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Drug overview for ENSACOVE (ensartinib hydrochloride):
Generic name: ENSARTINIB HYDROCHLORIDE (en-SAR-ti-nib)
Drug class: Antineoplastic - Protein-Tyrosine Kinase Inhibitors
Therapeutic class: Antineoplastics
Ensartinib hydrochloride, a kinase inhibitor of anaplastic lymphoma kinase (ALK), is an antineoplastic agent.
No enhanced Uses information available for this drug.
Generic name: ENSARTINIB HYDROCHLORIDE (en-SAR-ti-nib)
Drug class: Antineoplastic - Protein-Tyrosine Kinase Inhibitors
Therapeutic class: Antineoplastics
Ensartinib hydrochloride, a kinase inhibitor of anaplastic lymphoma kinase (ALK), is an antineoplastic agent.
No enhanced Uses information available for this drug.
DRUG IMAGES
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The following indications for ENSACOVE (ensartinib hydrochloride) have been approved by the FDA:
Indications:
Anaplastic lymphoma kinase positive non-small cell lung cancer
Professional Synonyms:
ALK positive NSCLC
Indications:
Anaplastic lymphoma kinase positive non-small cell lung cancer
Professional Synonyms:
ALK positive NSCLC
The following dosing information is available for ENSACOVE (ensartinib hydrochloride):
*Select patients for the treatment of locally advanced or metastatic NSCLC with ensartinib based on the presence of ALK rearrangement(s) in tumor specimens.
*Prior to initiating ensartinib, evaluate liver function tests and fastingblood glucose.
*Recommended dosage is 225 mg orally once daily with or without food until disease progression or unacceptable toxicity.
*See Full Prescribing Information for dosage modification recommendations for adverse reactions.
*Prior to initiating ensartinib, evaluate liver function tests and fastingblood glucose.
*Recommended dosage is 225 mg orally once daily with or without food until disease progression or unacceptable toxicity.
*See Full Prescribing Information for dosage modification recommendations for adverse reactions.
No enhanced Administration information available for this drug.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| ENSACOVE 25 MG CAPSULE | Maintenance | Adults take 1 capsule (25 mg) administer with 2 - 100 mg capsules (for a total dose of 225 mg) by oral route once daily |
| ENSACOVE 100 MG CAPSULE | Maintenance | Adults take 2 capsules (200 mg) administer with 1 - 25 mg capsule (for a total dose of 225 mg) by oral route once daily |
No generic dosing information available.
The following drug interaction information is available for ENSACOVE (ensartinib hydrochloride):
There are 0 contraindications.
There are 9 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Ensartinib/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inducers of CYP3A4 may induce the metabolism of ensartinib.(1) CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may reduce the clinical effectiveness of ensartinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The US manufacturer of ensartinib states that concurrent use of strong CYP3A4 inducers should be avoided.(1) DISCUSSION: Ensartinib is predominately metabolized by CYP3A4.(1) Strong CYP3A4 inducers linked to this monograph are: apalutamide, barbiturates, carbamazepine, encorafenib, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3) |
ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BRAFTOVI, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, DONNATAL, EPITOL, EQUETRO, ERLEADA, FIORICET, FIORICET WITH CODEINE, FOSPHENYTOIN SODIUM, LYSODREN, MITOTANE, MYSOLINE, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, PRIMIDONE, RIFADIN, RIFAMPIN, SEZABY, TEGRETOL, TEGRETOL XR, TENCON, TIBSOVO |
| Ensartinib/Selected Moderate CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Moderate inducers of CYP3A4 may induce the metabolism of ensartinib.(1) CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may reduce the clinical effectiveness of ensartinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The US manufacturer of ensartinib states that concurrent use of moderate CYP3A4 inducers should be avoided.(1) DISCUSSION: Ensartinib is predominately metabolized by CYP3A4.(1) Moderate CYP3A4 inducers linked to this monograph are: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, pacritinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) |
