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Drug overview for BOSULIF (bosutinib):
Generic name: bosutinib (boe-SUE-ti-nib)
Drug class: Antineoplastic - Protein-Tyrosine Kinase Inhibitors
Therapeutic class: Antineoplastics
Bosutinib, an inhibitor of multiple tyrosine kinases, is an antineoplastic agent.
No enhanced Uses information available for this drug.
Generic name: bosutinib (boe-SUE-ti-nib)
Drug class: Antineoplastic - Protein-Tyrosine Kinase Inhibitors
Therapeutic class: Antineoplastics
Bosutinib, an inhibitor of multiple tyrosine kinases, is an antineoplastic agent.
No enhanced Uses information available for this drug.
DRUG IMAGES
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The following indications for BOSULIF (bosutinib) have been approved by the FDA:
Indications:
Accelerated phase Philadelphia chromosome positive chronic myelocytic leukemia
Chronic phase Philadelphia chromosome positive chronic myelocytic leukemia
Lymphoid blast phase Philadelphia chromosome positive chronic myelocytic leukemia
Myeloid blast phase Philadelphia chromosome positive chronic myelocytic leukemia
Professional Synonyms:
Accelerated phase Ph(+) CML
Accelerated phase Ph1(+) CML
Accelerated phase Philadelphia chromosome positive chronic myeloid leukemia
Accelerated phase, BCR/ABL positive CML
BCR/ABL positive CML in lymphoid blast crisis
BCR/ABL positive CML in myeloid blast crisis
Chronic phase Ph(+) CML
Chronic phase Ph1(+) CML
Chronic phase Philadelphia chromosome positive chronic myeloid leukemia
Chronic phase, BCR/ABL positive CML
Lymphoid blast phase Ph(+) CML
Lymphoid blast phase Ph1(+) CML
Lymphoid blast phase Philadelphia chromosome positive chronic myeloid leukemia
Myeloid blast phase Ph(+) CML
Myeloid blast phase Ph1(+) CML
Myeloid blast phase philadelphia chromosome positive chronic myeloid leukemia
Ph(+) CML, accelerated phase
Ph(+) CML, chronic phase
Ph(+) CML, lymphoid blast phase
Ph(+) CML, myeloid blast phase
Ph1(+) CML, accelerated phase
Ph1(+) CML, chronic phase
Ph1(+) CML, lymphoid blast phase
Ph1(+) CML, myeloid blast phase
Philadelphia chromosome (+) CML in myeloid blast crisis
Philadelphia chromosome positive chronic myelocytic leukemia in lymphoid blast crisis
Indications:
Accelerated phase Philadelphia chromosome positive chronic myelocytic leukemia
Chronic phase Philadelphia chromosome positive chronic myelocytic leukemia
Lymphoid blast phase Philadelphia chromosome positive chronic myelocytic leukemia
Myeloid blast phase Philadelphia chromosome positive chronic myelocytic leukemia
Professional Synonyms:
Accelerated phase Ph(+) CML
Accelerated phase Ph1(+) CML
Accelerated phase Philadelphia chromosome positive chronic myeloid leukemia
Accelerated phase, BCR/ABL positive CML
BCR/ABL positive CML in lymphoid blast crisis
BCR/ABL positive CML in myeloid blast crisis
Chronic phase Ph(+) CML
Chronic phase Ph1(+) CML
Chronic phase Philadelphia chromosome positive chronic myeloid leukemia
Chronic phase, BCR/ABL positive CML
Lymphoid blast phase Ph(+) CML
Lymphoid blast phase Ph1(+) CML
Lymphoid blast phase Philadelphia chromosome positive chronic myeloid leukemia
Myeloid blast phase Ph(+) CML
Myeloid blast phase Ph1(+) CML
Myeloid blast phase philadelphia chromosome positive chronic myeloid leukemia
Ph(+) CML, accelerated phase
Ph(+) CML, chronic phase
Ph(+) CML, lymphoid blast phase
Ph(+) CML, myeloid blast phase
Ph1(+) CML, accelerated phase
Ph1(+) CML, chronic phase
Ph1(+) CML, lymphoid blast phase
Ph1(+) CML, myeloid blast phase
Philadelphia chromosome (+) CML in myeloid blast crisis
Philadelphia chromosome positive chronic myelocytic leukemia in lymphoid blast crisis
The following dosing information is available for BOSULIF (bosutinib):
Bosutinib is commercially available as the monohydrate; dosage is expressed in terms of anhydrous bosutinib.
Dose recommendations for pediatric patients with newly diagnosedchronic phase Ph+ CML or with chronic phasePh+ CML with resistance or intolerance to prior therapy are presented in Table 2.
Table 2. Dose Recommendations for Bosutinib in Pediatric Patients.
Body Surface Area (m2) Newly Diagnosed Resistant or Intolerant Recommended Dose (Once Recommended Dose (Once Daily) Daily) <0.55 150 mg 200 mg 0.55 to <0.63
200 mg 250 mg 0.63 to <0.75 200 mg 300 mg 0.75
to <0.9 250 mg 350 mg 0.9 to <1.1
300 mg 400 mg >=1.1 400 mg 500 mg
Maximum starting dose (corresponds to maximum starting dose for adult indication).
Dose recommendations for pediatric patients with newly diagnosedchronic phase Ph+ CML or with chronic phasePh+ CML with resistance or intolerance to prior therapy are presented in Table 2.
Table 2. Dose Recommendations for Bosutinib in Pediatric Patients.
Body Surface Area (m2) Newly Diagnosed Resistant or Intolerant Recommended Dose (Once Recommended Dose (Once Daily) Daily) <0.55 150 mg 200 mg 0.55 to <0.63
200 mg 250 mg 0.63 to <0.75 200 mg 300 mg 0.75
to <0.9 250 mg 350 mg 0.9 to <1.1
300 mg 400 mg >=1.1 400 mg 500 mg
Maximum starting dose (corresponds to maximum starting dose for adult indication).
Bosutinib is administered orally once daily with food; tolerability of the drug may be increased when taken with food. Bosutinib is available as tablets and capsules. Swallow tablets whole.
Tablets shouldnot be crushed, broken, chewed,or cut. Touching or handling of crushed or broken tablets should be avoided. Capsules may be swallowed whole.
If a patient is unable to swallow a whole capsule, the required number of capsules for the dose can be opened and contents mixed with room temperature applesauce or yogurt in a clean container (see Table 1). Patients should immediately consume the full mixture without chewing; do not store for later use. If the entire mixture is not swallowed, do not administer an additional dose.
Resume dosing on the next day. Table 1. Bosutinib Dose Using Capsules and Soft Food Volume Dose (mg) Volume of Applesauce or Yogurt 100 10 mL (2 teaspoons) 150 15 mL (3 teaspoons) 200 20 mL (4 teaspoons) 250 25 mL (5 teaspoons) 300 30 mL (6 teaspoons) 350 30 mL (6 teaspoons) 400 35 mL (7 teaspoons) 450 40 mL (8 teaspoons) 500 45 mL (9 teaspoons) 550 45 mL (9 teaspoons) 600 50 mL (10 teaspoons) If a dose of bosutinib is missed by more than 12 hours, the dose should be omitted, and the next dose should be taken at the regularly scheduled time.
Do not double the dose to make up for the missed dose. Store bosutinib tablets and capsulesat 20-25degreesC (excursions permitted between 15-30degreesC).
Tablets shouldnot be crushed, broken, chewed,or cut. Touching or handling of crushed or broken tablets should be avoided. Capsules may be swallowed whole.
If a patient is unable to swallow a whole capsule, the required number of capsules for the dose can be opened and contents mixed with room temperature applesauce or yogurt in a clean container (see Table 1). Patients should immediately consume the full mixture without chewing; do not store for later use. If the entire mixture is not swallowed, do not administer an additional dose.
Resume dosing on the next day. Table 1. Bosutinib Dose Using Capsules and Soft Food Volume Dose (mg) Volume of Applesauce or Yogurt 100 10 mL (2 teaspoons) 150 15 mL (3 teaspoons) 200 20 mL (4 teaspoons) 250 25 mL (5 teaspoons) 300 30 mL (6 teaspoons) 350 30 mL (6 teaspoons) 400 35 mL (7 teaspoons) 450 40 mL (8 teaspoons) 500 45 mL (9 teaspoons) 550 45 mL (9 teaspoons) 600 50 mL (10 teaspoons) If a dose of bosutinib is missed by more than 12 hours, the dose should be omitted, and the next dose should be taken at the regularly scheduled time.
Do not double the dose to make up for the missed dose. Store bosutinib tablets and capsulesat 20-25degreesC (excursions permitted between 15-30degreesC).
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| BOSULIF 100 MG CAPSULE | Maintenance | Adults take 4 capsules (400 mg) by oral route once daily |
No generic dosing information available.
