the bottom [6:<6 hours before the next dose); do not take 2 doses at the same time to make up for a missed dose. If vomiting occurs after dose, administer the next dose at the regularly scheduled time. Dosing: Geriatric Refer to adult dosing. Dosing: Renal Impairment CrCl 30 to 89 mL/minute: No dosage adjustment necessary. CrCl> <30 mL/minute not requiring dialysis: Initial: 250 mg once daily. Dosing: Hepatic Impairment Hepatotoxicity prior to treatment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); crizotinib undergoes extensive hepatic metabolism and systemic exposure may be increased with impairment; use with caution. Hepatotoxicity during treatment: Grade 3 or 4 ALT or AST elevation (ALT or AST> 5 x ULN) with grade 1 total bilirubin elevation (total bilirubin 1.5 x ULN): Withhold treatment until recovery to baseline or grade 1 ( <3 x ULN), then resume at a reduced dose (200 mg twice daily). Recurrent grade 3 or 4 ALT or AST elevation with grade 1 total bilirubin elevation: Withhold treatment until recovery to baseline or grade 1, then resume at the next lower reduced dose (250 mg once daily). Recurrent grade 3 or 4 ALT or AST elevation on 250 mg once daily: Permanently discontinue. Grade 2, 3, or 4 ALT or AST elevation (ALT or AST> 3 x ULN) with concurrent grade 2, 3, or 4 total bilirubin elevation (>1.5 x ULN) in the absence of cholestasis or hemolysis: Permanently discontinue. Dosing: Adjustment for Toxicity Note: If dose reduction is necessary, reduce dose to 200 mg orally twice daily; if necessary, further reduce to 250 mg once daily. If unable to tolerate 250 mg once daily, permanently discontinue therapy. Hematologic toxicity (except lymphopenia, unless lymphopenia is associated with clinical events such as opportunistic infection): Grade 3 toxicity (WBC 1,000 to 2,000/mm 3 , ANC 500 to 1,000/mm 3 , platelets 25,000 to 50,000/mm 3 ), grade 3 anemia: Withhold treatment until recovery to grade 2, then resume at the same dose and schedule. Grade 4 toxicity (WBC <1,000/mm 3 , ANC> <500/mm 3 , platelets> <25,000/mm 3 ), grade 4 anemia: Withhold treatment until recovery to grade 2, then resume at 200 mg twice daily. Recurrent grade 4 toxicity on 200 mg twice daily: Withhold treatment until recovery to grade 2, then resume at 250 mg once daily. Recurrent grade 4 toxicity on 250 mg once daily: Permanently discontinue. Nonhematologic toxicities: Cardiovascular toxicities: QTc prolongation: Grade 3 QTc prolongation (QTc> 500 msec without life-threatening signs or symptoms) on at least 2 separate ECGs: Withhold treatment until recovery to baseline or to grade 1 (QTc <481 msec), then resume at 200 mg twice daily. Recurrent grade 3 QTc prolongation at 200 mg twice daily: Withhold treatment until recovery to baseline or to grade 1, then resume at 250 mg once daily. Recurrent grade 3 QTc prolongation at 250 mg once daily: Permanently discontinue. Grade 4 QTc prolongation: QTc> 500 msec or 60 msec change from baseline with life-threatening symptoms: Permanently discontinue. Bradycardia: Grade 2 bradycardia (symptomatic with medical intervention indicated) or grade 3 bradycardia (severe/medically significant with intervention indicated): Withhold until recovery to asymptomatic bradycardia or to a heart rate of 60 beats/minute and evaluate concomitant medications. If contributing concomitant medication is identified and discontinued (or dose adjusted), then resume crizotinib at the previous dose. If no contributing concomitant medication is identified (or cannot be discontinued or dose adjusted), resume crizotinib at a reduced dose. Grade 4 bradycardia (life-threatening with urgent intervention indicated): Withhold until recovery to asymptomatic bradycardia or to a heart rate of 60 beats/minute and evaluate concomitant medications. If contributing concomitant medication is identified and discontinued (or dose adjusted), then resume crizotinib at 250 mg once daily with frequent monitoring. If no contributing concomitant medication is identified, permanently discontinue crizotinib. Permanently discontinue for recurrence. Hepatotoxicity: Refer to dosage adjustment in hepatic impairment. Ocular toxicity: Visual loss (grade 4 visual disorder) or new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes): Discontinue during evaluation of severe vision loss. Pulmonary toxicity: Interstitial lung disease (ILD)/pneumonitis (any grade; not attributable to disease progression, infection, other pulmonary disease or radiation therapy): Permanently discontinue. Administration Crizotinib is associated with a moderate emetic potential (Hesketh 2017); antiemetics may be needed to prevent nausea and vomiting. Swallow capsules whole (do not crush, dissolve, or open capsules). Administer with or without food. If vomiting occurs after dose, administer the next dose at the regularly scheduled time. Dietary Considerations Avoid grapefruit and grapefruit juice. Storage Store between 20 C and 25 C (68 F and 77 F); excursions are permitted between 15 C and 30 C (59 F and 86 F). Drug Interactions Abemaciclib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Abemaciclib. Monitor therapy Acalabrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Acalabrutinib. Management: Reduce acalabrutinib dose to 100 mg once daily with concurrent use of a moderate CYP3A4 inhibitor. Monitor patient closely for both acalabrutinib response and evidence of adverse effects with any concurrent use. Consider therapy modification Alfentanil: Crizotinib may increase the serum concentration of Alfentanil. Avoid combination AmLODIPine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of AmLODIPine. Monitor therapy Apixaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban. Monitor therapy Aprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant. Avoid combination ARIPiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy Asunaprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir. Avoid combination Avanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil adult dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects. Consider therapy modification Blonanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin. Monitor therapy Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy Bosentan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy Bosutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib. Avoid combination Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy Brexpiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Monitor therapy Bromocriptine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bromocriptine. Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations. Consider therapy modification Budesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Avoid combination Budesonide (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification Cannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination Cilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving moderate inhibitors of CYP3A4. Consider therapy modification Cobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily. Avoid combination Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Consider therapy modification Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination CycloSPORINE (Systemic): Crizotinib may increase the serum concentration of CycloSPORINE (Systemic). Avoid combination CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy CYP3A4 Inducers (Strong): May decrease the serum concentration of Crizotinib. Avoid combination CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy CYP3A4 Inhibitors (Strong): May increase the serum concentration of Crizotinib. Avoid combination CYP3A4 Substrates (High risk with Inhibitors): CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Exceptions: Alitretinoin (Systemic); Praziquantel; Vinorelbine. Monitor therapy Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification Dapoxetine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine. Management: The dose of dapoxetine should be limited to 30 mg per day when used together with a moderate inhibitor of CYP3A4. Consider therapy modification Dasatinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy Deflazacort: CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Deflazacort. Management: Administer one third of the recommended deflazacort dose when used together with a strong or moderate CYP3A4 inhibitor. Consider therapy modification Dihydroergotamine: Crizotinib may increase the serum concentration of Dihydroergotamine. Avoid combination Domperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone. Avoid combination DOXOrubicin (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification Dronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy Eletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Management: The use of eletriptan within 72 hours of a moderate CYP3A4 inhibitor should be avoided. Consider therapy modification Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: When used concomitantly with moderate inhibitors of CYP3A4, eplerenone dosing recommendations vary by indication and international labeling. See full drug interaction monograph for details. Consider therapy modification Ergotamine: Crizotinib may increase the serum concentration of Ergotamine. Avoid combination Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification FentaNYL: Crizotinib may increase the serum concentration of FentaNYL. Avoid combination Flibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Avoid combination Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination Grapefruit Juice: May increase the serum concentration of Crizotinib. Avoid combination GuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination. Consider therapy modification HYDROcodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HYDROcodone. Monitor therapy Hydroxychloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Avoid combination HydrOXYzine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HydrOXYzine. Management: This combination is specifically contraindicated in some non-U.S. labeling. Consider therapy modification Ibrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: When treating B-cell malignancies, decrease ibrutinib to 140 mg daily when combined with moderate CYP3A4 inhibitors. When treating graft versus host disease, monitor patients closely and reduce the ibrutinib dose as needed based on adverse reactions. Consider therapy modification Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination Ifosfamide: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy Imatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Imatinib. Monitor therapy Ivabradine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine. Avoid combination Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult full monograph content for specific age- and weight-based recommendations. No dose adjustment is needed when using ivacaftor/lumacaftor with a moderate CYP3A4 inhibitor. Consider therapy modification Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy Lomitapide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide. Avoid combination Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: Lurasidone US labeling recommends reducing lurasidone dose by half with a moderate