AUGTYRO, BOSENTAN, CAMZYOS, DUZALLO, EFAVIRENZ, EFAVIRENZ-EMTRIC-TENOFOV DISOP, EFAVIRENZ-LAMIVU-TENOFOV DISOP, ETRAVIRINE, INTELENCE, LORBRENA, MODAFINIL, NAFCILLIN, NAFCILLIN SODIUM, OJEMDA, PROVIGIL, PYRUKYND, RIFABUTIN, SYMFI, TAFINLAR, TALICIA, THIORIDAZINE HCL, THIORIDAZINE HYDROCHLORIDE, TRACLEER, TURALIO, VONJO, WELIREG, XCOPRI, XERMELO |
| Ensartinib/Selected Strong CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ensartinib is primarily metabolized by CYP3A4. Ensartinib metabolism may be inhibited by strong CYP3A4 inhibitors.(1) CLINICAL EFFECTS: The concurrent administration of a strong CYP3A4 inhibitor may result in elevated levels of and toxicity from ensartinib.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of ensartinib states that concurrent use of strong CYP3A4 inhibitors should be avoided.(1) DISCUSSION: Ensartinib is predominately metabolized by CYP3A4.(1) Strong CYP3A4 inhibitors include: adagrasib, ceritinib, grapefruit, idelalisib, ribociclib, troleandomycin, and voriconazole.(2,3) |
KISQALI, KRAZATI, VFEND, VFEND IV, VORICONAZOLE, ZYDELIG, ZYKADIA |
| Ensartinib/Selected Moderate CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ensartinib is primarily metabolized by CYP3A4. Ensartinib metabolism may be inhibited by moderate CYP3A4 inhibitors.(1) CLINICAL EFFECTS: The concurrent administration of a moderate CYP3A4 inhibitor may result in elevated levels of and toxicity from ensartinib.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of ensartinib states that concurrent use of moderate CYP3A4 inhibitors should be avoided.(1) DISCUSSION: Ensartinib is predominately metabolized by CYP3A4.(1) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, crizotinib, darunavir, duvelisib, fedratinib, fluconazole, fosamprenavir, fosnetupitant, imatinib, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, stiripentol, tofisopam, treosulfan, and voxelotor.(2,3) |
AKYNZEO, APONVIE, APREPITANT, ATAZANAVIR SULFATE, CINVANTI, CLOFAZIMINE, COPIKTRA, DANZITEN, DARUNAVIR, DIACOMIT, DIFLUCAN, EMEND, EVOTAZ, FLUCONAZOLE, FLUCONAZOLE-NACL, FOSAMPRENAVIR CALCIUM, GLEEVEC, GRAFAPEX, IMATINIB MESYLATE, IMKELDI, INREBIC, NILOTINIB HCL, NILOTINIB TARTRATE, OGSIVEO, ORLADEYO, PREVYMIS, PREZCOBIX, PREZISTA, REYATAZ, SUNLENCA, SYMTUZA, TASIGNA, TAVNEOS, XALKORI, XENLETA, YEZTUGO |
| Ensartinib/Selected P-glycoprotein (P-gp) Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ensartinib is a P-glycoprotein (P-gp) substrate. P-gp inhibitors may increase the levels of ensartinib.(1) CLINICAL EFFECTS: The concurrent administration of a P-glycoprotein (P-gp) inhibitor may result in elevated levels of and toxicity from ensartinib.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of ensartinib states that concurrent use of P-glycoprotein (P-gp) inhibitors should be avoided.(1) DISCUSSION: Ensartinib is a substrate of P-gp. Inhibitors of P-gp may increase toxicity of ensartinib.(1) Inhibitors of P-gp linked to this monograph include: abrocitinib, amiodarone, Asian ginseng (Panax ginseng), asunaprevir, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, danicopan, daridorexant, diosmin, eliglustat, flibanserin, fostamatinib, ginkgo biloba, glecaprevir and pibrentasvir, hydroquinidine, ivacaftor, lapatinib, mavorixafor, milk thistle (Silybum marianum), neratinib, osimertinib, propafenone, quercetin, quinidine, ranolazine, rolapitant, silibinin, silymarin, sotagliflozin, tepotinib, tezacaftor, valbenazine, velpatasvir, vemurafenib, venetoclax, vilazodone, vimseltinib, and voclosporin.(2,3) |
ADDYI, ALYFTREK, AMIODARONE HCL, AMIODARONE HCL-D5W, ASPRUZYO SPRINKLE, AZITHROMYCIN, CARVEDILOL, CARVEDILOL ER, CERDELGA, CIBINQO, CIMETIDINE, COREG, COREG CR, CYCLOSPORINE, CYCLOSPORINE MODIFIED, EPCLUSA, FLIBANSERIN, GENGRAF, INGREZZA, INGREZZA INITIATION PK(TARDIV), INGREZZA SPRINKLE, INPEFA, KALYDECO, LAPATINIB, LUPKYNIS, MAVYRET, NEORAL, NERLYNX, NEXTERONE, NUEDEXTA, PACERONE, PROPAFENONE HCL, PROPAFENONE HCL ER, QUINIDINE GLUCONATE, QUINIDINE SULFATE, QUVIVIQ, RANOLAZINE ER, REZUROCK, ROMVIMZA, SANDIMMUNE, SOFOSBUVIR-VELPATASVIR, SYMDEKO, TABRECTA, TAGRISSO, TAVALISSE, TEPMETKO, TRIKAFTA, TYKERB, VARUBI, VENCLEXTA, VENCLEXTA STARTING PACK, VIIBRYD, VILAZODONE HCL, VOSEVI, VOYDEYA, XOLREMDI, ZELBORAF, ZITHROMAX, ZITHROMAX TRI-PAK |