The following drug interaction information is available for BOSULIF (bosutinib):
There are 5 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Efalizumab; Natalizumab/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Natalizumab,(1-3) efalizumab,(4) immunosuppressives, and immunomodulators all suppress the immune system. CLINICAL EFFECTS: Concurrent use of natalizumab(1-3) or efalizumab(4) with immunosuppressives or immunomodulators may result in an increased risk of infections, including progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV). PREDISPOSING FACTORS: Previous JCV infection, longer duration of natalizumab treatment - especially if greater than 2 years, and prior or concomitant treatment with immunosuppressant medication are all independent risk factors which increase the risk for PML.(1,5) The FDA has estimated PML incidence stratified by risk factors: If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment less than 25 months, incidence <1/1,000. If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment less than 25 months, incidence 2/1,000 If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 4/1,000 If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 11/1,000. PATIENT MANAGEMENT: The US manufacturer of natalizumab states patients with Crohn's disease should not receive concurrent immunosuppressants, with the exception of limited overlap of corticosteroids, due to the increased risk for PML. For new natalizumab patients currently receiving chronic oral corticosteroids for Crohn's Disease, begin corticosteroid taper when therapeutic response to natalizumab has occurred. If corticosteroids cannot be discontinued within six months of starting natalizumab, discontinue natalizumab.(3) The US manufacturer of natalizumab states that natalizumab should not ordinarily be used in multiple sclerosis patients receiving immunosuppressants or immunomodulators due to the increased risk for PML. Immunosuppressives include, but are not limited to azathioprine, cyclophosphamide, cyclosporine, mercaptopurine, methotrexate, mitoxantrone, mycophenolate, and corticosteroids.(3,6) The UK manufacturer of natalizumab states that concurrent use with immunosuppressives or antineoplastic agents is contraindicated.(1) The Canadian manufacturer of natalizumab states that natalizumab should not be used with immunosuppressive or immunomodulatory agents.(2) The US manufacturer of certolizumab states that concurrent therapy with natalizumab is not recommended.(7) DISCUSSION: Progressive multifocal leukoencephalopathy has been reported in patients receiving concurrent natalizumab were recently or concomitantly taking immunomodulators or immunosuppressants.(1-5,8,9) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(10) |
TYSABRI |
| Live Vaccines; Live BCG/Selected Immunosuppressive Agents SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: A variety of disease modifying agents suppress the immune system. Immunocompromised patients may be at increased risk for uninhibited replication after administration of live, attenuated vaccines or intravesicular BCG. Immune response to vaccines may be decreased during periods of immunocompromise.(1) CLINICAL EFFECTS: The expected serum antibody response may not be obtained and/or the vaccine may result in illness.(1) After instillation of intravesicular BCG, immunosuppression may interfere with local immune response, or increase the severity of mycobacterial infection following inadvertent systemic exposure.(2) PREDISPOSING FACTORS: Immunosuppressive diseases (e.g. hematologic malignancies, HIV disease), treatments (e.g. radiation) and drugs may all increase the magnitude of immunodeficiency. PATIENT MANAGEMENT: The Centers for Disease Control(CDC) Advisory Committee on Immunization Practices (ACIP) states that live-virus and live, attenuated vaccines should not be administered to patients who are immunocompromised. The magnitude of immunocompromise and associated risks should be determined by a physician.(1) For patients scheduled to receive chemotherapy, vaccination should ideally precede the initiation of chemotherapy by 14 days. Patients vaccinated while on immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy.(1) Patients who receive anti-B cell therapies should not receive live vaccines for at least 6 months after such therapies due to a prolonged duration of immunosuppression. An exception is the Zoster vaccine, which can be given at least 1 month after receipt of anti-B cell therapies.(1) The US manufacturer of abatacept states live vaccines should not be given during or for up to 3 months after discontinuation of abatacept.(2) The US manufacturer of live BCG for intravesicular treatment of bladder cancer states use is contraindicated in immunosuppressed patients.(3) The US manufacturer of daclizumab states live vaccines are not recommended during and for up to 4 months after discontinuation of treatment.(4) The US manufacturer of guselkumab states that live vaccines should be avoided during treatment with guselkumab.(5) The US manufacturer of inebilizumab-cdon states that live vaccines are not recommended during treatment and after discontinuation until B-cell repletion. Administer all live vaccinations at least 4 weeks prior to initiation of inebilizumab-cdon.(6) The US manufacturer of ocrelizumab states that live vaccines are not recommended during treatment and until B-cell repletion occurs after discontinuation of therapy. Administer all live vaccines at least 4 weeks prior to initiation of ocrelizumab.(7) The US manufacturer of ozanimod states that live vaccines should be avoided during and for up to 3 months after discontinuation of ozanimod.(8) The US manufacturer of siponimod states that live vaccines are not recommended during treatment and for up to 4 weeks after discontinuation of treatment.(9) The US manufacturer of ustekinumab states BCG vaccines should not be given in the year prior to, during, or the year after ustekinumab therapy.(10) The US manufacturer of satralizumab-mwge states that live vaccines are not recommended during treatment and should be administered at least four weeks prior to initiation of satralizumab-mwge.(11) The US manufacturer of ublituximab-xiiy states that live vaccines are not recommended during treatment and until B-cell recovery. Live vaccines should be administered at least 4 weeks prior to initiation of ublituximab-xiiy.(12) The US manufacturer of etrasimod states that live vaccines should be avoided during and for 5 weeks after treatment. Live vaccines should be administered at least 4 weeks prior to initiation of etrasimod.(13) The US manufacturer of emapalumab-lzsg states that live vaccines should not be administered to patients receiving emapalumab-lzsg and for at least 4 weeks after the last dose of emapalumab-lzsg. The safety of immunization with live vaccines during or following emapalumab-lzsg therapy has not been studied.(14) DISCUSSION: Killed or inactivated vaccines do not pose a danger to immunocompromised patients.(1) Patients with a history of leukemia who are in remission and have not received chemotherapy for at least 3 months are not considered to be immunocompromised.(1) |
ACAM2000 (NATIONAL STOCKPILE), ADENOVIRUS TYPE 4, ADENOVIRUS TYPE 4 AND TYPE 7, ADENOVIRUS TYPE 7, BCG (TICE STRAIN), BCG VACCINE (TICE STRAIN), DENGVAXIA, ERVEBO (NATIONAL STOCKPILE), FLUMIST TRIVALENT 2024-2025, IXCHIQ, M-M-R II VACCINE, PRIORIX, PROQUAD, ROTARIX, ROTATEQ, STAMARIL, VARIVAX VACCINE, VAXCHORA ACTIVE COMPONENT, VAXCHORA VACCINE, VIVOTIF, YF-VAX |
| Talimogene laherparepvec/Selected Immunosuppressants SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Talimogene laherparepvec is a live, attenuated herpes simplex virus.(1) CLINICAL EFFECTS: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Talimogene laherparepvec is contraindicated in immunosuppressed patients.(1) The magnitude of immunocompromise and associated risks due to immunosuppressant drugs should be determined by a physician. DISCUSSION: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1) |
IMLYGIC |
| Sensitive CYP3A4 Substrates that Prolong QT/Oral Lefamulin SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Oral lefamulin is a moderate CYP3A4 inhibitor and may inhibit the metabolism of CYP3A4 substrates. Also, concurrent use of lefamulin with agents that prolong the QTc interval may result in additive effects on the QTc interval.(1) CLINICAL EFFECTS: Concurrent use of oral lefamulin with drugs sensitive to inhibition of the CYP3A4 pathway may lead to increased serum levels and adverse effects, including potentially life-threatening cardiac arrhythmias like torsades de pointes.(1) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2) With pimozide, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3) PATIENT MANAGEMENT: The combination of oral lefamulin with sensitive CYP3A4 substrates that prolong the QTc interval is contraindicated.(1) When concurrent therapy cannot be avoided, obtain ECGs and electrolyte values (serum calcium, magnesium, and potassium) prior to the start of treatment, after initiation of any drug known to prolong the QT interval, and periodically monitor during therapy. Correct any electrolyte abnormalities.(1) Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: In a thorough QT study, intravenous lefamulin increased the QTcF 13.6 msec (90% CI = 15.5 msec) and oral lefamulin increased the QTcF by 9.3 msec (90% CI = 10.9 msec).(1) In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) Sensitive CYP3A4 substrates that prolong the QTc interval linked to this monograph include: bosutinib, dasatinib, dronedarone, eliglustat, entrectinib, gepirone, ivabradine, levomethadyl, lumefantrine, midostaurin, mobocertinib, pimozide, quetiapine, saquinavir, tacrolimus, and terfenadine.(4-6) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or torsades de pointes in clinical trials and/or postmarketing reports.(6) |
XENLETA |
| Nadofaragene Firadenovec/Selected Immunosuppressants SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Nadofaragene firadenovec may contain low levels of replication-competent adenovirus.(1) CLINICAL EFFECTS: Concurrent use of nadofaragene firadenovec in patients receiving immunosuppressive therapy may cause disseminated adenovirus infection.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Individuals who are immunosuppressed or immune-deficient should not receive nadofaragene firadenovec.(1) DISCUSSION: Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy but may contain low levels of replication-competent adenovirus. Immunocompromised persons, including those receiving immunosuppressant therapy, may be at risk for disseminated adenovirus infection.(1) |
ADSTILADRIN |
There are 27 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 |
|---|---|
| Bosutinib/Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may induce the metabolism of bosutinib.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of bosutinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with bosutinib. Consider the use of alternative agents with less enzyme induction potential.(1) DISCUSSION: In a study in 24 healthy subjects, rifampin decreased bosutinib area-under-curve (AUC) and maximum concentration (Cmax) by 94% and 86%.(1) In a study, 24 healthy subjects received a single dose of bosutinib 500 mg (days 1 and 14) and rifampin 600 mg (days 8-17). Bosutinib Cmax and AUC decreased by 86% and 92%, respectively. Bosutinib clearance increased by 13-fold.(2) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(3,4) |
ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BRAFTOVI, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, CEREBYX, DILANTIN, DILANTIN-125, DONNATAL, 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, TENCON, TIBSOVO, XTANDI |
