Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral:
Zykadia: 150 mg [DSC] [contains fd&c blue #2 (indigotine)]
Tablet, Oral:
Zykadia: 150 mg [contains fd&c blue #2 aluminum lake]
Pharmacology
Mechanism of Action
Ceritinib is a potent inhibitor of anaplastic lymphoma kinase (ALK), a tyrosine kinase involved in the pathogenesis of non-small cell lung cancer. ALK gene abnormalities due to mutations or translocations may result in expression of oncogenic fusion proteins (eg, ALK fusion protein) which alter signaling and expression and result in increased cellular proliferation and survival in tumors which express these fusion proteins. ALK inhibition reduces proliferation of cells expressing the genetic alteration. Ceritinib also inhibits insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (InsR), and ROS1. Ceritinib has demonstrated activity in crizotinib-resistant tumors in NSCLC xenograft models.
Pharmacokinetics/Pharmacodynamics
Absorption
AUC and Cmax increased 73% and 41%, respectively, when a single ceritinib 500 mg was administered with a high-fat meal, and 58% and 43%, respectively when taken with a low-fat meal (when compared to fasting). A dose optimization study (comparing ceritinib 450 mg or 600 mg daily with food to ceritinib 750 mg [fasted]) found no clinically meaningful difference in the systemic steady-state exposure of ceritinib 450 mg (with food) compared to the 750 mg fasted arm (Cho 2017).
Distribution
4,230 L (following a single 750 mg fasted dose), with a small preferential distribution to red blood cells versus plasma
Metabolism
Primarily hepatic via CYP3A
Excretion
Feces (~92% with 68% as unchanged drug); urine (~1%)
Time to Peak
~4 to 6 hours
Half-Life Elimination
41 hours (following a single 750 mg fasted dose)
Protein Binding
97% to human plasma proteins
Use in Specific Populations
Special Populations: Hepatic Function Impairment
Following a single 750 mg dose of ceritinib (under fasted conditions), the geometric mean systemic exposure (AUCinf) was increased by 66% and unbound ceritinib AUCinf was increased by 108% in subjects with severe impairment (Child-Pugh class C), compared to subjects with normal hepatic function.
Use: Labeled Indications
Non-small cell lung cancer, metastatic: Treatment of anaplastic lymphoma kinase (ALK)-positive (as detected by an approved test) metastatic non-small cell lung cancer (NSCLC).
Contraindications
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Known hypersensitivity to ceritinib or any component of the formulation; congenital long QT syndrome or persistent Fridericia-corrected electrocardiogram interval (QTcF) of >500 msec.
Dosage and Administration
Dosing: Adult
Note: Ceritinib is associated with a moderate emetic potential (Hesketh 2017; Roila 2016); antiemetics may be needed to prevent nausea and vomiting.
Non-small cell lung cancer (ALK-positive), metastatic: Oral: 450 mg once daily (with food); continue until disease progression or unacceptable toxicity.
Note: The recommended ceritinib dose is now 450 mg once daily with food (dose adjustment levels are also altered); the previous ceritinib dose was 750 mg once daily and administered on an empty stomach. Ceritinib 750 mg once daily in a fasted state may still be the approved dose in some regions outside of the US.
Missed doses: If a dose is missed, take the missed dose unless the next dose is due within 12 hours. If vomiting occurs, do not administer an additional dose, patients should continue with the next scheduled dose.
Dosage adjustment for concomitant therapy:
Strong CYP3A inhibitors: Avoid concomitant use of strong CYP3A inhibitors; if concurrent administration cannot be avoided, reduce ceritinib dose by approximately one-third (rounded to the nearest multiple of the 150 mg strength). After discontinuation of the strong CYP3A inhibitor, resume ceritinib therapy at the dose used prior to initiation of the CYP3A inhibitor.
Strong CYP3A inducers: Avoid concurrent use of strong CYP3A inducers during treatment with ceritinib.
Dosing: Geriatric
Refer to adult dosing.
Dosing: Adjustment for Toxicity
Recommended ceritinib dosage adjustment levels (when administered with food):
Initial starting dose: 450 mg once daily
First dose reduction: 300 mg once daily
Second dose reduction: 150 mg once daily
Discontinue if patients are unable to tolerate 150 mg daily.
Note: If dosage adjustments are required due to toxicity in regions outside of the US where the approved ceritinib dose remains 750 mg once daily (fasted), reduce the dose in decrements of 150 mg and discontinue if patients are unable to tolerate 300 mg daily (Soria 2017).
Cardiac:
Bradycardia:
Symptomatic bradycardia (not life-threatening): Interrupt therapy and evaluate concomitant medications known to cause bradycardia.
Upon recovery to asymptomatic bradycardia or to a heart rate ≥60 beats per minute, adjust the dose.
Alternatively, the following recommendations have been made: Upon recovery to asymptomatic bradycardia or to a heart rate ≥60 beats per minute. If concomitant medication is identified and discontinued or its dose adjusted, reinitiate ceritinib at its previous dose. If no concomitant medication is identified or if it is identified but not discontinued or not dose-adjusted, reinitiate ceritinib with the dose reduced by 150 mg (Zykadia Canadian product labeling).
Symptomatic bradycardia (life-threatening or requiring intervention) in patients taking concomitant medications known to cause bradycardia/hypotension: Interrupt therapy until recovery to asymptomatic bradycardia or to a heart rate ≥60 beats per minute.
If the concomitant medication can be adjusted or discontinued, resume ceritinib therapy with the dose reduced by 150 mg.
Symptomatic bradycardia (life-threatening) in patients not taking concomitant medications known to cause bradycardia/hypotension: Permanently discontinue therapy.
QTc prolongation:
QTc interval >500 msec on at least 2 separate ECGs: Interrupt therapy until QTc interval is <481 msec or recovers to baseline if baseline QTc is ≥481 msec, then resume therapy with a 150 mg dose reduction.
QTc prolongation in combination with torsades de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia: Permanently discontinue therapy.