CYP3A4 inhibitor. Some non-US labeling recommends initiating lurasidone at 20 mg/day and limiting dose to 40 mg/day; avoid concurrent use of grapefruit products. Consider therapy modification Manidipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Manidipine. Monitor therapy MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Avoid combination Mirodenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mirodenafil. Monitor therapy Naldemedine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naldemedine. Monitor therapy Nalfurafine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nalfurafine. Monitor therapy Naloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol. Avoid combination Neratinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Neratinib. Avoid combination Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy NiMODipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NiMODipine. Monitor therapy Olaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 200 mg twice daily. Avoid combination OxyCODONE: CYP3A4 Inhibitors (Moderate) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Monitor therapy Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Monitor therapy Pimozide: Crizotinib may enhance the QTc-prolonging effect of Pimozide. Crizotinib may increase the serum concentration of Pimozide. Avoid combination Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification Probucol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Avoid combination Promazine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Avoid combination QTc-Prolonging Agents (Highest Risk): QTc-Prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Highest Risk). Avoid combination QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Monitor therapy QTc-Prolonging Agents (Moderate Risk): May enhance the QTc-prolonging effect of other QTc-Prolonging Agents (Moderate Risk). Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification QuiNIDine: Crizotinib may enhance the QTc-prolonging effect of QuiNIDine. Crizotinib may increase the serum concentration of QuiNIDine. Avoid combination Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). Consider therapy modification Rupatadine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rupatadine. Monitor therapy Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy Ruxolitinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ruxolitinib. Monitor therapy Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Monitor therapy Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy SAXagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SAXagliptin. Monitor therapy Sildenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sildenafil. Monitor therapy Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy Simeprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir. Avoid combination Sirolimus: Crizotinib may increase the serum concentration of Sirolimus. Avoid combination Sonidegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sonidegib. Management: Avoid concomitant use of sonidegib and moderate CYP3A4 inhibitors when possible. When concomitant use cannot be avoided, limit CYP3A4 inhibitor use to less than 14 days and monitor for sonidegib toxicity (particularly musculoskeletal adverse reactions). Consider therapy modification St John's Wort: May decrease the serum concentration of Crizotinib. Avoid combination Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification Suvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Consider therapy modification Tacrolimus (Systemic): Crizotinib may increase the serum concentration of Tacrolimus (Systemic). Avoid combination Tamsulosin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tamsulosin. Monitor therapy Tetrahydrocannabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy Ticagrelor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor. Monitor therapy Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Avoid combination Trabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin. Monitor therapy Udenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Udenafil. Monitor therapy Ulipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity. Avoid combination Venetoclax: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Monitor therapy Vindesine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine. Monitor therapy Vinflunine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Avoid combination Xipamide: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Monitor therapy Zopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Management: The starting adult dose of zopiclone should not exceed 3.75 mg if combined with a moderate CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification Adverse Reactions >10%: Cardiovascular: Edema (31% to 49%), bradycardia (5% to 14%) Central nervous system: Fatigue (27% to 29%), neuropathy (19% to 25%; includes dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, parasthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin), headache (22%), dizziness (18% to 22%) Dermatologic: Skin rash (9 % to 11%) Endocrine & metabolic: Hypophosphatemia (28% to 32%), hypokalemia (18%) Gastrointestinal: Diarrhea (60% to 61%), nausea (55% to 56%), vomiting (46% to 47%), constipation (42% to 43%), decreased appetite (30%), abdominal pain (26%), dysgeusia (26%), dyspepsia (8% to 14%) Genitourinary: Decreased estimated GFR (eGFR) ( <90 mL/min/1.73 m 2 : 76%;> <60 mL/min/1.73 m 2 : 38%;> <30 mL/min/1.73 m 2 : 4%) Hematologic & oncologic: Neutropenia (49% to 52%; grades 3/4: 11% to 12%), lymphocytopenia (48% to 51%; grades 3/4: 7% to 9%) Hepatic: Increased serum ALT (76% to 79%), increased serum AST (61% to 66%) Neuromuscular & skeletal: Limb pain (16%) Ophthalmic: Visual disturbance (60% to 71%; onset:> <2 weeks; includes blurred vision, diplopia, photophobia, photopsia, visual acuity decreased, visual brightness, visual field defect, visual impairment, vitreous floaters) Respiratory: Upper respiratory tract infection (26% to 32%) Miscellaneous: Fever (19%) 1% to 10%: Cardiovascular: Pulmonary embolism (6%), prolonged Q-T interval on ECG (5% to 6%), syncope (1% to 3%) Endocrine & metabolic: Weight loss (10%), weight gain (8%), diabetic ketoacidosis ( 2%), decreased plasma testosterone (1%; hypogonadism) Gastrointestinal: Dysphagia (10%), esophagitis (2% to 6%) Hepatic: Hepatic failure (1%) Infection: Sepsis ( 5%) Neuromuscular & skeletal: Muscle spasm (8%) Renal: Renal cyst (3% to 5%) Respiratory: Adult respiratory distress syndrome ( 5%), interstitial pulmonary disease ( 5%; grades 3/4: 1%; includes acute respiratory distress syndrome, pneumonitis), pneumonia ( 5%), respiratory failure ( 5%), dyspnea (2%) Frequency not defined: Cardiovascular: Cardiac arrhythmia, septic shock> <1%, postmarketing, and/or case reports: Hepatotoxicity Warnings/Precautions Concerns related to adverse effects: Bradycardia: Symptomatic bradycardia may occur; heart rate> <50 beats/minute has occurred. If possible, avoid concurrent use with other agents known to cause bradycardia (eg, beta blockers, nondihydropyridine calcium channel blockers, clonidine, digoxin). Monitor heart rate and blood pressure regularly. If symptomatic bradycardia (not life-threatening) occurs, withhold treatment until recovery to asymptomatic bradycardia or to a heart rate of 60 beats/minute, evaluate concurrent medications, and potentially reduce crizotinib dose. Permanently discontinue for life-threatening bradycardia due to crizotinib; if life-threatening bradycardia occurs and concurrent medications associated with bradycardia can be discontinued or dose adjusted, restart crizotinib at a reduced dose (with frequent monitoring). GI toxicity: Crizotinib is associated with a moderate emetic potential (Hesketh 2017); antiemetics may be needed to prevent nausea and vomiting. Hepatotoxicity: Fatalities due to crizotinib-induced hepatotoxicity have occurred. Grade 3 or 4 ALT increases (usually asymptomatic and reversible) have been observed in clinical trials. May require dosage interruption and/or reduction; permanent discontinuation was necessary in some cases. Elevations in ALT or AST> 5 ULN were observed; concurrent ALT or AST elevations 3 ULN and total bilirubin elevations 2 ULN (without alkaline phosphatase elevations) occurred rarely. Transaminase elevation onset generally was within 2 months of treatment initiation. Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks during the first 2 months of therapy, then monthly and as clinically necessary. Ocular toxicities: Ocular toxicities (eg, blurred vision, diplopia, photophobia, photopsia, visual acuity decreased, visual brightness, visual field defect, visual impairment, and/or vitreous floaters) commonly occur. Onset is generally within 1 week of treatment initiation. Grade 4 visual field defect with vision loss had been reported (rare); optic atrophy and optic nerve disorder have been reported as potential causes of vision loss. Discontinue with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). Obtain ophthalmic evaluation (including best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography, and other evaluations as appropriate). The risks of restarting crizotinib after severe vision loss have not been evaluated; the decision to resume therapy should consider the potential benefits of treatment. Pulmonary toxicity: Severe, life-threatening, and potentially fatal interstitial lung disease (ILD)/pneumonitis has been associated with crizotinib. Onset was generally within 3 months of treatment initiation. Monitor for pulmonary symptoms which may indicate ILD/pneumonitis; exclude other potential causes (eg, disease progression, infection, other pulmonary disease, or radiation therapy). Permanently discontinue if treatment-related ILD/pneumonitis is confirmed. QT prolongation: QTc prolongation has been observed. Monitor ECG and electrolytes in patients with heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications known to prolong the QT interval. May require treatment interruption, dosage reduction, or discontinuation. Avoid use in patients with congenital long QT syndrome. Disease-related concerns: Hepatic impairment: Use with caution in patients with hepatic impairment; has not been studied; patients with ALT or AST >2.5 times ULN (>5 times ULN if due to liver metastases) and total bilirubin >1.5 times ULN were excluded from studies. Crizotinib is extensively metabolized in the liver and liver impairment is likely to increase crizotinib levels. Renal impairment: Reduce initial dose in patients with severe renal impairment not requiring dialysis. Concurrent drug therapy issues: Drug-drug/drug-food interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Avoid concomitant use with strong CYP3A4 inhibitors and inducers and with CYP3A4 substrates. Other warnings/precautions: ALK or ROS1 positivity: Approved for use only in patients with metastatic non-small cell lung cancer (NSCLC) who test positive for the abnormal anaplastic lymphoma kinase (ALK) gene or ROS1 rearrangements. The Vysis ALK break-apart FISH probe kit is approved to test for the ALK gene abnormality. An approved test is customer service
a quirky Crizotinib weakness
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