| Selected Kinase Inhibitors/Proton Pump Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The solubility of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib(8), and pexidartinib (9) is pH dependent. Changes in gastric pH from proton pump inhibitors may decrease the absorption of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib,(8) and pexidartinib.(9) CLINICAL EFFECTS: Use of proton pump inhibitors may result in decreased levels and effectiveness of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib,(8) and pexidartinib.(9) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the use of proton pump inhibitors (PPIs) in patients receiving treatment with bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) pazopanib,(8) and pexidartinib.(9) Consider the use of short-acting antacids in these patients.(1-9) If antacids are used, separate the administration times by several hours(1-9) but at least 2 hours for bosutinib,(1) dasatinib,(3) nilotinib,(7) and pexidartinib(9), 6 hours for gefitinib,(5) and 3 hours for neratinib.(6) If PPIs are required with gefitinib, administer gefitinib 12 hours after the last dose or 12 hours before the next dose of the PPI. Administer gefitinib 6 hours before or after H2-antagonists or antacids.(5) If H2 antagonist therapy is used with bosutinib, separate administration by at least 2 hours.(1) If H2 antagonist therapy is required with dacomitinib, dacomitinib must be given once daily 10 hours after the H2 blocker and 6 hours before the next dose of the H2 blocker.(2) If H2 antagonist therapy is required with erlotinib, neratinib, nilotinib, or pexidartinib, the kinase inhibitor must be given 10 hours after the H2 blocker and at least 2 hours before the next dose of the H2 blocker.(4,6,7,9) If H2 antagonist therapy is required with gefitinib, gefitinib should be given at least 6 hours before or after the H2 antagonist.(5) The manufacturer of Phyrago states that it can be administered with gastric acid reducing agents. Administration times should be separated with antacids. DISCUSSION: In a study, concurrent rabeprazole decreased the Cmax and AUC of dacomitinib by 51% and 39%, respectively.(2) In a study in 24 healthy subjects, administration of a single dose of dasatinib (50 mg) 10 hours after famotidine decreased dasatinib area-under-curve (AUC) and maximum concentration (Cmax) by 61% and 63%, respectively.(3) In a study in 14 healthy subjects, administration of a single dose of dasatinib (100 mg) 22 hours after omeprazole (40 mg at steady state) decreased dasatinib AUC and Cmax by 43% and 42%, respectively.(3) In a study in 24 healthy subjects, simultaneous administration of dasatinib (50 mg) with aluminum hydroxide/magnesium hydroxide (30 ml) decreased dasatinib AUC and Cmax by 55% and 58%, respectively. In the same subjects, administration of the antacid 2 hours before dasatinib decreased dasatinib Cmax by 26%, but had no effect on dasatinib AUC.(3) In a study, concurrent omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively.(4) In a study, administration of erlotinib two hours after a dose of ranitidine (300 mg), erlotinib AUC and Cmax decreased by 33% and 54%, respectively. Administration of erlotinib 10 hours after and two hours before ranitidine (150 mg twice daily), erlotinib AUC and Cmax decreased by 15% and 17%, respectively.(4) In a case report, a patient that was given erlotinib (150 mg daily,) with algeldrate/magnesium hydroxide (800/400 mg four times daily 4 hours before or 2 hours after erlotinib) did not see a significant reduction in serum trough concentrations of erlotinib. When the patient was switched to intravenous pantoprazole via continuous infusion (8 mg per hour), serum erlotinib levels decreased significantly below minimal trough concentrations for effective tyrosine kinase inhibition. When the patient was switched to oral pantoprazole (40 mg twice daily), serum trough levels of erlotinib returned to therapeutic levels.(9) In a study in healthy subjects, high dose ranitidine with sodium carbonate was administered to maintain gastric pH above 5.0 and gefitinib AUC decreased 47%.(5) In a study in 15 healthy subjects, lansoprazole (30 mg at steady state) decreased the Cmax and AUC of a single dose of neratinib (240 mg) by 71% and 65%, respectively.(6) In a study in 22 healthy subjects, pretreatment with esomeprazole (40 mg daily), decreased the Cmax and AUC of a single dose of nilotinib (400 mg) by 27% and 34%, respectively.(7,10) Increasing the dosage of nilotinib or separating the administration time of nilotinib and the proton pump inhibitor is not expected to eliminate the interaction.(7) There were no significant changes in nilotinib pharmacokinetics when famotidine was administered 10 hours before or 2 hours after nilotinib.(7) There were no significant changes in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered 2 hours before or after nilotinib.(7) In a study in 13 patients, esomeprazole (40 mg daily for 5 days) decreased the Cmax and AUC of pazopanib (400 mg daily) by 42% and 40%, respectively, when compared to the administration of pazopanib alone.(11) In an open-label, crossover study in 17 evaluable patients, omeprazole (40 mg daily) had no significant effects on the pharmacokinetics, pharmacodynamics, or safety of bortezomib (1.3 mg/m2).(12) Coadministration of esomeprazole decreased pexidartinib Cmax and AUC by 55% and 50%. (13) Phyrago is not sensitive to increased gastric pH due to its polymer formulation. No clinically significant dasatinib pharmacokinetic changes were seen with concurrent administration of Phyrago with omeprazole (proton pump inhibitor) or famotidine (H2 receptor antagonist).(14) |
ACIPHEX, ACIPHEX SPRINKLE, DEXILANT, DEXLANSOPRAZOLE DR, ESOMEPRAZOLE MAGNESIUM, ESOMEPRAZOLE SODIUM, KONVOMEP, LANSOPRAZOL-AMOXICIL-CLARITHRO, LANSOPRAZOLE, NAPROXEN-ESOMEPRAZOLE MAG, NEXIUM, OMECLAMOX-PAK, OMEPRAZOLE, OMEPRAZOLE-SODIUM BICARBONATE, PANTOPRAZOLE SODIUM, PANTOPRAZOLE SODIUM-0.9% NACL, PREVACID, PRILOSEC, PROTONIX, PROTONIX IV, RABEPRAZOLE SODIUM, TALICIA, VIMOVO, YOSPRALA |
| Deferiprone/Selected Myelosuppressive Agents SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1) CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal. PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2) PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1) DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3) |
DEFERIPRONE, DEFERIPRONE (3 TIMES A DAY), FERRIPROX, FERRIPROX (2 TIMES A DAY), FERRIPROX (3 TIMES A DAY) |
| Bosutinib/Moderate CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Agents that inhibit CYP3A4 may inhibit the metabolism of bosutinib.(1) CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from bosutinib.(1) Elevated levels of bosutinib may result in QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP). Other toxicities include nausea, vomiting, diarrhea, abdominal pain, myelosuppression, transaminitis, renal toxicity, and cardiac failure.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the use of moderate CYP3A4 inhibitors in patients undergoing therapy with bosutinib.(1) DISCUSSION: In a study in 24 healthy subjects, ketoconazole (400 mg daily for 5 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of bosutinib (100 mg) by 5.2-fold and 8.6-fold, respectively.(1) In a cross-over study in 18 healthy subjects, aprepitant (125 mg) increased the Cmax and AUC of bosutinib (single dose 500 mg) by 1.5-fold and 2.0-fold, respectively.(1) A study using PKPB modeling found concurrent use of bosutinib and schisandra would result in an increase in bosutinib exposure with an increased AUC by 3.0-fold.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, boceprevir, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, ledipasvir, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, schisandra, treosulfan and verapamil.(3-4) |
AKYNZEO, APONVIE, APREPITANT, CARDIZEM, CARDIZEM CD, CARDIZEM LA, CARTIA XT, CINVANTI, CLOFAZIMINE, CONIVAPTAN-D5W, COPIKTRA, CRESEMBA, DANZITEN, DARUNAVIR, DIFLUCAN, 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, EMEND, ERY-TAB, ERYPED 200, ERYPED 400, ERYTHROCIN LACTOBIONATE, ERYTHROCIN STEARATE, ERYTHROMYCIN, ERYTHROMYCIN ESTOLATE, ERYTHROMYCIN ETHYLSUCCINATE, ERYTHROMYCIN LACTOBIONATE, FLUCONAZOLE, FLUCONAZOLE-NACL, FLUVOXAMINE MALEATE, FLUVOXAMINE MALEATE ER, FOSAMPRENAVIR CALCIUM, GLEEVEC, GRAFAPEX, IMATINIB MESYLATE, IMKELDI, INREBIC, MATZIM LA, NILOTINIB HCL, OGSIVEO, ORLADEYO, PREVYMIS, PREZISTA, SUNLENCA, TASIGNA, TAVNEOS, TIADYLT ER, TIAZAC, TRANDOLAPRIL-VERAPAMIL ER, VAPRISOL-5% DEXTROSE, VERAPAMIL ER, VERAPAMIL ER PM, VERAPAMIL HCL, VERAPAMIL SR, XALKORI |
| Tofacitinib/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of tofacitinib and azathioprine, other biologic disease-modifying antirheumatic drugs (DMARDs), or potent immunosuppressants may result in additive or synergistic effects on the immune system.(1) CLINICAL EFFECTS: Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants use may increase the risk of serious infections.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Tofacitinib should not be used concurrently with azathioprine, other biologic DMARDs, or cyclosporine.(1) Patient should be monitored for decreases in lymphocytes and neutrophils. Therapy should be adjusted based on the indication. - For all indications: If absolute neutrophil count (ANC) or lymphocyte count is less than 500 cells/mm3, discontinue tofacitinib. - For rheumatoid arthritis or psoriatic arthritis and absolute neutrophil count (ANC) 500 to 1000 cells/mm3: interrupt dosing. When ANC is greater than 1000 cells/mm3, resume Xeljanz 5 mg twice daily or Xeljanz XR 11 mg once daily. - For ulcerative colitis and ANC 500 to 1000 cells/mm3: -If taking Xeljanz 10 mg twice daily, decrease to 5 mg twice daily. When ANC is greater than 1000 cells/mm3, increase to 10 mg twice daily based on clinical response. -If taking Xeljanz 5 mg twice daily, interrupt dosing. When ANC is greater than 1000 cells/mm3, resume 5 mg twice daily. -If taking Xeljanz XR 22 mg once daily, decrease to 11 mg once daily. When ANC is greater than 1000 cells/mm3, increase to 22 mg once daily based on clinical response. -If taking Xeljanz XR 11 mg once daily, interrupt dosing. When ANC is greater than 1000 cells/mm3, resume 11 mg once daily. - For polyarticular course juvenile idiopathic arthritis (pcJIA) and ANC 500 to 1000 cells/mm3: interrupt dosing until ANC is greater than 1000 cells/mm3.(1) DISCUSSION: Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants may increase the risk of infection.(1) |
TOFACITINIB CITRATE, XELJANZ, XELJANZ XR |
| Clozapine/Selected Myelosuppressive Agents SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2) CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal. PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia. PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent ANC monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. Clozapine is only available through a restricted distribution system which requires documentation of the absolute neutrophil count (ANC) prior to dispensing.(1-2) For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2) DISCUSSION: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing.(1) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26) |
CLOZAPINE, CLOZAPINE ODT, CLOZARIL, VERSACLOZ |