Gastrointestinal:
Severe or intolerable nausea, vomiting, or diarrhea (despite appropriate management): Interrupt therapy until improved, then resume treatment with a 150 mg dose reduction.
Lipase or amylase elevation >2 times ULN: Interrupt therapy and monitor serum lipase and amylase; upon recovery to <1.5 times ULN, resume treatment with a 150 mg dose reduction.
Metabolic: Persistent hyperglycemia >250 mg/dL (despite optimal antihyperglycemic therapy): Interrupt therapy until hyperglycemia is adequately controlled, then resume therapy with a 150 mg dose reduction. If hyperglycemia cannot be controlled (with optimal medical management), discontinue ceritinib.
Pulmonary: Treatment-related interstitial lung disease/pneumonitis (any grade): Permanently discontinue therapy.
Administration
Ceritinib is associated with a moderate emetic potential (Hesketh 2017; Roila 2016); antiemetics may be needed to prevent nausea and vomiting.
Oral: Administer with food. Note: Ceritinib was previously recommended to be administered at a higher dose on an empty stomach, but should now be administered as 450 mg once daily with food.
Dietary Considerations
Avoid grapefruit and grapefruit juice.
Storage
Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).
Drug Interactions
Abemaciclib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Abemaciclib. Management: In patients taking abemaciclib at a dose of 200 mg or 150 mg twice daily, reduce the dose to 100 mg twice daily when combined with strong CYP3A4 inhibitors. In patients taking abemaciclib 100 mg twice daily, decrease the dose to 50 mg twice daily. Consider therapy modification
Acalabrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Acalabrutinib. Avoid combination
Ado-Trastuzumab Emtansine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ado-Trastuzumab Emtansine. Specifically, strong CYP3A4 inhibitors may increase concentrations of the cytotoxic DM1 component. Avoid combination
Ajmaline: May enhance the bradycardic effect of Ceritinib. Ajmaline may enhance the QTc-prolonging effect of Ceritinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification
Alfuzosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin. Avoid combination
Alitretinoin (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP3A4 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP3A4 inhibitor. Consider therapy modification
Almotriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Almotriptan. Management: Limit initial almotriptan adult dose to 6.25 mg and maximum adult dose to 12.5 mg/24-hrs when used with a strong CYP3A4 inhibitor. Avoid concurrent use in patients with impaired hepatic or renal function. Consider therapy modification
Alosetron: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron. Monitor therapy
ALPRAZolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ALPRAZolam. Management: Consider using an alternative agent that is less likely to interact. If combined, monitor for increased therapeutic/toxic effects of alprazolam if combined with a strong CYP3A4 inhibitor. Consider therapy modification
Amiodarone: May enhance the bradycardic effect of Ceritinib. Amiodarone may enhance the QTc-prolonging effect of Ceritinib. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification
AmLODIPine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of AmLODIPine. Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Apixaban: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Apixaban. Monitor therapy
Aprepitant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Aprepitant. Avoid combination
ARIPiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph for details. Consider therapy modification
ARIPiprazole Lauroxil: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Please refer to the full interaction monograph for details concerning the recommended dose adjustments. Consider therapy modification
Astemizole: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Astemizole. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Astemizole. Avoid combination
Asunaprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Asunaprevir. Avoid combination
Avanafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil. Avoid combination
Avapritinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avapritinib. Avoid combination
Axitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Axitinib. Management: Avoid concurrent use of axitinib with any strong CYP3A inhibitor whenever possible. If a strong CYP3A inhibitor must be used with axitinib, a 50% axitinib dose reduction is recommended. Consider therapy modification
Barnidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Barnidipine. Avoid combination
Bedaquiline: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Bedaquiline. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Bedaquiline. Management: Consider alternatives to this drug combination and avoid use for more than 14 days. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification
Benperidol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Benperidol. Monitor therapy
Benzhydrocodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Benzhydrocodone. Specifically, the concentration of hydrocodone may be increased. Monitor therapy
Betamethasone (Ophthalmic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Betamethasone (Ophthalmic). Monitor therapy
Bictegravir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bictegravir. Monitor therapy
Blonanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Blonanserin. Avoid combination
Bortezomib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bortezomib. Monitor therapy
Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Bosentan: CYP3A4 Inhibitors (Strong) 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 (Strong) may increase the serum concentration of Bosutinib. Avoid combination
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. Exceptions are discussed in separate monographs. Exceptions: Crizotinib; Lofexidine; Pilsicainide; Propafenone. Consider therapy modification
Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy
Brentuximab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy
Brexpiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose 50% with strong CYP3A4 inhibitors; reduce to 25% of usual if used with both a moderate CYP3A4 inhibitor and a CYP2D6 inhibitor in patients not being treated for MDD, or strong CYP3A4 inhibitor used in a CYP2D6 poor metabolizer. Consider therapy modification
Brigatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with strong CYP3A4 inhibitors when possible. If combination cannot be avoided, reduce the brigatinib dose by approximately 50%, rounding to the nearest tablet strength (ie, from 180 mg to 90 mg, or from 90 mg to 60 mg). Consider therapy modification
Brinzolamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brinzolamide. Monitor therapy
Bromocriptine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromocriptine. Avoid combination
Budesonide (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Nasal). Monitor therapy
Budesonide (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Oral Inhalation). Monitor therapy
Budesonide (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Systemic). Avoid combination
Budesonide (Topical): CYP3A4 Inhibitors (Strong) 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
Buprenorphine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Buprenorphine. Monitor therapy
BusPIRone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of BusPIRone. Management: Limit the buspirone dose to 2.5 mg daily and monitor patients for increased buspirone effects/toxicities if combined with strong CYP3A4 inhibitors. Consider therapy modification
Cabazitaxel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabazitaxel. Management: Concurrent use of cabazitaxel with strong inhibitors of CYP3A4 should be avoided when possible. If such a combination must be used, consider a 25% reduction in the cabazitaxel dose. Consider therapy modification
Cabozantinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabozantinib. Management: Avoid use of a strong CYP3A4 inhibitor with cabozantinib if possible. If combined, cabozantinib dose adjustments are recommended and vary based on the cabozantinib product used and the indication for use. See monograph for details. Consider therapy modification