| Ensartinib/Dual Strong CYP3A4 & P-gp Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ensartinib is primarily metabolized by CYP3A4 and is transported by P-glycoprotein (P-gp).(1) Inhibitors of CYP3A4 and P-gp may inhibit the absorption and metabolism of ensartinib.(1) CLINICAL EFFECTS: Concurrent use with dual inhibitors of CYP3A4 and P-gp may result in elevated systemic levels and toxicity from ensartinib.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of ensartinib states concurrent use with both P-gp and strong CYP3A4 inhibitors should be avoided.(1) DISCUSSION: Ensartinib is predominately metabolized by CYP3A4 and is a P-gp substrate.(1) Dual P-gp and strong CYP3A4 inhibitors linked to this monograph include: boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, and tucatinib.(2,3) |
APTIVUS, CLARITHROMYCIN, CLARITHROMYCIN ER, EVOTAZ, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KALETRA, KETOCONAZOLE, KORLYM, LANSOPRAZOL-AMOXICIL-CLARITHRO, LOPINAVIR-RITONAVIR, MIFEPREX, MIFEPRISTONE, NEFAZODONE HCL, NORVIR, NOXAFIL, OMECLAMOX-PAK, PAXLOVID, POSACONAZOLE, PREZCOBIX, RECORLEV, RITONAVIR, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, TYBOST, VIRACEPT, VOQUEZNA TRIPLE PAK, ZOKINVY |
| Ensartinib/Dual Moderate CYP3A4 & P-gp Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ensartinib is primarily metabolized by CYP3A4 and is transported by P-glycoprotein (P-gp).(1) Inhibitors of CYP3A4 and P-gp may inhibit the absorption and metabolism of ensartinib.(1) CLINICAL EFFECTS: Concurrent use with dual inhibitors of CYP3A4 and P-gp may result in elevated systemic levels and toxicity from ensartinib.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of ensartinib states concurrent use with both P-gp and moderate CYP3A4 inhibitors should be avoided.(1) DISCUSSION: Ensartinib is predominately metabolized by CYP3A4 and is a P-gp substrate.(1) Dual P-gp and moderate CYP3A4 inhibitors linked to this monograph include: conivaptan, diltiazem, dronedarone, erythromycin, fluvoxamine, isavuconazonium, Schisandra, and verapamil.(2,3) |
CARDIZEM, CARDIZEM CD, CARDIZEM LA, CARTIA XT, CONIVAPTAN-D5W, CRESEMBA, DILT-XR, DILTIAZEM 12HR ER, DILTIAZEM 24HR ER, DILTIAZEM 24HR ER (CD), DILTIAZEM 24HR ER (LA), DILTIAZEM 24HR ER (XR), DILTIAZEM HCL, DILTIAZEM HCL-0.7% NACL, DILTIAZEM HCL-0.9% NACL, DILTIAZEM HCL-NACL, DILTIAZEM-D5W, E.E.S. 200, E.E.S. 400, ERY-TAB, ERYPED 200, ERYPED 400, ERYTHROCIN LACTOBIONATE, ERYTHROCIN STEARATE, ERYTHROMYCIN, ERYTHROMYCIN ESTOLATE, ERYTHROMYCIN ETHYLSUCCINATE, ERYTHROMYCIN LACTOBIONATE, FLUVOXAMINE MALEATE, FLUVOXAMINE MALEATE ER, MATZIM LA, MULTAQ, TIADYLT ER, TIAZAC, TRANDOLAPRIL-VERAPAMIL ER, VAPRISOL-5% DEXTROSE, VERAPAMIL ER, VERAPAMIL ER PM, VERAPAMIL HCL, VERAPAMIL SR |
| Ensartinib/Dual Moderate CYP3A4 Inducers & P-gp Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ensartinib is primarily metabolized by CYP3A4 and is transported by P-glycoprotein (P-gp).(1) Inducers of CYP3A4 may induce the metabolism of ensartinib while inhibitors of P-gp may increase the absorption of ensartinib.(1) CLINICAL EFFECTS: The net effect of this interaction is unknown. Concurrent use of ensartinib with CYP3A4 inducers may result in decreased levels and effectiveness of ensartinib while concurrent use of P-gp inhibitors may result in elevated systemic levels and toxicity from ensartinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of ensartinib states concurrent use with both P-gp inhibitors and moderate CYP3A4 inducers should be avoided.(1) DISCUSSION: Ensartinib is predominately metabolized by CYP3A4 and is a P-gp substrate.(1) Dual moderate CYP3A4 inducers and P-gp inhibitors linked to this monograph include: elagolix and sotorasib.(2,3) |
LUMAKRAS, ORIAHNN, ORILISSA |