| Selected Multiple Sclerosis Agents/Immunosuppressants; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ocrelizumab or ofatumumab in combination with immunosuppressives and immune-modulators all suppress the immune system.(1,2) CLINICAL EFFECTS: Concurrent use of ocrelizumab or ofatumumab with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1,2) PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications. PATIENT MANAGEMENT: The ocrelizumab US prescribing information states: - Ocrelizumab and other immune-modulating or immunosuppressive therapies, (including immunosuppressant doses of corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with ocrelizumab. When switching from drugs with prolonged immune effects, such as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating ocrelizumab.(1) The ofatumumab US prescribing information states: - Ofatumumab and other immunosuppressive therapies (including systemic corticosteroids) may have the potential for increased immunosuppressive effects and increase the risk of infection. When switching between therapies, the duration and mechanism of action of each therapy should be considered due to the potential for additive immunosuppressive effects. Ofatumumab for MS therapy has not been studied in combination with other MS agents that suppress the immune system.(2) DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1,2) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(3) |
KESIMPTA PEN, OCREVUS, OCREVUS ZUNOVO |
| Bosutinib/Strong CYP3A4 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of bosutinib.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from bosutinib.(1) Elevated levels of bosutinib may result in QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP). Other toxicities include nausea, vomiting, diarrhea, abdominal pain, myelosuppression, transaminitis, renal toxicity, and cardiac failure.(1) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with bosutinib.(1) Consider alternatives with no or minimal enzyme inhibition. Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and bosutinib should be monitored for prolongation of the QTc interval. When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: In a randomized, phase I, double-blind, placebo-controlled, sequential group study, 48 healthy adults received a single dose of bosutinib 100, 200, 300, 400, 500, or 600 mg with ketoconazole 400 mg days -1 and days 1-4. Bosutinib area-under-curve (AUC) and maximum concentration (Cmax) increased 7.3-fold and 7.7-fold.(3) In an open-label, randomized, 2-period, crossover study, healthy subjects received a single dose of bosutinib 100 mg alone and with multiple doses of ketoconazole 400 mg. Bosutinib Cmax and AUC increased 5.2-fold and 8.6-fold, respectively.(4) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received bosutinib, QTc prolongation was identified in 8 patients(38.1%), with 5 (62.5%) having Grade 1 (QTc 450-480 ms) and 3 (37.5%) having Grade 2 (QTc 480-500 ms) events. Grade 3 events occurred in 1 (12.5%) patient having QTc greater than or equal to 500 ms. No patients had a QTc change greater than or equal to 60 ms, ventricular tachycardia (VT), sudden cardiac death (SCD), or TdP.(5) Strong inhibitors of CYP3A4 include: boceprevir, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, telaprevir, tipranavir, troleandomycin, and tucatinib.(6,7) |
APTIVUS, EVOTAZ, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KETOCONAZOLE, KORLYM, MIFEPREX, MIFEPRISTONE, NEFAZODONE HCL, PAXLOVID, PREZCOBIX, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, TYBOST, VIRACEPT, ZOKINVY, ZYDELIG |
| Upadacitinib/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Upadacitinib, immunosuppressives, and immunomodulators all suppress the immune system. CLINICAL EFFECTS: Concurrent use of upadacitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of upadacitinib states that concurrent use of upadacitinib with immunosuppressives or immunomodulators is not recommended. DISCUSSION: Serious infections have been reported in patients receiving upadacitinib. Reported infections included pneumonia, cellulitis, tuberculosis, multidermatomal herpes zoster, oral/esophageal candidiasis, cryptococcosis. Reports of viral reactivation, including herpes virus reactivation and hepatitis B reactivation, were reported in clinical studies with upadacitinib.(1) |
RINVOQ, RINVOQ LQ |
| Inebilizumab/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inebilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of inebilizumab with immunosuppressive or immunomodulating agents may result in myelosuppression including neutropenia resulting in an increased risk for serious infections.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of inebilizumab states that the concurrent use of inebilizumab with immunosuppressive agents, including systemic corticosteroids, may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1) DISCUSSION: Inebilizumab has not been studied in combination with other immunosuppressants. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents. The most common infections reported by inebilizumab treated patients in the randomized and open-label clinical trial periods included urinary tract infections (20%), nasopharyngitis (13%), upper respiratory tract infections (8%), and influenza (7%). Although there been no cases of Hepatitis B virus reactivation or progressive multifocal leukoencephalopathy reported in patients taking inebilizumab, these infections have been observed in patients taking other B-cell-depleting antibodies.(1) |
UPLIZNA |
| Baricitinib/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of baricitinib with other biologic disease-modifying antirheumatic drugs (DMARDs) or potent immunosuppressants such as azathioprine or cyclosporine may result in additive or synergistic effects on the immune system. CLINICAL EFFECTS: Concurrent use of baricitinib with other biologic DMARDs or potent immunosuppressants such as azathioprine or cyclosporine may increase the risk of serious infections.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of baricitinib states that concurrent use of baricitinib with biologic DMARDs or potent immunosuppressants is not recommended.(1) DISCUSSION: Most patients who developed serious infections while being treated with baricitinib were on concomitant immunosuppressants like methotrexate and corticosteroids. The combination of baricitinib with other biologic DMARDs has not been studied.(1) |
OLUMIANT |
| Bosutinib/Strong CYP3A4 Inhibitors that Prolong QT SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of bosutinib and result in additive risk of QT prolongation.(1) CLINICAL EFFECTS: Concurrent use of strong inhibitors of CYP3A4 that prolong QT may result in elevated levels of and toxicity from bosutinib, including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1) Other toxicities include nausea, vomiting, diarrhea, abdominal pain, myelosuppression, transaminitis, renal toxicity, and cardiac failure.(1) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors that prolong QT in patients undergoing therapy with bosutinib.(1) Consider alternatives with no or minimal enzyme inhibition and with no effect on the QTc interval. Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and bosutinib should be monitored for prolongation of the QTc interval. When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: In a randomized, phase I, double-blind, placebo-controlled, sequential group study, 48 healthy adults received a single dose of bosutinib 100, 200, 300, 400, 500, or 600 mg with ketoconazole 400 mg days -1 and days 1-4. Bosutinib area-under-curve (AUC) and maximum concentration (Cmax) increased 7.3-fold and 7.7-fold.(3) In an open-label, randomized, 2-period, crossover study, healthy subjects received a single dose of bosutinib 100 mg alone and with multiple doses of ketoconazole 400 mg. Bosutinib Cmax and AUC increased 5.2-fold and 8.6-fold, respectively.(4) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received bosutinib, QTc prolongation was identified in 8 patients(38.1%), with 5 patients (62.5%) having Grade 1 (QTc 450-480 ms) and 3 patients(37.5%) having Grade 2 (QTc 480-500 ms) events. Grade 3 events occurred in 1 (12.5%) patient having QTc greater than or equal to 500 ms. No patients had a QTc change greater than or equal to 60 ms, ventricular tachycardia (VT), sudden cardiac death (SCD), or TdP.(5) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(6) Strong inhibitors of CYP3A4 that prolong QT include: adagrasib, ceritinib, clarithromycin, levoketoconazole, lopinavir, posaconazole, ribociclib, saquinavir, telithromycin, and voriconazole.(7,8) |
CLARITHROMYCIN, CLARITHROMYCIN ER, KALETRA, KISQALI, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, LOPINAVIR-RITONAVIR, NOXAFIL, OMECLAMOX-PAK, POSACONAZOLE, RECORLEV, VFEND, VFEND IV, VORICONAZOLE, ZYKADIA |
| Leflunomide; Teriflunomide/Selected Immunosuppressants SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of leflunomide or teriflunomide and potent immunosuppressants may result in additive or synergistic effects on the immune system.(1,2) Leflunomide is a prodrug and is converted to its active metabolite teriflunomide.(1) CLINICAL EFFECTS: Concurrent use of leflunomide or teriflunomide with immunosuppressants may result in an increased risk of serious infections, including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: If leflunomide or teriflunomide is used concurrently with immunosuppressive agents, chronic CBC monitoring should be performed more frequently, every month instead of every 6 to 8 weeks. If bone marrow suppression or a serious infection occurs, leflunomide or teriflunomide should be stopped and rapid drug elimination procedure should be performed.(1,2) DISCUSSION: Pancytopenia, agranulocytosis and thrombocytopenia have been reported in patients receiving leflunomide or teriflunomide alone, but most frequently in patients taking concurrent immunosuppressants.(1,2) Severe and potentially fatal infections, including sepsis, have been reported in patients receiving leflunomide or teriflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Tuberculosis has also been reported.(1,2) |
ARAVA, AUBAGIO, LEFLUNICLO, LEFLUNOMIDE, TERIFLUNOMIDE |