Calcifediol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Calcifediol. Monitor therapy
Cannabidiol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabidiol. Monitor therapy
Cannabis: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy
Cariprazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cariprazine. Management: Cariprazine dose reductions of 50% are required; specific recommended management varies slightly for those stable on cariprazine versus those just starting cariprazine. See prescribing information or full interaction monograph for details. Consider therapy modification
Cilostazol: CYP3A4 Inhibitors (Strong) 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 strong inhibitors of CYP3A4. Consider therapy modification
Cinacalcet: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cinacalcet. Monitor therapy
Cisapride: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Cisapride. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Cisapride. Avoid combination
Citalopram: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Citalopram. Monitor therapy
Cobimetinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cobimetinib. Avoid combination
Codeine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Codeine. Monitor therapy
Colchicine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Colchicine. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a strong CYP3A4 inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. Consider therapy modification
Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Conivaptan. Avoid combination
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
Copanlisib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Copanlisib. Management: If concomitant use of copanlisib and strong CYP3A4 inhibitors cannot be avoided, reduce the copanlisib dose to 45 mg. Monitor patients for increased copanlisib effects/toxicities. Consider therapy modification
Corticosteroids (Orally Inhaled): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Orally Inhaled). Management: Orally inhaled fluticasone propionate with a strong CYP3A4 inhibitor is not recommended. Exceptions: Beclomethasone (Oral Inhalation); Triamcinolone (Systemic). Monitor therapy
Corticosteroids (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Systemic). Exceptions: MethylPREDNISolone; PrednisoLONE (Systemic); PredniSONE. Monitor therapy
Crizotinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Crizotinib. Management: Avoid concomitant use of crizotinib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, decrease crizotinib dose to 250 mg daily. Monitor patients for crizotinib toxicities including QTc prolongation and arrhythmias. Consider therapy modification
CycloSPORINE (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of CycloSPORINE (Systemic). Consider therapy modification
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 Ceritinib. 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 Ceritinib. Management: If such combinations cannot be avoided, the ceritinib dose should be reduced by approximately one-third (to the nearest 150 mg). Resume the prior ceritinib dose after cessation of the strong CYP3A4 inhibitor. Exceptions discussed in separate monographs. Exceptions: Clarithromycin; Saquinavir; Voriconazole. Consider therapy modification
CYP3A4 Substrates (High risk with Inhibitors): CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Exceptions: Alitretinoin (Systemic); AmLODIPine; Benzhydrocodone; Buprenorphine; Gefitinib; HYDROcodone; Mirtazapine; Praziquantel; Telithromycin; Vinorelbine. Consider therapy modification
Dabrafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dabrafenib. Avoid combination
Daclatasvir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Daclatasvir. Management: Decrease the daclatasvir dose to 30 mg once daily if combined with a strong CYP3A4 inhibitor. No dose adjustment is needed when daclatasvir is used with darunavir/cobicistat. Consider therapy modification
Dapoxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dapoxetine. Avoid combination
Dasatinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Dasatinib. Management: Avoid concomitant use of dasatinib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, dasatinib dose reductions are required. Monitor patients for dasatinib toxicities including QTc prolongation and arrhythmias. Consider therapy modification
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Deflazacort: CYP3A4 Inhibitors (Strong) 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
Delamanid: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Delamanid. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Delamanid. Management: If coadministration of delamanid with any strong CYP3A4 inhibitor is considered necessary, very frequent monitoring of ECGs is recommended throughout the full delamanid treatment period. Consider therapy modification
DexAMETHasone (Ophthalmic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of DexAMETHasone (Ophthalmic). Monitor therapy
Dienogest: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dienogest. Monitor therapy
DOCEtaxel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOCEtaxel. Management: Avoid the concomitant use of docetaxel and strong CYP3A4 inhibitors when possible. If combined use is unavoidable, consider a 50% docetaxel dose reduction and monitor for increased docetaxel toxicities. Consider therapy modification
Domperidone: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Domperidone. Avoid combination
Doxercalciferol: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Doxercalciferol. Monitor therapy
DOXOrubicin (Conventional): CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong 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 (Strong) may increase the serum concentration of Dronabinol. Monitor therapy
Dronedarone: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Dronedarone. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Dronedarone. Avoid combination
Drospirenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Drospirenone. Management: Drospirenone use is contraindicated specifically when the strong CYP3A4 inhibitors atazanavir and cobicistat are administered concurrently. Caution should be used when drospirenone is coadministered with other strong CYP3A4 inhibitors. Consider therapy modification
Dutasteride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride. Monitor therapy
Duvelisib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Duvelisib. Management: Reduce the dose of duvelisib to 15 mg twice a day when used together with a strong CYP3A4 inhibitor. Consider therapy modification
Elagolix: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Elagolix. Management: Use of the elagolix 200 mg twice daily dose with a strong CYP3A4 inhibitor for longer than 1 month is not recommended. Limit combined use of the elagolix 150 mg once daily dose with a strong CYP3A4 inhibitor to a maximum of 6 months. Consider therapy modification
Eletriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eletriptan. Avoid combination
Elexacaftor, Tezacaftor, and Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Elexacaftor, Tezacaftor, and Ivacaftor. Management: When combined with strong CYP3A4 inhibitors, administer two elexacaftor/tezacaftor/ivacaftor tablets (100 mg/50 mg/75 mg) in the morning, twice a week, approximately 3 to 4 days apart. No evening doses of ivacaftor (150 mg) alone should be administered. Consider therapy modification
Eliglustat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification
Encorafenib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Encorafenib. Management: Avoid using strong CYP3A4 inhibitors together with encorafenib if possible. If the combination must be used, reduce the encorafenib dose and monitor QT interval. See monograph for details. Consider therapy modification
Enfortumab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Enfortumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy
Entrectinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Entrectinib. Avoid combination
Eplerenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone. Avoid combination
Erdafitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erdafitinib. Management: Avoid concomitant use of erdafitinib and strong CYP3A4 inhibitors when possible. If combined, monitor closely for erdafitinib adverse reactions and consider dose modifications accordingly. Consider therapy modification
Erlotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of severe adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements). Consider therapy modification
Erythromycin (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
Estrogen Derivatives: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Estrogen Derivatives. Monitor therapy
Eszopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eszopiclone. Management: Limit the eszopiclone dose to 2 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased eszopiclone effects and toxicities (eg, somnolence, drowsiness, CNS depression). Consider therapy modification
Etizolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Etizolam. Management: Consider use of lower etizolam doses when using this combination; specific recommendations concerning dose adjustment are not available. Monitor clinical response to the combination closely. Consider therapy modification
Everolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus. Avoid combination
Evogliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Evogliptin. Monitor therapy
Fedratinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fedratinib. Management: Consider alternatives when possible. If used together, decrease fedratinib dose to 200 mg/day. After the inhibitor is stopped, increase fedratinib to 300 mg/day for the first 2 weeks and then to 400 mg/day as tolerated. Consider therapy modification
FentaNYL: CYP3A4 Inhibitors (Strong) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification
Fesoterodine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Management: Avoid fesoterodine doses greater than 4 mg daily in adult patients who are also receiving strong CYP3A4 inhibitors. Consider therapy modification
Fexinidazole [INT]: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination
Fexinidazole [INT]: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole [INT]. Avoid combination
Flibanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Flibanserin. Avoid combination
Fluconazole: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
Fluticasone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Nasal). Avoid combination
Fluticasone (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Oral Inhalation). Management: Use of orally inhaled fluticasone propionate with strong CYP3A4 inhibitors is not recommended. Use of orally inhaled fluticasone furoate with strong CYP3A4 inhibitors should be done with caution. Monitor patients using such a combination more closely. Consider therapy modification
Fosaprepitant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fosaprepitant. Avoid combination
Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Fostamatinib: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fostamatinib. Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
Gefitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Gefitinib. Monitor therapy
Gilteritinib: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Gilteritinib. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Gilteritinib. Management: Consider alternatives to the use of gilteritinib with strong CYP3A4 inhibitors that prolong the QTc interval whenever possible Consider therapy modification
Glasdegib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Glasdegib. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor closely for evidence of QT interval prolongation and other adverse reactions to glasdegib. Consider therapy modification
Grapefruit Juice: May increase the serum concentration of Ceritinib. Avoid combination
GuanFACINE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination. Consider therapy modification
Halofantrine: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Halofantrine. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Halofantrine. Avoid combination
HYDROcodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of HYDROcodone. Monitor therapy
Ibrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ibrutinib. Management: Avoid concomitant use of ibrutinib and strong CYP3A4 inhibitors. If a strong CYP3A4 inhibitor must be used short-term (eg, anti-infectives for 7 days or less), interrupt ibrutinib therapy until the strong CYP3A4 inhibitor is discontinued. Avoid combination
Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
Ifosfamide: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy
Iloperidone: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolites P88 and P95 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP3A4 inhibitor. Consider therapy modification
Imatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imatinib. Monitor therapy
Imidafenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imidafenacin. Monitor therapy
Irinotecan Products: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Irinotecan Products. Avoid combination
Isavuconazonium Sulfate: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Strong) may increase isavuconazole serum concentrations. Management: Combined use is considered contraindicated per US labeling. Lopinavir/ritonavir (and possibly other uses of ritonavir doses less than 400 mg every 12 hours) is treated as a possible exception to this contraindication despite strongly inhibiting CYP3A4. Avoid combination
Istradefylline: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Istradefylline. Management: Limit the maximum istradefylline dose to 20 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased istradefylline effects/toxicities. Consider therapy modification
Ivabradine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivabradine. Avoid combination
Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult full monograph content for age- and weight-specific recommendations. Consider therapy modification
Ivosidenib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ivosidenib. Management: Avoid using strong CYP3A4 inhibitors together with ivosidenib if possible. If the combination must be used, reduce the ivosidenib dose to 250 mg once daily. Consider therapy modification
Ixabepilone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone. Consider therapy modification
Lacosamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lacosamide. Monitor therapy
Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy
Lapatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lapatinib. Management: If an overlap in therapy cannot be avoided, consider reducing lapatinib adult dose to 500 mg/day during, and within 1 week of completing, treatment with the strong CYP3A4 inhibitor. Avoid combination
Larotrectinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inhibitors with larotrectinib. If this combination cannot be avoided, reduce the larotrectinib dose by 50%. Increase to previous dose after stopping the inhibitor after a period of 3 to 5 times the inhibitor half-life. Consider therapy modification
Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination
Lefamulin: May enhance the QTc-prolonging effect of QT-prolonging CYP3A4 Substrates. Management: Do not use lefamulin tablets with QT-prolonging CYP3A4 substrates. Lefamulin prescribing information lists this combination as contraindicated. Avoid combination
Lefamulin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets and strong inhibitors of CYP3A4. Avoid combination
Lemborexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lemborexant. Avoid combination
Lercanidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lercanidipine. Avoid combination
Levamlodipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levamlodipine. Monitor therapy
Levobupivacaine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine. Monitor therapy
Levomilnacipran: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levomilnacipran. Management: Do not exceed a maximum adult levomilnacipran dose of 80 mg/day in patients also receiving strong CYP3A4 inhibitors. Consider therapy modification
Lomitapide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lomitapide. Avoid combination
Lorlatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with strong CYP3A4 inhibitors. If the combination cannot be avoided, reduce the lorlatinib dose from 100 mg once daily to 75 mg once daily, or from 75 mg once daily to 50 mg once daily. Consider therapy modification
Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification
Lovastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lovastatin. Avoid combination
Lumateperone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumateperone. Avoid combination
Lumefantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine. Monitor therapy
Lurasidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurasidone. Avoid combination
Macitentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Macitentan. Avoid combination
Manidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Manidipine. Management: Consider avoiding concomitant use of manidipine and strong CYP3A4 inhibitors. If combined, monitor closely for increased manidipine effects and toxicities. Manidipine dose reductions may be required. Consider therapy modification
Maraviroc: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Maraviroc. Management: Reduce the adult dose of maraviroc to 150 mg twice daily when used with a strong CYP3A4 inhibitor. Do not use maraviroc with strong CYP3A4 inhibitors in patients with Clcr less than 30 mL/min. Consider therapy modification
MedroxyPROGESTERone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MedroxyPROGESTERone. Monitor therapy
Meperidine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Meperidine. Monitor therapy
Methadone: Ceritinib may enhance the QTc-prolonging effect of Methadone. Ceritinib may increase the serum concentration of Methadone. Management: Consider alternatives to this combination. Methadone dose reduction may be necessary when used with ceritinib. With any concurrent use, monitor closely for evidence of methadone toxicities such as QT-prolongation or respiratory depression. Consider therapy modification
MethylPREDNISolone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose reduction in patients receiving strong CYP3A4 inhibitors and monitor for increased steroid related adverse effects. Consider therapy modification
Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy
Midostaurin: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Midostaurin. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Midostaurin. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification
MiFEPRIStone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MiFEPRIStone. Management: Limit mifepristone adult dose, when used for treatment of hyperglycemia in Cushing's syndrome, to a maximum of 900 mg/day when combined with a strong CYP3A4 inhibitor. Monitor for increased mifepristone toxicity regardless of dose or indication. Consider therapy modification
MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification
Mirodenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirodenafil. Management: Consider using a lower dose of mirodenafil when used with strong CYP3A4 inhibitors. Monitor for increased mirodenafil effects/toxicities with the use of this combination. Consider therapy modification
Mirtazapine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirtazapine. Monitor therapy
Naldemedine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naldemedine. Monitor therapy
Nalfurafine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nalfurafine. Monitor therapy
Naloxegol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naloxegol. Avoid combination
Neratinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Neratinib. Avoid combination
Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Nilotinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Nilotinib. Management: Avoid concomitant use of nilotinib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, nilotinib dose reductions are required. Monitor patients for nilotinib toxicities including QTc prolongation and arrhythmias. Consider therapy modification
NiMODipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of NiMODipine. Avoid combination
Nisoldipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine. Avoid combination
Olaparib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Olaparib. Management: Avoid use of strong CYP3A4 inhibitors in patients being treated with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 100 mg twice daily. Consider therapy modification
Ondansetron: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Ondansetron. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
Osimertinib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification
Ospemifene: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ospemifene. Monitor therapy
Oxybutynin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Oxybutynin. Monitor therapy
OxyCODONE: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Strong) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite oxymorphone may also be increased. Consider therapy modification
Palbociclib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palbociclib. Avoid combination
Panobinostat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Panobinostat. Management: Reduce the panobinostat dose to 10 mg when it must be used with a strong CYP3A4 inhibitor. Consider therapy modification
Parecoxib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Monitor therapy
Paricalcitol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol. Monitor therapy
PAZOPanib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PAZOPanib. Management: Avoid concurrent use of pazopanib with strong inhibitors of CYP3A4 whenever possible. If it is not possible to avoid such a combination, reduce pazopanib adult dose to 400 mg. Further dose reductions may also be required. Consider therapy modification
Pentamidine (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
Pexidartinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pexidartinib. Management: Avoid use of pexidartinib with strong CYP3A4 inhibitors if possible. If combined use cannot be avoided, the pexidartinib dose should be reduced. Decrease 800 mg or 600 mg daily doses to 200 mg twice daily. Decrease doses of 400 mg/day to 200 mg/day. Consider therapy modification
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
Pimavanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimavanserin. Management: Decrease the pimavanserin dose to 10 mg daily when combined with strong CYP3A4 inhibitors. Consider therapy modification
Pimecrolimus: CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus. Monitor therapy
Pimozide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimozide. Avoid combination
Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination
Piperaquine: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Piperaquine. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Piperaquine. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification
Polatuzumab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be increased. Monitor therapy
PONATinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PONATinib. Management: Per ponatinib U.S. prescribing information, the adult starting dose of ponatinib should be reduced to 30 mg daily during treatment with any strong CYP3A4 inhibitor. Consider therapy modification
Posaconazole: May increase the serum concentration of QT-prolonging CYP3A4 Substrates. Such increases may lead to a greater risk for proarrhythmic effects and other similar toxicities. Avoid combination
Pranlukast: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pranlukast. Monitor therapy
Praziquantel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Praziquantel. Monitor therapy
PrednisoLONE (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of PrednisoLONE (Systemic). Monitor therapy
PredniSONE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PredniSONE. Monitor therapy
QT-prolonging Antidepressants (Moderate Risk): QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). Exceptions: Citalopram. Monitor therapy
QT-prolonging Antipsychotics (Moderate Risk): Ceritinib may enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Pimozide; QUEtiapine. Monitor therapy
QT-prolonging Class IA Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of Ceritinib. Ceritinib may enhance the QTc-prolonging effect of QT-prolonging Class IA Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Ajmaline. Consider therapy modification
QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