| Ensartinib/Dual Strong CYP3A4 Inducers & P-gp Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ensartinib is primarily metabolized by CYP3A4 and is transported by P-glycoprotein (P-gp).(1) Inducers of CYP3A4 may induce the metabolism of ensartinib while inhibitors of P-gp may increase the absorption of ensartinib.(1) CLINICAL EFFECTS: The net effect of this interaction is unknown. Concurrent use of ensartinib with CYP3A4 inducers may result in decreased levels and effectiveness of ensartinib while concurrent use of P-gp inhibitors may result in elevated systemic levels and toxicity from ensartinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of ensartinib states concurrent use with both P-gp inhibitors and strong CYP3A4 inducers should be avoided.(1) DISCUSSION: Ensartinib is predominately metabolized by CYP3A4 and is a P-gp substrate.(1) Dual strong CYP3A4 inducers and P-gp inhibitors linked to this monograph include: enzalutamide, lumacaftor-ivacaftor, and St. John's wort.(2,3) |
ORKAMBI, XTANDI |
There are 2 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Apixaban/Strong and Moderate CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Apixaban is a substrate of CYP3A4 and P-glycoprotein (P-gp). It is about 20% metabolized, mainly by CYP3A4.(1-4) Strong and moderate CYP3A4 inhibitors may inhibit the metabolism of apixaban by CYP3A4. CLINICAL EFFECTS: Concurrent use of a CYP3A4 inhibitor may result in elevated levels of and clinical effects of apixaban, including an increased risk of bleeding, especially in the setting of concurrent therapy with an agent that inhibits P-gp.(1-4) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug-associated risk factors include concurrent use of P-gp inhibitors and concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: The US manufacturer of apixaban provides recommendations regarding concurrent use with strong inhibitors of both CYP3A4 and P-gp, but does not provide guidance for concurrent use with agents that inhibit CYP3A4 alone.(1) The Australian, Canadian, and UK labels for apixaban state that no dose adjustment for apixaban is required when co-administered with agents that are not strong inhibitors of both CYP3A4 and P-gp.(2-4) Expert opinion on the clinical significance of this interaction is varied and depends on the inhibitor. Some experts state that specific agents (i.e., voriconazole, imatinib, and crizotinib) should be contraindicated.(5) Others state that concurrent use is acceptable if there are no other pharmacokinetic interactions; otherwise, a 50% dose reduction of apixaban is suggested.(6) In patients who are also on concurrent P-gp inhibitors, consider the manufacturer recommendations for use with dual CYP3A4 and P-gp inhibitors. The US manufacturer of apixaban states that if concurrent use of strong CYP3A4 and P-gp inhibitors cannot be avoided, the dosage of apixaban should be reduced by 50%. In patients already receiving apixaban 2.5 mg twice daily, avoid the concurrent use of strong inhibitors of both P-gp and CYP3A4.(1) The Australian(2) and Canadian(3) manufacturers of apixaban states that the concurrent use of agents that are strong inhibitors of both P-gp and CYP3A4 with apixaban is contraindicated. The UK manufacturer of apixaban states that concurrent use of these agents is not recommended.(4) Concurrent use of agents that are dual P-gp and moderate CYP3A4 inhibitors are expected to increase apixaban levels to a lesser extent than agents that are P-gp and strong CYP3A4 inhibitors. No dose adjustment of apixaban is necessary. Use caution when administering apixaban with moderate inhibitors of CYP3A4. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: The US manufacturer of apixaban states that apixaban dose reduction is recommended when apixaban exposure increases by more than 50%, while efficacy is maintained when exposure is 25% lower. Therefore, no dose adjustment of apixaban is recommended for drug interactions that affect apixaban exposure by 75% to 150%.(7) In a microdose cocktail study using apixaban 25 mcg, voriconazole 400 mg every 12 hours for 2 doses then 200 mg every 12 hours (strong CYP3A4 inhibitor) had "only a minor interaction," increasing the AUC of apixaban by 1.33-fold (95% CI 1.01-1.75) while the Cmax and half-life remained unchanged.(8) Another microdose cocktail study with apixaban 25 mcg and voriconazole 400 mg twice daily found that apixaban AUC increased by 1.24-fold with a non-significant change in Cmax.