| Antineoplastic Systemic Enzyme Inhibitors/Carbamazepine SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme, such as carbamazepine, may induce the metabolism of antineoplastic systemic enzyme inhibitors, including bosutinib,(1) cabozantinib,(2,3) dasatinib,(4) erlotinib,(5) gefitinib,(6) ibrutinib,(7) lapatinib,(8) pazopanib,(9) sorafenib,(10) sunitinib,(11) and vandetanib.(12) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of antineoplastic systemic enzyme inhibitors, including bosutinib,(1) cabozantinib,(2,3) dasatinib,(4) erlotinib,(5) gefitinib,(6) ibrutinib,(7) lapatinib,(8) pazopanib,(9) sorafenib,(10) sunitinib,(11) and vandetanib.(12) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with antineoplastic enzyme inhibitors. Consider the use of alternative agents with less enzyme induction potential.(1-12) Pazopanib should not be administered to patients who cannot avoid chronic use of strong CYP3A4 inducers.(8) If concurrent use of a CYP3A4 inducer cannot be avoided with other antineoplastic enzyme inhibitors: Increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer.(2) Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 180 mg. If the CYP3A4 inducer is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of the inducer 2 to 3 days after discontinuation of the strong inducer.(3) Consider increasing the dose of dasatinib.(4) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued. If the inducer is dexamethasone, monitor the patient for sign of gastrointestinal perforation. Discontinue erlotinib in patients who develop gastrointestinal perforation.(5) Consider a dose increase to 500 mg daily of gefitinib in the absence of severe adverse drug reaction. Clinical response and adverse events should be closely monitored.(6) The dose of lapatinib should be gradually titrated from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer indication) or from 1,500 mg/day up to 5,500 mg/day (hormone receptor positive, HER2 positive breast cancer indication) based on patient tolerability. If the inducer is discontinued, the dose of lapatinib should be adjusted to the normal dose.(8) A dosage increase of sunitinib to a maximum of 87.5 mg daily in patients with gastrointestinal stromal tumors (GIST) or advanced renal cell carcinoma (RCC) or to a maximum of 62.5 mg in patients with pancreatic neuroendocrine tumors (pNET) should be considered.(11) DISCUSSION: In a study in 24 healthy subjects, rifampin (a strong CYP3A4 inducer) decreased bosutinib area-under-curve (AUC) and maximum concentration (Cmax) by 94% and 86%. Bosutinib clearance increased by 13-fold.(1,14) In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(2) In a study in healthy subjects, concurrent rifampin (600 mg daily) decreased the Cmax and AUC of a single dose of dasatinib by 81% and 82%, respectively.(4) Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(5) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(5) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(14) In a study in healthy male volunteers, rifampicin decreased AUC of gefitinib by 85%.(6) The coadministration of rifampin decreased the Cmax and AUC of ibrutinib by more than 13-fold and 10-fold.(7) In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200 mg twice daily for 17 days), another CYP3A4 inducer, decreased the AUC of lapatinib by 72%. The dose adjustment recommendations are based on pharmacokinetic studies and are predicted to adjust lapatinib AUC to the range observed without concurrent CYP3A4 inducers; however, there are no clinical data with these doses in patients receiving strong CYP3A4 inducers.(8) Pazopanib is primarily metabolized by CYP3A4.(9) Concurrent rifampin (600 mg daily for 5 days) decreased the AUC of a single dose of sorafenib (400 mg) by 37%.(10) In a study with healthy subjects, concurrent rifampin decreased the combined (sunitinib plus primary active metabolite) Cmax and AUC by 23% and 46%, respectively, of a single dose of sunitinib.(11) Strong CYP3A4 inducers are expected to alter vandetanib concentrations. The patient developed nystagmus, a sign of phenytoin toxicity.(12) |
CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, EPITOL, EQUETRO, TEGRETOL, TEGRETOL XR |
| Antineoplastic Systemic Enzyme Inhibitors/Apalutamide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Apalutamide(1) may induce the metabolism of antineoplastic systemic enzyme inhibitors, including bosutinib,(2) cabozantinib,(3) erlotinib,(4) gefitinib,(5) ibrutinib,(6) idelalisib,(7) and imatinib.(8) CLINICAL EFFECTS: Concurrent use of apalutamide may decrease the levels and effectiveness of antineoplastic systemic enzyme inhibitors, including bosutinib,(2) cabozantinib,(3) erlotinib,(4) gefitinib,(5) ibrutinib,(6) idelalisib,(7) and imatinib.(8) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the concurrent use of apalutamide in patients receiving therapy with antineoplastic enzyme inhibitors. Consider the use of alternative agents with less enzyme induction potential.(1-8) If concurrent use of apalutamide cannot be avoided with antineoplastic enzyme inhibitors: Increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer.(9) Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 180 mg. If the CYP3A4 inducer is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of the inducer 2 to 3 days after discontinuation of the strong inducer.(3) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued.(4) Consider a dose increase to 500 mg daily of gefitinib in the absence of severe adverse drug reaction. Clinical response and adverse events should be closely monitored.(5) The dose of imatinib should be increased by at least 50% and clinical response should be carefully monitored. Dosages up to 1200 mg/day (600 mg twice daily) have been used in patients receiving concurrent therapy with strong CYP3A4 inducers.(8) DISCUSSION: In a study in 24 healthy subjects, rifampin (a strong CYP3A4 inducer) decreased bosutinib area-under-curve (AUC) and maximum concentration (Cmax) by 94% and 86%. Bosutinib clearance increased by 13-fold.(2,11) In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(3) Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(4) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(4) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(10) In a study in healthy male volunteers, rifampicin decreased AUC of gefitinib by 85%.(5) The coadministration of rifampin decreased the Cmax and AUC of ibrutinib by more than 13-fold and 10-fold.(6) In a study in healthy subjects, rifampin (600 mg daily for 8 days) decreased the Cmax and AUC of idelalisib (150 mg single dose) by 58% and 75%, respectively.(7) Pretreatment of 14 healthy subjects with rifampin (600 mg daily for 10 days) increased the clearance of a single dose of imatinib (400 mg) by 3.8-fold. The area-under-curve (AUC) and maximum concentration (Cmax) decreased by 74% and 54%, respectively.(8,12) The Cmax of the CGP74588 metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(12) |
ERLEADA |
| Slt Antineoplastic Systemic Enzyme Inh/Lumacaftor-Ivacaftor SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Lumacaftor-ivacaftor(1) may induce the metabolism of antineoplastic systemic enzyme inhibitors, including bosutinib,(2) cabozantinib,(3) crizotinib,(4) dasatinib,(5) erlotinib,(6) gefitinib,(7) ibrutinib,(8) imatinib,(9) lapatinib,(10) nilotinib,(11) pazopanib,(12) sorafenib,(13) sunitinib,(14) and vandetanib.(15) CLINICAL EFFECTS: Concurrent use of lumacaftor-ivacaftor may decrease the levels and effectiveness of antineoplastic systemic enzyme inhibitors, including bosutinib,(2) cabozantinib,(3) crizotinib,(4) dasatinib,(5) erlotinib,(6) gefitinib,(7) ibrutinib,(8) imatinib,(9) lapatinib,(10) nilotinib,(11) pazopanib,(12) sorafenib,(13) sunitinib,(14) and vandetanib.(15) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the concurrent use of lumacaftor-ivacaftor in patients receiving therapy with antineoplastic enzyme inhibitors. Consider the use of alternative agents with less enzyme induction potential.(2-15) Because of the nonlinear pharmacokinetic profile of nilotinib, increasing its dose is unlikely to compensate for enzyme induction.(11) Pazopanib should not be administered to patients who cannot avoid chronic use of strong CYP3A4 inducers.(12) If concurrent use of a CYP3A4 inducer cannot be avoided with other antineoplastic enzyme inhibitors: Increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer.(16) Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 180 mg. If the CYP3A4 inducer is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of the inducer 2 to 3 days after discontinuation of the strong inducer.(2) Consider increasing the dose of dasatinib.(5) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued. If the inducer is dexamethasone, monitor the patient for sign of gastrointestinal perforation. Discontinue erlotinib in patients who develop gastrointestinal perforation.(6) Consider a dose increase to 500 mg daily of gefitinib in the absence of severe adverse drug reaction. Clinical response and adverse events should be closely monitored.(7) The dose of imatinib should be increased by at least 50% and clinical response should be carefully monitored. Dosages up to 1200 mg/day (600 mg twice daily) have been used in patients receiving concurrent therapy with strong CYP3A4 inducers.(9) The dose of lapatinib should be gradually titrated from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer indication) or from 1,500 mg/day up to 5,500 mg/day (hormone receptor positive, HER2 positive breast cancer indication) based on patient tolerability. If the inducer is discontinued, the dose of lapatinib should be adjusted to the normal dose.(10) A dosage increase of sunitinib to a maximum of 87.5 mg daily in patients with gastrointestinal stromal tumors (GIST) or advanced renal cell carcinoma (RCC) or to a maximum of 62.5 mg in patients with pancreatic neuroendocrine tumors (pNET) should be considered.(14) DISCUSSION: In a study, 24 healthy subjects received a single dose of bosutinib 500 mg (days 1 and 14) and rifampin 600 mg (days 8-17). Bosutinib Cmax and AUC decreased by 86% and 92%, respectively. Bosutinib clearance increased by 13-fold.(2,17) In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(3) Rifampin (600 mg daily) decreased the Cmax and AUC of a single dose of crizotinib (250 mg) by 69% and 82%, respectively.(4) In a study in healthy subjects, concurrent rifampin (600 mg daily) decreased the Cmax and AUC of a single dose of dasatinib by 81% and 82%, respectively.(5) Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(6) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(6) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(18) In a study in healthy male volunteers, rifampicin decreased AUC of gefitinib by 85%.(7) The coadministration of rifampin decreased the Cmax and AUC of ibrutinib by more than 13-fold and 10-fold.(8) Pretreatment of 14 healthy subjects with rifampin (600 mg daily for 10 days) increased the clearance of a single dose of imatinib (400 mg) by 3.8-fold. The area-under-curve (AUC) and maximum concentration (Cmax) decreased by 74% and 54%, respectively.(9,19) The Cmax of the CGP74588 metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(19) In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200 mg twice daily for 17 days), another CYP3A4 inducer, decreased the AUC of lapatinib by 72%. The dose adjustment recommendations are based on pharmacokinetic studies and are predicted to adjust lapatinib AUC to the range observed without concurrent CYP3A4 inducers; however, there are no clinical data with these doses in patients receiving strong CYP3A4 inducers.(10) In a study in healthy subjects, concurrent rifampin (600 mg daily for 12 days) decreased nilotinib AUC by 80%.(11) Pazopanib is primarily metabolized by CYP3A4.(12) Concurrent rifampin (600 mg daily for 5 days) decreased the AUC of a single dose of sorafenib (400 mg) by 37%.(13) In a study with healthy subjects, concurrent rifampin decreased the combined (sunitinib plus primary active metabolite) Cmax and AUC by 23% and 46%, respectively, of a single dose of sunitinib.(14) Strong CYP3A4 inducers are expected to alter vandetanib concentrations. The patient developed nystagmus, a sign of phenytoin toxicity.(15) |
ORKAMBI |
| Ponesimod/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ponesimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of ponesimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1) PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications. PATIENT MANAGEMENT: The ponesimod US prescribing information states ponesimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ponesimod after alemtuzumab is not recommended. However, ponesimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1) DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1) |
PONVORY |
| Sodium Iodide I 131/Myelosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1) DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1) |
HICON, SODIUM IODIDE I-131 |
