizotinib is administered orally. Protein binding in vitro is 91% and is independent of drug concentration. The geometric mean volume of distribution (Vss) is 1,772 L after a single IV dose. In single dose studies, the mean apparent terminal half-life was 42 hours. Single dose studies in healthy subjects demonstrated that 63% of the dose was recovered in the feces (53% as unchanged drug) and 22% was recovered in the urine (2.3% as unchanged drug). The mean apparent clearance of crizotinib was lower at steady state after 250 mg PO twice daily (60 L/h) than after single doses (100 L/h).
Affected cytochrome P450 isoenzymes: CYP3A4, CYP2B6, P-glycoprotein (P-gp)
Crizotinib is predominantly metabolized by CYP3A4; it is also a substrate of P-gp in vitro. It is a moderate CYP3A4 inhibitor, as well as an in vitro inhibitor of CYP2B6, P-gp, OCT1, and OCT2.
-Route-Specific Pharmacokinetics
Oral Route
The mean absolute bioavailability of crizotinib capsules is 43% (range, 32% to 66%) after a single oral dose; oral pellets had a comparable bioavailability to the capsules. The median time to achieve peak concentrations (Tmax) for crizotinib capsules is 4 to 6 hours and steady-state is reached within 15 days with a median accumulation ratio of 4.8. Steady-state observed minimum concentration (Cmin) and AUC increased in a greater than dose-proportional manner over the dose range of 200 to 300 mg PO twice daily (0.8 to 1.2 times the approved recommended dose).
A high-fat meal reduced the AUC and Cmax of crizotinib capsules by approximately 14%; therefore, the manufacturer states that it may be administered with or without food. The AUC and Cmax of crizotinib pellets were reduced by approximately 15% and 23%, respectively, after a high-fat meal. No clinically significant differences in crizotinib pharmacokinetics were observed when used concomitantly with a proton pump inhibitor.
-Special Populations
Hepatic Impairment
The mean steady-state AUC and Cmax of crizotinib decreased by 9% in patients with mild hepatic impairment (AST greater than the upper limit of normal (ULN) and total bilirubin less than or equal to the upper limit of normal, OR total bilirubin 1.1 to 1.5 times ULN with any AST) compared to patients with normal hepatic function. The steady-state mean crizotinib AUC and Cmax increased by 14% and 9%, respectively, in patients with moderate hepatic impairment (total bilirubin 1.6 to 3 times ULN and any AST) receiving a reduced dose of crizotinib 200 mg PO twice daily compared with patients with normal hepatic function receiving the full dose of 250 mg PO twice daily. The mean AUC and Cmax of crizotinib decreased by 35% and 27%, respectively, in patients with severe hepatic impairment (total bilirubin greater than 3 times ULN and any AST) receiving a reduced dose of 250 mg PO once daily compared with patients with normal hepatic function receiving the full dose of 250 mg PO twice daily.
Renal Impairment
Mild to moderate renal impairment (CrCl 30 to 89 mL/min) does not have a clinically significant effect on crizotinib exposure. In a single-dose study, the mean AUC for crizotinib increased by 79% and mean Cmax increased by 34% in patients with severe renal impairment who did not require dialysis (CrCl less than 30 mL/min) who did not require dialysis compared with patients with normal renal function (CrCl 90 mL/min or more); similar changes were observed for the major active metabolite of crizotinib.
Geriatric
Age does not have a clinically significant effect on the pharmacokinetics of crizotinib.
Gender Differences
Gender does not have a clinically significant effect on the pharmacokinetics of crizotinib.
Ethnic Differences
Ethnicity (Asian, non-Asian) does not have a clinically significant effect on the pharmacokinetics of crizotinib.
Obesity
Body weight does not have a clinically significant effect on the pharmacokinetics of crizotinib.