(9) A retrospective cohort study of 50 oncology patients on apixaban identified 14 patients on concurrent voriconazole, with 3 of those patients receiving reduced-dose apixaban. No bleeding or thrombosis occurred in any of the patients on concurrent voriconazole.(10) An article evaluating the clinical significance of efflux transporters like P-gp and BCRP in apixaban exposure analyzed pharmacokinetic data from drug-drug interaction studies and concluded that all apixaban interactions can be explained by inhibition of intestinal CYP3A4. The authors explain that apixaban is a highly permeable and soluble compound, so its ability to undergo passive diffusion renders the role of membrane transporters irrelevant, as evidenced by a lack of change in apixaban absorption rate in the presence of drugs known to inhibit P-gp and BCRP.(11) A review article on DOAC drug-drug interactions suggests that the combination of voriconazole, crizotinib or imatinib with apixaban or rivaroxaban is contraindicated due to the potential for significant increases in DOAC AUC. The authors state that data with voriconazole is missing and thus the interactions are unpredictable.(5) Another review article states that apixaban may be used with voriconazole if no other pharmacokinetic inhibitor is present; otherwise, concurrent use requires a 50% apixaban dose reduction. No dose adjustment is recommended with moderate CYP3A4 inhibitors.(6) Strong CYP3A4 inhibitors linked to this monograph include: boceprevir, ceritinib, ensartinib, idelalisib, mibefradil, nefazodone, ribociclib, troleandomycin, and voriconazole.(12,13) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, clofazimine, crizotinib, duvelisib, fedratinib, fosnetupitant, imatinib, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, schisandra, stiripentol, tofisopam, treosulfan, and voxelotor.(12,13) |
ELIQUIS |
| Rivaroxaban/Strong and Moderate CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Rivaroxaban is a substrate of CYP3A4 and P-glycoprotein (P-gp). It is about 18% metabolized, mainly by CYP3A4.(1-4) Strong and moderate CYP3A4 inhibitors may inhibit the metabolism of rivaroxaban by CYP3A4. CLINICAL EFFECTS: Concurrent use of a CYP3A4 inhibitor may result in elevated levels of and clinical effects of rivaroxaban, including an increased risk of bleeding, especially in the setting of concurrent therapy with an agent that inhibits P-gp.(1-4) PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Patients with renal impairment may be at higher risk of elevated rivaroxaban levels. Drug-associated risk factors include concurrent use of P-gp inhibitors and concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism or have an inherent risk for bleeding (e.g. NSAIDs). PATIENT MANAGEMENT: The US manufacturer of rivaroxaban provides recommendations regarding concurrent use with strong and moderate inhibitors of both CYP3A4 and P-gp, but does not provide guidance for concurrent use with agents that inhibit CYP3A4 alone.(1) The Canadian manufacturer of rivaroxaban states that increases in rivaroxaban levels by drugs inhibiting only CYP3A4 are expected to be less clinically relevant compared to drugs inhibiting both CYP3A4 and P-gp.(2) The UK manufacturer of rivaroxaban states that drug interactions with agents that inhibit only CYP3A4 are likely not clinically relevant in most patients but may be significant in high-risk patients (e.g., renal impairment).(3) The Australian manufacturer of rivaroxaban states that drug interactions with drugs that inhibit only CYP3A4 are not clinically relevant.(4) Expert opinion on the clinical significance of this interaction is varied and depends on the inhibitor. Some experts state that specific agents (i.e., voriconazole, imatinib, and crizotinib) should be contraindicated.(5) Others state that concurrent use is acceptable if there are no other pharmacokinetic interactions; otherwise, the combination should be avoided.(6) In patients who are also on concurrent P-gp inhibitors, consider the manufacturer recommendations for use with dual CYP3A4 and P-gp inhibitors. The Australian and Canadian manufacturers of rivaroxaban state that the concurrent use of agents that are both an inhibitor of P-gp and a strong inhibitor of CYP3A4 with rivaroxaban is contraindicated.