| Fingolimod/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Fingolimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-3) CLINICAL EFFECTS: Concurrent use of fingolimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-3) PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications. PATIENT MANAGEMENT: Recommendations for fingolimod regarding this interaction differ between regulatory approving agencies. The fingolimod US prescribing information states: - Antineoplastic, immune-modulating, or immunosuppressive therapies, (including corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with fingolimod. When switching from drugs with prolonged immune effects, such as natalizumab, teriflunomide or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating fingolimod.(1) The fingolimod Canadian prescribing information states: - Concurrent use with immunosuppressive or immunomodulatory agents is contraindicated due to the risk of additive immune system effects. However, co-administration of a short course of corticosteroids (up to 5 days) did not increase the overall rate of infection in patients participating Phase III clinical trials.(2) The fingolimod UK specific product characteristics states: - Fingolimod is contraindicated in patients currently receiving immunosuppressive therapies or those immunocompromised by prior therapies. When switching patients from another disease modifying therapy to Gilenya, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimizing the risk of disease activation.(3) DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-3) |
FINGOLIMOD, GILENYA, TASCENSO ODT |
| Ozanimod/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ozanimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of ozanimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1) PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications. PATIENT MANAGEMENT: The ozanimod US prescribing information state this information regarding this interaction: -Ozanimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ozanimod after alemtuzumab is not recommended. However, ozanimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1) DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1) |
ZEPOSIA |
| Siponimod/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Siponimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of siponimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1) PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications. PATIENT MANAGEMENT: The siponimod US prescribing information state this information regarding this interaction: -Siponimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with siponimod after alemtuzumab is not recommended. However, siponimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1) DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1) |
MAYZENT |
| Cladribine/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-2) CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-2) PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications. PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US prescribing information states: -Concomitant use with myelosuppressive or other immunosuppressive drugs is not recommended. Acute short-term therapy with corticosteroids can be administered. In patients who have previously been treated with immunomodulatory or immunosuppressive drugs, consider potential additive effect, the mode of action, and duration of effect of the other drugs prior to initiation of cladribine.(1) The cladribine Canadian prescribing information states: -Use of cladribine in immunocompromised patients is contraindicated because of a risk of additive effects on the immune system. Acute short-term therapy with corticosteroids can be administered during cladribine treatment.(2) DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-2) |
CLADRIBINE, MAVENCLAD |
| Bosutinib/Vonoprazan-Clarithromycin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The solubility of bosutinib is pH dependent. Changes in gastric pH from proton pump inhibitors (PPIs) may decrease the absorption of bosutinib. Vonoprazan is a PPI.(1) If bosutinib is absorbed, strong inhibitors of CYP3A4 that prolong the QTc interval may inhibit the metabolism of bosutinib and result in additive risk of QT prolongation. Clarithromycin is a strong CYP3A4 inhibitor.(1) CLINICAL EFFECTS: Use of proton pump inhibitors may result in decreased levels and effectiveness of bosutinib.(1) If bosutinib is absorbed, concurrent use of strong inhibitors of CYP3A4 that prolong QT may result in elevated levels of and toxicity from bosutinib, including additive QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias, including torsades de pointes (TdP).(1) Other toxicities include nausea, vomiting, diarrhea, abdominal pain, myelosuppression, transaminitis, renal toxicity, and cardiac failure.(1) PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: Avoid the use of proton pump inhibitors (PPIs) in patients receiving treatment with bosutinib.(1) Consider the use of short-acting antacids in these patients. If antacids are used, separate the administration times by at least 2 hours for bosutinib.(1) The manufacturer of bosutinib also recommends avoiding the use of strong CYP3A4 inhibitors that prolong QT in patients undergoing therapy with bosutinib.(1) Consider alternatives with no or minimal enzyme inhibition and with no effect on the QTc interval. Patients receiving concurrent therapy with a strong CYP3A4 inhibitor and bosutinib should be monitored for prolongation of the QTc interval. When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: In a randomized, phase I, double-blind, placebo-controlled, sequential group study, 48 healthy adults received a single dose of bosutinib 100, 200, 300, 400, 500, or 600 mg with ketoconazole 400 mg days -1 and days 1-4. Bosutinib area-under-curve (AUC) and maximum concentration (Cmax) increased 7.3-fold and 7.7-fold.(3) In an open-label, randomized, 2-period, crossover study, healthy subjects received a single dose of bosutinib 100 mg alone and with multiple doses of ketoconazole 400 mg. Bosutinib Cmax and AUC increased 5.2-fold and 8.6-fold, respectively.(4) A retrospective review of 618 cancer patients treated with 902 administrations of tyrosine kinase inhibitors were evaluated for rate and incidence of QTc prolongation. In patients who received bosutinib, QTc prolongation was identified in 8 patients(38.1%), with 5 patients (62.5%) having Grade 1 (QTc 450-480 ms) and 3 patients(37.5%) having Grade 2 (QTc 480-500 ms) events. Grade 3 events occurred in 1 (12.5%) patient having QTc greater than or equal to 500 ms. No patients had a QTc change greater than or equal to 60 ms, ventricular tachycardia (VT), sudden cardiac death (SCD), or TdP.(5) Agents that are linked to this monograph may have varying degrees of potential to prolong the QTc interval but are generally accepted to have a risk of causing Torsades de Pointes. Agents linked to this monograph have been shown to prolong the QTc interval either through their mechanism of action, through studies on their effects on the QTc interval, or through reports of QTc prolongation and/or Torsades de Pointes in clinical trials and/or post-marketing reports.(6) Strong inhibitors of CYP3A4 that prolong QT include: clarithromycin.(7,8) |
VOQUEZNA TRIPLE PAK |
| Selected Kinase Inhibitors/Vonoprazan SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The solubility of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) and pazopanib(8) is pH dependent. Changes in gastric pH from vonoprazan(9) may decrease the absorption of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) and pazopanib.(8) CLINICAL EFFECTS: Use of vonoprazan may result in decreased levels and effectiveness of bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) and pazopanib.(8) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid the use of vonoprazan(9) in patients receiving treatment with bosutinib,(1) dacomitinib,(2) dasatinib,(3) erlotinib,(4) gefitinib,(5) neratinib,(6) nilotinib,(7) and pazopanib.(8) Consider the use of short-acting antacids in these patients.(1-8) If antacids are used, separate the administration times by several hours(1-8) but at least 2 hours for bosutinib,(1) dasatinib,(3) and nilotinib,(7) 6 hours for gefitinib,(5) and 3 hours for neratinib.(6) If H2 antagonist therapy is required with dacomitinib, dacomitinib must be given once daily 10 hours after the H2 blocker and 6 hours before the next dose of the H2 blocker.(2) If H2 antagonist therapy is required with gefitinib, administer gefitinib 6 hours before or after H2-antagonists or antacids.(5) If H2 antagonist therapy is required with erlotinib, neratinib, or nilotinib, the kinase inhibitor must be given 10 hours after the H2 blocker and at least 2 hours before the next dose of the H2 blocker.(4,6,7) The manufacturer of Phyrago states that it can be administered with gastric acid reducing agents. Administration times should be separated with antacids.(14) DISCUSSION: Vonoprazan decreases gastric acidity by suppressing gastric acid secretion and is characterized as a type of gastric proton-pump inhibitor.(9) In a pharmacodynamic study, a single 20 mg dose of vonoprazan, elevated the intragastric pH compared to placebo and was sustained for over 24-hours after dosing. The inhibitory effect of vonoprazan on acid secretion increased with repeated daily dosing and antisecretory effect reached steady state by Day 4 with a mean 24-hour intragastric pH of 6.0 following 20 mg once daily dose.(9) In a study, concurrent rabeprazole decreased the Cmax and AUC of dacomitinib by 51% and 39%, respectively.(2) In a study in 24 healthy subjects, administration of a single dose of dasatinib (50 mg) 10 hours after famotidine decreased dasatinib area-under-curve (AUC) and maximum concentration (Cmax) by 61% and 63%, respectively.(3) In a study in 14 healthy subjects, administration of a single dose of dasatinib (100 mg) 22 hours after omeprazole (40 mg at steady state) decreased dasatinib AUC and Cmax by 43% and 42%, respectively.(3) In a study in 24 healthy subjects, simultaneous administration of dasatinib (50 mg) with aluminum hydroxide/magnesium hydroxide (30 ml) decreased dasatinib AUC and Cmax by 55% and 58%, respectively. In the same subjects, administration of the antacid 2 hours before dasatinib decreased dasatinib Cmax by 26%, but had no effect on dasatinib AUC.(3) In a study, concurrent omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively.(4) In a study, administration of erlotinib two hours after a dose of ranitidine (300 mg), erlotinib AUC and Cmax decreased by 33% and 54%, respectively. Administration of erlotinib 10 hours after and two hours before ranitidine (150 mg twice daily), erlotinib AUC and Cmax decreased by 15% and 17%, respectively.(4) In a case report, a patient that was given erlotinib (150 mg daily,) with algeldrate/magnesium hydroxide (800/400 mg four times daily 4 hours before or 2 hours after erlotinib) did not see a significant reduction in serum trough concentrations of erlotinib. When the patient was switched to intravenous pantoprazole via continuous infusion (8 mg per hour), serum erlotinib levels decreased significantly below minimal trough concentrations for effective tyrosine kinase inhibition. When the patient was switched to oral pantoprazole (40 mg twice daily), serum trough levels of erlotinib returned to therapeutic levels.(10) In a study in healthy subjects, high dose ranitidine with sodium carbonate was administered to maintain gastric pH above 5.0 and gefitinib AUC decreased 47%.(5) In a study in 15 healthy subjects, lansoprazole (30 mg at steady state) decreased the Cmax and AUC of a single dose of neratinib (240 mg) by 71% and 65%, respectively.(6) In a study in 22 healthy subjects, pretreatment with esomeprazole (40 mg daily), decreased the Cmax and AUC of a single dose of nilotinib (400 mg) by 27% and 34%, respectively.(7,11) Increasing the dosage of nilotinib or separating the administration time of nilotinib and the proton pump inhibitor is not expected to eliminate the interaction.(7) There were no significant changes in nilotinib pharmacokinetics when famotidine was administered 10 hours before or 2 hours after nilotinib.(7) There were no significant changes in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered 2 hours before or after nilotinib.(7) In a study in 13 patients, esomeprazole (40 mg daily for 5 days) decreased the Cmax and AUC of pazopanib (400 mg daily) by 42% and 40%, respectively, when compared to the administration of pazopanib alone.(12) In an open-label, crossover study in 17 evaluable patients, omeprazole (40 mg daily) had no significant effects on the pharmacokinetics, pharmacodynamics, or safety of bortezomib (1.3 mg/m2).(13) Phyrago is not sensitive to increased gastric pH due to its polymer formulation. No clinically significant pharmacokinetic changes were seen with concurrent administration of Phyrago with omeprazole (proton pump inhibitor) or famotidine (H2 receptor antagonist).(14) |