QT-prolonging Class III Antiarrhythmics (Highest Risk): May enhance the QTc-prolonging effect of Ceritinib. Ceritinib may enhance the QTc-prolonging effect of QT-prolonging Class III Antiarrhythmics (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Dronedarone; Sotalol. Consider therapy modification
QT-prolonging Kinase Inhibitors (Highest Risk): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Kinase Inhibitors (Highest Risk). Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Ivosidenib. Consider therapy modification
QT-prolonging Miscellaneous Agents (Highest Risk): QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Highest Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Highest Risk). Exceptions: Astemizole; Bedaquiline; Cisapride; Delamanid; Terfenadine. Avoid combination
QT-prolonging Miscellaneous Agents (Moderate Risk): QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Moderate Risk). Exceptions: Domperidone; Halofantrine; Midostaurin; Piperaquine; Toremifene. Avoid combination
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of Ceritinib. Ceritinib may enhance the QTc-prolonging effect of QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ceritinib. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
QT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): Ceritinib may enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ceritinib. Management: Avoid concomitant use of ceritinib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, decrease ceritinib dose by one-third and monitor patients for ceritinib toxicities including QTc prolongation and arrhythmias. Exceptions: Ceritinib. Consider therapy modification
QUEtiapine: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QUEtiapine. Management: Reduce the quetiapine dose to one-sixth of the regular dose when combined with strong CYP3A4 inhibitors. Monitor patients for quetiapine toxicities, including QTc prolongation and torsades de pointes. Consider therapy modification
Radotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Radotinib. Avoid combination
Ramelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ramelteon. Monitor therapy
Ranolazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine. Avoid combination
Reboxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Reboxetine. Consider therapy modification
Red Yeast Rice: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin and related compounds found in Red Yeast Rice may be increased. Avoid combination
Regorafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Regorafenib. Avoid combination
Repaglinide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Repaglinide. Management: The addition of a CYP2C8 inhibitor to this drug combination may substantially increase the magnitude of increase in repaglinide exposure. Monitor therapy
Retapamulin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Retapamulin. Management: Avoid this combination in patients less than 2 years old. No action is required in other populations. Monitor therapy
Ribociclib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Ribociclib. Management: Avoid concomitant use of ribociclib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, decrease the ribociclib dose to 400 mg daily. Monitor for ribociclib toxicities including QTc prolongation and arrhythmias. Consider therapy modification
Rilpivirine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rilpivirine. Monitor therapy
RomiDEPsin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of RomiDEPsin. Monitor therapy
Rupatadine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rupatadine. Avoid combination
Ruxolitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details. Consider therapy modification
Salmeterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol. Avoid combination
Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
SAXagliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SAXagliptin. Management: Limit the saxagliptin dose to 2.5 mg daily when combined with strong CYP3A4 inhibitors. When using the saxagliptin combination products saxagliptin/dapagliflozin or saxagliptin/dapagliflozin/metformin, avoid use with strong CYP3A4 inhibitors. Consider therapy modification
Sibutramine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Sibutramine. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sibutramine. Monitor therapy
Sildenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sildenafil. Management: Use of sildenafil for pulmonary hypertension should be avoided with strong CYP3A4 inhibitors. When used for erectile dysfunction, starting adult dose should be reduced to 25 mg. Maximum adult dose with ritonavir or cobicistat is 25 mg per 48 hours. Consider therapy modification
Silodosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin. Avoid combination
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Simeprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simeprevir. Avoid combination
Simvastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simvastatin. Avoid combination
Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. Consider therapy modification
Sirolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sirolimus. Management: Consider avoiding concurrent use of sirolimus with strong CYP3A4 inhibitors in order to minimize the risk for sirolimus toxicity. Concomitant use of sirolimus and voriconazole or posaconazole is contraindicated. Consider therapy modification
Solifenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Solifenacin. Management: Limit solifenacin doses to 5 mg daily when combined with strong CYP3A4 inhibitors. Consider therapy modification
Sonidegib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sonidegib. Avoid combination
SORAfenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SORAfenib. Monitor therapy
Sotalol: Ceritinib may enhance the bradycardic effect of Sotalol. Ceritinib may enhance the QTc-prolonging effect of Sotalol. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification
St John's Wort: May decrease the serum concentration of Ceritinib. 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
SUFentanil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SUFentanil. Management: If a strong CYP3A4 inhibitor is initiated in a patient on sufentanil, consider a sufentanil dose reduction and monitor for increased sufentanil effects and toxicities (eg, respiratory depression). Consider therapy modification
SUNItinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, sunitinib dose decreases are recommended, and vary by indication. See full monograph for details. Consider therapy modification
Suvorexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Suvorexant. Avoid combination
Tacrolimus (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tacrolimus (Systemic). Management: Monitor clinical tacrolimus response closely and frequently monitor tacrolimus serum concentrations with concurrent use of any strong CYP3A4 inhibitor. Tacrolimus dose reductions and/or prolongation of the dosing interval will likely be required. Consider therapy modification
Tadalafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tadalafil. Management: Recommendations regarding use of tadalafil in patients also receiving strong CYP3A4 inhibitors may vary based on indication and/or international labeling. Consult appropriate product labeling. Consider therapy modification
Tamsulosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Avoid combination
Tasimelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tasimelteon. Monitor therapy
Tazemetostat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tazemetostat. Avoid combination
Temsirolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Temsirolimus. Management: Avoid concomitant use of temsirolimus and strong CYP3A4 inhibitors whenever possible. If combined, decrease temsirolimus dose to 12.5 mg per week and monitor patients for increased temsirolimus effects and toxicities. Consider therapy modification
Terfenadine: QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may enhance the QTc-prolonging effect of Terfenadine. QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Terfenadine. Avoid combination
Terlipressin: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy
Tetrahydrocannabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy
Tetrahydrocannabinol and Cannabidiol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol and Cannabidiol. Monitor therapy
Tezacaftor and Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tezacaftor and Ivacaftor. Management: When combined with strong CYP3A4 inhibitors, tezacaftor/ivacaftor should be administered in the morning, twice a week, approximately 3 to 4 days apart. No evening doses of ivacaftor alone should be administered. Consider therapy modification
Thiotepa: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Thiotepa. Management: Thiotepa prescribing information recommends avoiding concomitant use of thiotepa and strong CYP3A4 inhibitors. If concomitant use is unavoidable, monitor for adverse effects and decreased efficacy. Consider therapy modification
Ticagrelor: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ticagrelor. Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Tofacitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tofacitinib. Management: Tofacitinib dose reductions are recommended when combined with strong CYP3A4 inhibitors. Recommended dose adjustments vary by tofacitinib formulation and therapeutic indication. See full monograph for details. Consider therapy modification
Tolterodine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Management: The maximum recommended adult dose of tolterodine is 2 mg/day when used together with a strong CYP3A4 inhibitor. Consider therapy modification
Tolvaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan. Avoid combination
Toremifene: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Toremifene. Management: Avoid concomitant use of toremifene and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined, monitor patients for toremifene toxicities including QTc prolongation and TdP. Consider therapy modification
Trabectedin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Trabectedin. Avoid combination
TraMADol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraMADol. Monitor therapy
TraZODone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraZODone. Management: Consider the use of a lower trazodone dose and monitor for increased trazodone effects (eg, sedation, QTc prolongation) if combined with strong CYP3A4 inhibitors. Consider therapy modification
Triazolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Triazolam. Avoid combination
Ubrogepant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ubrogepant. Avoid combination
Udenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Udenafil. Avoid combination
Ulipristal: CYP3A4 Inhibitors (Strong) 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 combo should be monitored for ulipristal toxicity. Avoid combination
Upadacitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Upadacitinib. Monitor therapy
Valbenazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Valbenazine. Management: Reduce the valbenazine dose to 40 mg daily when combined with strong CYP3A4 inhibitors. Consider therapy modification
Vardenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vardenafil. Management: Recommendations regarding concomitant use of vardenafil with strong CYP3A4 inhibitors may vary depending on brand name (e.g., Levitra, Staxyn) or by international labeling. See full drug interaction monograph for details. Consider therapy modification
Vemurafenib: May enhance the QTc-prolonging effect of QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of Vemurafenib. Management: Avoid concomitant use of vemurafenib and strong CYP3A4 inhibitors that prolong the QTc interval whenever possible. If combined monitor patients for vemurafenib toxicities including QTc prolongation and TdP. Consider therapy modification
Venetoclax: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Venetoclax. Management: This combination is contraindicated during venetoclax initiation and ramp-up in patients with CLL/SLL. Reduced venetoclax doses are required during ramp-up for patients with AML, and reduced doses are required for all patients during maintenance therapy. Consider therapy modification
Vilanterol: May increase the serum concentration of CYP3A4 Inhibitors (Strong). Monitor therapy
Vilazodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. Management: Limit maximum adult vilazodone dose to 20 mg daily in patients receiving strong CYP3A4 inhibitors. The original vilazodone dose can be resumed following discontinuation of the strong CYP3A4 inhibitor. Consider therapy modification
VinCRIStine (Liposomal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination
Vindesine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vindesine. Monitor therapy
Vinflunine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinflunine. Avoid combination
Vinorelbine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinorelbine. Monitor therapy
Vorapaxar: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vorapaxar. Avoid combination
Voxelotor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and strong CYP3A4 inhibitors. If concomitant use is unavoidable, reduce the voxelotor dose to 1,000 mg once daily. Consider therapy modification
Warfarin: Ceritinib may increase the serum concentration of Warfarin. Monitor therapy
Zanubrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zanubrutinib. Management: Decrease the zanubrutinib dose to 80 mg once daily during coadministration with a strong CYP3A4 inhibitor. Further dose adjustments may be required for zanubrutinib toxicities, refer to prescribing information for details. Consider therapy modification
Zolpidem: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zolpidem. Monitor therapy
Zopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zopiclone. Management: The initial starting adult dose of zopiclone should not exceed 3.75 mg if combined with a strong CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification
Zuclopenthixol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zuclopenthixol. Management: Consider zuclopenthixol dosage reduction with concomitant use of a strong CYP3A4 inhibitor (eg, ketoconazole) in poor CYP2D6 metabolizers or with strong CYP2D6 inhibitors (eg, paroxetine). Monitor for increased zuclopenthixol levels/toxicity. Consider therapy modification
Adverse Reactions
>10%:
Cardiovascular: Prolonged Q-T interval on ECG (4% to 12%)
Central nervous system: Fatigue (45% to 52%), noncardiac chest pain (21%), headache (19%), neuropathy (17%), dizziness (12%)
Dermatologic: Skin rash (16% to 21%), pruritus (11%)
Endocrine & metabolic: Increased gamma-glutamyl transferase (84%), hyperglycemia (49% to 53%), decreased serum phosphate (36% to 38%), weight loss (24%)
Gastrointestinal: Diarrhea (56% to 86%), nausea (45% to 80%), vomiting (35% to 67%), abdominal pain (40% to 54%), increased serum amylase (37%), decreased appetite (34%), constipation (20% to 29%), increased serum lipase (13% to 28%), dyspepsia (≤16%), dysphagia (≤16%), gastroesophageal reflux disease (≤16%)
Hematologic & oncologic: Anemia (67% to 84%; grades 3/4: 4% to 5%), neutropenia (27%; grades 3/4: 2%), thrombocytopenia (16%; grades 3/4: 1%)
Hepatic: Increased serum ALT (80% to 91%; >5x ULN: 28%), increased serum AST (75% to 86%; >5x ULN: 16%), increased serum alkaline phosphatase (81%), increased serum bilirubin (15%)
Neuromuscular & skeletal: Back pain (19%), limb pain (13%), musculoskeletal pain (11%)
Renal: Increased serum creatinine (58% to 77%)
Respiratory: Cough (25%)
Miscellaneous: Fever (19%)
1% to 10%:
Cardiovascular: Pericarditis (4%), bradycardia (1% to 4%) pericardial effusion (≥2%), sinus bradycardia (1%)
Central nervous system: Seizure (≥2%)
Endocrine & metabolic: Dehydration (≥2%)
Hepatic: Hepatotoxicity (2%)
Ophthalmic: Visual disturbance (4% to 9%)
Renal: Renal failure (2%)
Respiratory: Pleural effusion (4%), pneumonia (4%), interstitial pulmonary disease (2% to 4%), pulmonary infection (≥2%), severe dyspnea (≥2%)
<1%, postmarketing and/or case reports: Pancreatitis
Warnings/Precautions
Concerns related to adverse effects:
- Bradycardia: Symptomatic bradycardia has been reported; 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 adjust ceritinib dose. Permanently discontinue for life-threatening bradycardia due to ceritinib; if life-threatening bradycardia occurs and concurrent medications associated with bradycardia can be discontinued or dose adjusted, restart ceritinib at a reduced dose (with frequent monitoring).