(2,4) The US manufacturer states that concurrent use of strong CYP3A4 and P-gp inhibitors should be avoided(1) while the UK manufacturer states that concurrent use is not recommended.(3) Agents that are not strong inhibitors of both CYP3A4 and P-gp, including fluconazole, are expected to increase rivaroxaban levels to a lesser extent and can be used with rivaroxaban with caution in patients with normal renal function; however, in patients with decreased renal function (CrCL of 15 ml/min to 80 ml/min) these agents should only be used if the benefits of concurrent therapy outweigh the increased risk of bleeding.(1-4) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: In a microdose cocktail study using rivaroxaban 25 mcg, voriconazole 400 mg every 12 hours for 2 doses then 200 mg every 12 hours (strong CYP3A4 inhibitor) had "only a minor interaction," increasing the AUC of rivaroxaban by 1.33-fold (p<0.05) while the Cmax and half-life remained unchanged.(7) Another microdose cocktail study with rivaroxaban 25 mcg and voriconazole 400 mg twice daily found that rivaroxaban AUC increased by 1.16-fold with a non-significant change in Cmax.(8) A review article on DOAC drug-drug interactions suggests that the combination of voriconazole, crizotinib or imatinib with apixaban or rivaroxaban is contraindicated due to the potential for significant increases in DOAC AUC. The authors state that data with voriconazole is missing and thus the interactions are unpredictable.(5) Another review article states that rivaroxaban may be used with voriconazole if no other pharmacokinetic inhibitor is present; otherwise, concurrent use should be avoided. No dose adjustment is recommended with moderate CYP3A4 inhibitors.(6) Strong CYP3A4 inhibitors linked to this monograph include: boceprevir, ceritinib, ensartinib, idelalisib, mibefradil, nefazodone, ribociclib, troleandomycin, and voriconazole.(9,10) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, avacopan, berotralstat, clofazimine, crizotinib, duvelisib, fedratinib, fosnetupitant, imatinib, oral lefamulin, lenacapavir, letermovir, netupitant, nirogacestat, schisandra, stiripentol, tofisopam, treosulfan, and voxelotor.(9,10) |
RIVAROXABAN, XARELTO |
The following contraindication information is available for ENSACOVE (ensartinib hydrochloride):
Drug contraindication overview.
Hypersensitivity reaction to ensartinib hydrochloride, FD&C Yellow No. 5 (tartrazine), or to any of its components.
Hypersensitivity reaction to ensartinib hydrochloride, FD&C Yellow No. 5 (tartrazine), or to any of its components.
There are 1 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Lactation |
There are 1 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Pregnancy |
There are 4 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Bradycardia |
| Diabetes mellitus |
| Hyperuricemia |
| Interstitial lung disease |
The following adverse reaction information is available for ENSACOVE (ensartinib hydrochloride):
Adverse reaction overview.
Most common adverse reactions (incidence >=20%) were rash, musculoskeletal pain, constipation, pruritus, cough, nausea, edema, vomiting, fatigue, and pyrexia. Most common Grade 3-4 laboratory abnormality (incidence >=2%) were increased uric acid, decreased lymphocytes, increased alanine aminotransferase, decreased phosphate, increased gamma glutamyl transferase, increased magnesium, increased amylase, decreased sodium, increased glucose, decreased hemoglobin, increased bilirubin, decreased potassium, and increased creatine phosphokinase.
Most common adverse reactions (incidence >=20%) were rash, musculoskeletal pain, constipation, pruritus, cough, nausea, edema, vomiting, fatigue, and pyrexia. Most common Grade 3-4 laboratory abnormality (incidence >=2%) were increased uric acid, decreased lymphocytes, increased alanine aminotransferase, decreased phosphate, increased gamma glutamyl transferase, increased magnesium, increased amylase, decreased sodium, increased glucose, decreased hemoglobin, increased bilirubin, decreased potassium, and increased creatine phosphokinase.