VOQUEZNA, VOQUEZNA DUAL PAK |
| Ritlecitinib/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ritlecitinib, immunosuppressives, and immunomodulators all suppress the immune system. CLINICAL EFFECTS: Concurrent use of ritlecitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of ritlecitinib states that concurrent use of ritlecitinib with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants is not recommended.(1) DISCUSSION: Serious infections have been reported in patients receiving ritlecitinib. Reported infections included appendicitis, COVID-19 infection (including pneumonia), and sepsis. Reports of viral reactivation, including herpes virus reactivation was reported in clinical studies with ritlecitinib.(1) |
LITFULO |
| Etrasimod/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Etrasimod causes reversible sequestration of lymphocytes in lymphoid tissues, resulting in a mean 55% decrease in peripheral blood lymphocyte count at 52 weeks.(1) Other immunosuppressives and immune-modulators also suppress the immune system. CLINICAL EFFECTS: Concurrent use of etrasimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious and fatal infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML).(1) PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications increases the risk of adverse effects. PATIENT MANAGEMENT: The etrasimod US prescribing information states etrasimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Concomitant administration of these therapies with etrasimod should be avoided because of the risk of additive immune effects during therapy and in the weeks following administration. Etrasimod's effect on peripheral lymphocytes may persist for up to 5 weeks after discontinuation.(1) When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects.(1) DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with other sphingosine-1 phosphate receptor modulators.(1) |
VELSIPITY |
| Ropeginterferon alfa-2b/Slt Immunosuppress; Immunomodulator SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ropeginterferon alfa-2b and immunosuppressives both suppress the immune system. CLINICAL EFFECTS: Concurrent use of ropeginterferon alfa-2b with immunosuppressives may result in an increased risk of serious infections. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concurrent use of myelosuppressive agents.(1-2) If concurrent use cannot be avoided, monitor for effects of excessive immunosuppression. DISCUSSION: In clinical trials, 20% of patients experienced leukopenia. Interferon alfa products may cause fatal or life-threatening infections.(1-2) |
BESREMI |
There are 7 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 |
|---|---|
| Selected Kinase Inhibitors/Antacids SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The solubility of bosutinib,(1) dasatinib,(2) erlotinib,(3) gefitinib,(4) neratinib,(5) nilotinib(6), pazopanib,(7) and pexidartinib(8) is pH dependent. Antacid-induced changes in gastric pH may decrease the absorption of these agents.(1-8) CLINICAL EFFECTS: Simultaneous administration of antacids may result in decreased levels and effectiveness of bosutinib,(1) dasatinib,(2) erlotinib,(3) gefitinib,(4) neratinib,(5) nilotinib(6), pazopanib,(7) and pexidartinib.(8) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Antacid use should be considered in place of H2 blockers or proton pump inhibitors in patients receiving bosutinib,(1) dasatinib,(2) erlotinib,(3) gefitinib,(4) neratinib,(5) nilotinib(6), pazopanib,(7) and pexidartinib;(8) however, separation of administration times is required. If antacids are used, separate the administration times by several hours(1-8) but at least 2 hours for bosutinib,(1) dasatinib,(2) nilotinib,(6) and pexidartinib(8), 6 hours for gefitinib,(4) and 3 hours for neratinib.(5) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well. DISCUSSION: In a study in 24 healthy subjects, lansoprazole (60 mg) decreased bosutinib (400 mg single dose) area-under-curve (AUC) and maximum concentration (Cmax) by 26% and 46%, respectively.(1) In a study in 24 healthy subjects, simultaneous administration of dasatinib (50 mg) with aluminum hydroxide/magnesium hydroxide (30 ml) decreased dasatinib AUC and Cmax by 55% and 58%, respectively. In the same subjects, administration of the antacid 2 hours before dasatinib decreased dasatinib Cmax by 26%, but had no effect on dasatinib AUC.(2) In a study in 24 healthy subjects, administration of a single dose of dasatinib (50 mg) 10 hours after famotidine decreased dasatinib AUC and Cmax by 61% and 63%, respectively.(2) In a study, concurrent omeprazole decreased the AUC and Cmax of erlotinib by 46% and 61%, respectively.3) In a study, concurrent esomeprazole decreased the AUC of nilotinib by 34%.(6) In a study in 15 healthy subjects, lansoprazole (30 mg at steady state) decreased the Cmax and AUC of a single dose of neratinib (240 mg) by 71% and 65%, respectively.(5) There were no significant changes in nilotinib pharmacokinetics when famotidine was administered 10 hours before or 2 hours after nilotinib.(6) There were no significant changes in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered 2 hours before or after nilotinib.(6) Coadministration of esomeprazole decreased pexidartinib Cmax and AUC by 55% and 50%.(8) |
ALUMINUM HYDROXIDE, GAVILYTE-C, GAVILYTE-G, GAVILYTE-N, GOLYTELY, KONVOMEP, OMEPRAZOLE-SODIUM BICARBONATE, PEG 3350-ELECTROLYTE, PEG-3350 AND ELECTROLYTES, SODIUM BICARBONATE, VAXCHORA BUFFER COMPONENT |
| Bosutinib; Neratinib/Selected H2 Antagonists SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The solubility of bosutinib(1) and neratinib(2) is pH dependent. Changes in gastric pH from H2 antagonists may decrease the absorption of bosutinib and neratinib. CLINICAL EFFECTS: Use of H2 antagonists may result in decreased levels and effectiveness of bosutinib(1) and neratinib.(2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Consider the use of short-acting antacids in patients taking bosutinib(1) and neratinib.(2) If antacids are used, separate the administration times by at least 2 hours for bosutinib(1) and 3 hours for neratinib.(2) If H2 antagonist therapy is required with bosutinib, separate administration of the H2 blocker by at least 2 hours before or 2 hours after bosutinib.(1) If H2 antagonist therapy is required with neratinib, then neratinib must be given 10 hours after the H2 blocker and at least 2 hours before the next dose of the H2 blocker.(2) Avoid the use of proton pump inhibitors (PPIs) in patients receiving treatment with bosutinib(1) and neratinib.(2) DISCUSSION: A single dose of bosutinib 400 mg was administered alone or following multiple doses of lansoprazole 60 mg without food. Lansoprazole decreased bosutinib maximum concentration (Cmax) and area-under-curve (AUC) by 46% and 26%, respectively.(1) In a study in 15 healthy subjects, lansoprazole 30 mg daily decreased the Cmax and AUC of a single dose of neratinib (240 mg) by 71% and 65%, respectively.(2) |
CIMETIDINE, FAMOTIDINE, IBUPROFEN-FAMOTIDINE, NIZATIDINE, PEPCID |
| Ustekinumab/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Ustekinumab, immunosuppressives, and immunomodulators all suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of ustekinumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of ustekinumab recommends caution because the concurrent use of ustekinumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1) DISCUSSION: Ustekinumab has not been studied in combination with other immunosuppressants in psoriasis studies. In psoriatic arthritis studies, concomitant methotrexate use did not appear to influence the safety or efficacy of ustekinumab. In Crohn's disease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of ustekinumab. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by ustekinumab treated patients in the clinical trial periods included nasopharyngitis(8%) and upper respiratory tract infection(5%). Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab. Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia resulting in respiratory failure or prolonged hospitalization have been reported in patients receiving ustekinumab.(1) |
OTULFI, PYZCHIVA, SELARSDI, STELARA, STEQEYMA, USTEKINUMAB, USTEKINUMAB-AEKN, USTEKINUMAB-TTWE, WEZLANA, YESINTEK |
| COVID-19 Vaccines/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Immunosuppressants and immunomodulators may prevent the immune system from properly responding to the COVID-19 vaccine.(1,2) CLINICAL EFFECTS: Administration of a COVID-19 vaccine with immunosuppressants or immunomodulators may interfere with vaccine-induced immune response and impair the efficacy of the vaccine. However, patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: In an effort to optimize COVID-19 vaccine response, the American College of Rheumatology (ACR) published conditional recommendations for administration of COVID-19 vaccines with immunosuppressants and immunomodulators.(1) The CDC also provides clinical considerations for COVID-19 vaccination in patients on immunosuppressants.(2) The CDC states that all immunocompromised patients over 6 months of age should receive at least 1 dose of COVID-19 vaccine if eligible. See the CDC's Interim Clinical Considerations for Use of COVID-19 Vaccines for specific recommendations based on age, vaccination history, and vaccine manufacturer.(2) The ACR states that in general, immunosuppressants and immunomodulators should be held for 1-2 weeks after each vaccine dose. See below for specific recommendations for certain agents.(1) The CDC advises planning for vaccination at least 2 weeks before starting or resuming immunosuppressive therapy.(2) Patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted.(1,2) B-cell depleting agents, including rituximab: The ACR recommends consulting with the rheumatologist to determine optimal timing of COVID-19 vaccination. Measuring CD19 B cells may be considered to determine need for a booster vaccine dose. If B cell levels are not measured, a supplemental vaccine dose 2-4 weeks before the next scheduled dose of rituximab is recommended.(1) The CDC states that the utility of B-cell quantification to guide clinical care is not known and is not recommended. Patients who receive B-cell depleting therapy should receive COVID-19 vaccines about 4 weeks before the next scheduled dose. For patients who received 1 or more doses of COVID-19 vaccine during treatment with B-cell-depleting therapies that were administered over a limited period (e.g., as part of a treatment regimen for certain malignancies), revaccination may be considered. The suggested interval to start revaccination is about 6 months after completion of the B-cell-depleting therapy.