- Gastrointestinal toxicity: Severe and/or persistent gastrointestinal toxicity has occurred with ceritinib (at a dose of 750 mg in a fasted state). Diarrhea, nausea, vomiting, or abdominal pain occurred in the majority of patients in clinical trials using ceritinib 750 mg daily fasted (including some grade 3 and 4 events); over one-third of patients required treatment interruptions or dose reductions due to severe or persistent gastrointestinal toxicity. The incidence and severity of gastrointestinal toxicity were reduced in a clinical study utilizing ceritinib 450 mg daily with food (Cho 2017); most events were grade 1. Manage symptoms medically with appropriate therapy (eg, antidiarrheals, antiemetics, fluid replacement) as indicated. May require therapy interruption and/or dosage reduction. Ceritinib is associated with a moderate emetic potential (Hesketh 2017; Roila 2016); antiemetics may be needed to prevent nausea and vomiting. If vomiting occurs, do not administer an additional dose; continue with the next scheduled dose.
- Hepatotoxicity: Hepatotoxicity has been observed in patients treated with ceritinib in clinical trials, including ALT levels >5 times ULN in over one-quarter of patients and AST elevations in nearly one-fifth of patients. Concurrent ALT elevations >3 times ULN with total bilirubin >2 times ULN (with normal alkaline phosphatase) occurred rarely. Monitor liver function tests (eg, ALT, AST, total bilirubin) monthly and as clinically necessary, more frequently in patients who develop transaminase abnormalities. May require therapy interruption, dosage reduction, and/or permanent discontinuation.
- Hyperglycemia: Hyperglycemia, including grade 3 and 4 toxicity, has been observed in ceritinib-treated patients. Monitor fasting blood glucose levels at baseline and as clinically necessary. May require initiation or optimization of antihyperglycemic therapy. Temporarily interrupt therapy for hyperglycemia until adequately controlled; reduce dose upon recovery. If adequate glycemic control is not possible with medical management, permanently discontinue ceritinib.
- Pancreatitis: Although rare, pancreatitis (with fatality) has been reported. Grade 3 to 4 lipase and amylase elevations occurred in clinical trials. Monitor lipase and amylase prior to treatment and periodically during treatment as clinically necessary. May require treatment interruption and dose reduction.
- Pulmonary toxicity: Severe and life-threatening interstitial lung disease (ILD)/pneumonitis have been reported, including grade 3 or 4 events and fatalities. Monitor for signs/symptoms of pulmonary toxicity; permanently discontinue in patients diagnosed with treatment-related ILD/pneumonitis.
- QTc prolongation: QTc interval prolongation has occurred in clinical studies, and may be concentration-dependent. Based on post-baseline ECG assessment, a QTc interval increase of >60 msec over baseline was observed in a small percentage of patients; some patients experienced a QTc >500 msec (when taking ceritinib 750 mg daily fasted). QT prolongation may lead to an increased risk for ventricular tachyarrhythmias (eg, torsades de pointes) or sudden death. Avoid use in patients with congenital long QTc syndrome. Correct electrolyte abnormalities prior to initiating therapy. Periodically monitor ECG and electrolytes in patients with heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications known to prolong the QTc interval. QT prolongation may require treatment interruption, dosage reduction, or discontinuation. Permanently discontinue in patients who develop QTc interval prolongation in combination with torsades de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia.
Disease-related concerns:
- Hepatic impairment: Systemic exposure is increased and reduced initial doses are recommended in patients with severe impairment (Child-Pugh class C).
Concurrent drug therapy issues:
- Drug-drug 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.
Other warnings/precautions:
- Administration: A pharmacokinetic study determined that ceritinib 450 mg once daily administered with food had similar exposure and with lower GI toxicities when compared to 750 mg administered in a fasted state (Cho 2017). Based on this, the recommended ceritinib dose is now 450 mg once daily with food.
- Anaplastic lymphoma kinase testing: 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. Information on approved tests for detection of ALK gene rearrangements may be found at http://www.fda.gov/CompanionDiagnostics.
Monitoring Parameters
ALK positivity; renal function, liver function (ALT, AST, total bilirubin at baseline, monthly and as clinically necessary, more frequently in patients who develop transaminase abnormalities), fasting blood glucose (baseline and as clinically necessary), lipase and amylase (baseline and periodically as clinically necessary); electrolytes (baseline and periodically thereafter); cardiac monitoring (heart rate and QTc interval; ECG in patients with heart failure, bradyarrhythmias, electrolyte abnormalities, or on concomitant medications known to prolong the QTc interval); blood pressure; signs/symptoms of gastrointestinal, pulmonary toxicity, and/or pancreatitis. Monitor adherence.
Pregnancy
Pregnancy Considerations
Based on findings in animal reproduction studies and its mechanism of action, ceritinib may cause fetal harm if administered to a pregnant woman. Women of reproductive potential should use effective contraception during treatment and for 6 months following therapy discontinuation. Based on the potential for genotoxicity, males with female partners of reproductive potential should use condoms during treatment and for 3 months following completion of therapy.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience constipation, heartburn, weight loss, back pain, muscle pain, cough, headache, or lack of appetite. Have patient report immediately to prescriber signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), bruising, bleeding, fast heartbeat, slow heartbeat, abnormal heartbeat, chest pain, passing out, dizziness, burning or numbness feeling, chills, severe loss of strength and energy, severe abdominal pain, severe nausea, severe vomiting, severe diarrhea, change in balance, muscle weakness, or vision changes (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