There are 5 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
| None. |
Hemorrhage Pneumonia |
| Rare/Very Rare |
|---|
|
Cellulitis DRESS syndrome Drug-induced hepatitis |
There are 36 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Abnormal hepatic function tests Anemia Constipation Cough Edema Elevated serum amylase Fatigue Fever Gamma-glutamyl transferase raised Hyperbilirubinemia Hyperglycemia Hypermagnesemia Hyperuricemia Hypoalbuminemia Hypocalcemia Hypokalemia Hyponatremia Hypophosphatemia Increased creatine kinase level Kidney disease with reduction in glomerular filtration rate (GFr) Lymphopenia Musculoskeletal pain Nausea Pruritus of skin Skin rash Vomiting |
Alopecia Anorexia Bradycardia Dizziness Dry skin Dysgeusia Interstitial pneumonitis Skin photosensitivity Upper respiratory infection Visual changes |
| Rare/Very Rare |
|---|
| None. |
The following precautions are available for ENSACOVE (ensartinib hydrochloride):
The safety and effectiveness of ensartinib in pediatric patients have not been established.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Based on findings from animal studies and its mechanism of action, ensartinib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of ensartinib in pregnant women to inform a drug-associated risk. Oral administration of ensartinib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, alterations to growth, and structural abnormalities.
Adverse embryo-fetal findings were seen at maternal exposures approximately equivalent to the human exposure at the recommended dose of 225 mg/day based on AUC. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Adverse embryo-fetal findings were seen at maternal exposures approximately equivalent to the human exposure at the recommended dose of 225 mg/day based on AUC. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
There are no data on the presence of ensartinib or its metabolites in human milk, the effects onthe breastfed child, or the effects on milk production. Because of the potential for serious adversereactions in breastfed children, advise women not to breastfeed during treatment withensartinib and for 1 week after the last dose.
Of the 458 patients enrolled in clinical studies and received ensartinib 225 mg once daily, 16% of the participants were 65 years of age or older. Clinical studies of ensartinib did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. Exploratory analysis suggests a higher incidence of serious adverse events (43% vs 27%), more frequent adverse events leading to treatment discontinuations (18% vs 10%), and dose modifications (34% vs 16%) in patients 65 years of age orolder as compared to those younger than 65 years.
The following prioritized warning is available for ENSACOVE (ensartinib hydrochloride):
No warning message for this drug.
No warning message for this drug.
The following icd codes are available for ENSACOVE (ensartinib hydrochloride)'s list of indications:
| ALK positive non-small cell lung cancer | |
| C34 | Malignant neoplasm of bronchus and lung |
| C34.0 | Malignant neoplasm of main bronchus |
| C34.00 | Malignant neoplasm of unspecified main bronchus |
| C34.01 | Malignant neoplasm of right main bronchus |
| C34.02 | Malignant neoplasm of left main bronchus |
| C34.1 | Malignant neoplasm of upper lobe, bronchus or lung |
| C34.10 | Malignant neoplasm of upper lobe, unspecified bronchus or lung |
| C34.11 | Malignant neoplasm of upper lobe, right bronchus or lung |
| C34.12 | Malignant neoplasm of upper lobe, left bronchus or lung |
| C34.2 | Malignant neoplasm of middle lobe, bronchus or lung |
| C34.3 | Malignant neoplasm of lower lobe, bronchus or lung |
| C34.30 | Malignant neoplasm of lower lobe, unspecified bronchus or lung |
| C34.31 | Malignant neoplasm of lower lobe, right bronchus or lung |
| C34.32 | Malignant neoplasm of lower lobe, left bronchus or lung |
| C34.8 | Malignant neoplasm of overlapping sites of bronchus and lung |
| C34.80 | Malignant neoplasm of overlapping sites of unspecified bronchus and lung |
| C34.81 | Malignant neoplasm of overlapping sites of right bronchus and lung |
| C34.82 | Malignant neoplasm of overlapping sites of left bronchus and lung |
| C34.9 | Malignant neoplasm of unspecified part of bronchus or lung |
| C34.90 | Malignant neoplasm of unspecified part of unspecified bronchus or lung |
| C34.91 | Malignant neoplasm of unspecified part of right bronchus or lung |
| C34.92 | Malignant neoplasm of unspecified part of left bronchus or lung |
| C39.9 | Malignant neoplasm of lower respiratory tract, part unspecified |
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