(2) Abatacept: - Subcutaneous abatacept should be withheld for 1-2 weeks after each vaccine dose, as disease activity allows. - For intravenous abatacept, time administration so that vaccination will occur 1 week before the next abatacept infusion.(1) Cyclophosphamide: When feasible, administer cyclophosphamide one week after each COVID-19 vaccine dose.(1) Recipients of hematopoietic cell transplant or CAR-T-cell therapy who received one or more doses of COVID-19 vaccine prior to or during treatment should undergo revaccination following the current CDC recommendations for unvaccinated patients. Revaccination should start at least 3 months (12 weeks) after transplant or CAR-T-cell therapy.(2) TNF-alpha inhibitors and cytokine inhibitors: The ACR was not able to reach consensus on whether to modify dosing or timing of these agents with COVID-19 vaccination.(1) The CDC includes these agents in their general recommendation to hold therapy for at least 2 weeks following vaccination.(2) DISCUSSION: The ACR convened a COVID-19 Vaccine Guidance Task Force to provide guidance on optimal use of COVID-19 vaccines in rheumatology patients. These recommendations are based on limited clinical evidence of COVID-19 vaccines in patients without rheumatic and musculoskeletal disorders and evidence of other vaccines in this patient population.(1) The ACR recommendation for rituximab is based on studies of humoral immunity following receipt of other vaccines. These studies have uncertain generalizability to vaccination against COVID-19, as it is unknown if efficacy is attributable to induction of host T cells versus B cell (antibody-based) immunity.(1) The ACR recommendation for mycophenolate is based on preexisting data of mycophenolate on non-COVID-19 vaccine immunogenicity. Emerging data suggests that mycophenolate may impair SARS-CoV-2 vaccine response in rheumatic and musculoskeletal disease and transplant patients.(1) The ACR recommendation for methotrexate is based on data from influenza vaccines and pneumococcal vaccines with methotrexate.(1) The ACR recommendation for JAK inhibitors is based on concerns related to the effects of JAK inhibitors on interferon signaling that may result in a diminished vaccine response.(1) The ACR recommendation for subcutaneous abatacept is based on several studies suggesting a negative effect of abatacept on vaccine immunogenicity. The first vaccine dose primes naive T cells, naive T cell priming is inhibited by CTLA-4, and abatacept is a CTLA-4Ig construct. CTLA-4 should not inhibit boosts of already primed T cells at the time of the second vaccine dose.(1) |
COMIRNATY 2024-2025, MODERNA COVID 24-25(6M-11Y)EUA, NOVAVAX COVID 2024-2025 (EUA), PFIZER COVID 2024-25(5-11Y)EUA, PFIZER COVID 2024-25(6M-4Y)EUA, SPIKEVAX 2024-2025 |
| Sarilumab/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Sarilumab, immunosuppressives, and immunomodulators all suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of sarilumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of sarilumab recommends caution because the concurrent use of sarilumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1) DISCUSSION: Sarilumab was studied as monotherapy and in combination with methotrexate or conventional disease modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis studies. Sarilumab has not been studied with biological DMARDs and concurrent use should be avoided. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by sarilumab treated patients in the clinical trial periods included pneumonia and cellulitis. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving sarilumab. Cases of tuberculosis, candidiasis, and pneumocystis with sarilumab have been reported.(1) |
KEVZARA |
| Ublituximab/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Ublituximab, immunosuppressives, and immunomodulators all suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of ublituximab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1) PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications. PATIENT MANAGEMENT: The US manufacturer of ublituximab recommends caution because the concurrent use of ublituximab with immunomodulating or immunosuppressive agents, including immunosuppressant doses of corticosteroids, may increase the risk of infection.(1) If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents. When switching from agents with immune effects, the half-life and mechanism of action of these drugs must be taken into consideration in order to prevent additive immunosuppressive effects.(1) DISCUSSION: The most common infections reported by ublituximab-treated patients in the clinical trial periods included upper respiratory tract infections and urinary tract infections. Serious, including life-threatening or fatal, bacterial and viral infections were observed in patients receiving ublituximab.(1) Serious and/or fatal bacterial, fungal, and new or reactivated viral infections have been associated with other anti-CD20 B-cell depleting therapies. There were no cases of progressive multifocal leukoencephalopathy (PML) reported during the clinical trials; however, there have been reports of PML during or following completion of other anti-CD20 B-cell depleting therapies.(1) |
BRIUMVI |
| Tocilizumab/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Tocilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of tocilizumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of tocilizumab recommends caution because the concurrent use of tocilizumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1) DISCUSSION: Tocilizumab was studied as monotherapy and in combination with methotrexate, non-biologic DMARDs or corticosteroids, depending on the indication. Tocilizumab has not been studied with biological DMARDs and concurrent use should be avoided. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by tocilizumab treated patients in the clinical trial periods included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving tocilizumab. Cases of tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis have been reported.(1) |
ACTEMRA, ACTEMRA ACTPEN, TOFIDENCE, TYENNE, TYENNE AUTOINJECTOR |
The following contraindication information is available for BOSULIF (bosutinib):
Drug contraindication overview.
*Known hypersensitivity to bosutinib.
*Known hypersensitivity to bosutinib.
There are 1 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Lactation |
There are 22 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Anemia |
| Child-pugh class A hepatic impairment |
| Child-pugh class B hepatic impairment |
| Child-pugh class C hepatic impairment |
| Chronic heart failure |
| Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min |
| Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min |
| Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min |
| Chronic kidney disease stage 5 (failure) GFr<15 ml/min |
| Congenital long QT syndrome |
| Disease of liver |
| Hyperbilirubinemia |
| Hypokalemia |
| Hypomagnesemia |
| Neutropenic disorder |
| Pericardial effusion |
| Peripheral edema |
| Pleural effusions |
| Pregnancy |
| Pulmonary edema |
| Severe diarrhea |
| Thrombocytopenic disorder |
There are 1 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Viral hepatitis B |
The following adverse reaction information is available for BOSULIF (bosutinib):
Adverse reaction overview.
Adverse effects reported in 20% or more of adult and pediatricpatients receiving bosutinib include diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, decreased appetite, respiratory tract infection, and constipation. Laboratory abnormalities reported in 20% or more of adult and pediatricpatients receiving bosutinib include increased serum creatinine concentrations, decreased hemoglobin concentrations, decreased lymphocyte count, decreased white blood cell count, decreased absolute neutrophil count, decreased platelet count, increased aminotransferase concentrations (ALT, AST), increased alkaline phosphatase concentrations, decreased calcium concentrations, decreased phosphorus concentrations, increased glucose concentrations, increased urate concentrations, increased lipase concentrations, increased creatine kinase (CK, creatine phosphokinase, CPK) concentrations, and increased amylase concentrations.
Adverse effects reported in 20% or more of adult and pediatricpatients receiving bosutinib include diarrhea, abdominal pain, vomiting, nausea, rash, fatigue, hepatic dysfunction, headache, pyrexia, decreased appetite, respiratory tract infection, and constipation. Laboratory abnormalities reported in 20% or more of adult and pediatricpatients receiving bosutinib include increased serum creatinine concentrations, decreased hemoglobin concentrations, decreased lymphocyte count, decreased white blood cell count, decreased absolute neutrophil count, decreased platelet count, increased aminotransferase concentrations (ALT, AST), increased alkaline phosphatase concentrations, decreased calcium concentrations, decreased phosphorus concentrations, increased glucose concentrations, increased urate concentrations, increased lipase concentrations, increased creatine kinase (CK, creatine phosphokinase, CPK) concentrations, and increased amylase concentrations.
There are 42 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Abnormal hepatic function tests Anemia Diarrhea Elevated serum lipase Increased alanine transaminase Increased aspartate transaminase Increased creatine kinase level Kidney disease with reduction in glomerular filtration rate (GFr) Lower respiratory infection Neutropenic disorder Thrombocytopenic disorder |
Dehydration Elevated serum amylase Hepatitis Hyperbilirubinemia Hyperkalemia Hypersensitivity drug reaction Hypertension Lymphopenia Pericardial effusion Pleural effusions Pneumonia |
| Rare/Very Rare |
|---|
|
Acute eruptions of skin Acute hepatic failure Acute pancreatitis Acute renal failure Acute respiratory failure Anaphylaxis Erythema multiforme Gastrointestinal hemorrhage Heart failure Hyperthyroidism Interstitial lung disease Left ventricular failure Myocardial ischemia Pericarditis Pulmonary edema Pulmonary hypertension Reactivation of hepatitis B Rectal bleeding Stevens-johnson syndrome Thrombotic thrombocytopenic purpura |
There are 29 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Acute abdominal pain Anorexia Back pain Cough Dizziness Dyspnea Fatigue Fever General weakness Headache disorder Hyperglycemia Nausea Pharyngitis Pruritus of skin Skin rash Upper respiratory infection Vomiting |
Acne vulgaris Body fluid retention Chest pain Dysgeusia Gastritis Hypothyroidism Myalgia Pain Peripheral edema Tinnitus Urticaria |
| Rare/Very Rare |
|---|
|
Exfoliative dermatitis |
The following precautions are available for BOSULIF (bosutinib):
Bosutinib is used for the treatment of chronic phase Ph+ CML in pediatric patients 1 year of age and older who are newly diagnosed or resistant or intolerant to prior therapy. This indication is based primarily on the results of a multicenter, non-randomized, open-label study (BCHILD). The BCHILD study enrolled 28 patients with chronic phase Ph+ CML with resistance or intolerance to prior therapy and 21 patients with newly diagnosed chronic phase Ph+ CML.
Patients in the prior treatment failure group received bosutinib at doses of 300 to 400 mg/m2 orally once daily and those in the newly diagnosed group were administered bosutinib 300 mg/m2 orally once daily. Efficacy outcomes included complete cytogenetic response, major cytogenetic response, and major molecular response. Patients with newly diagnosed chronic phase Ph+ CML had a median age of 14 years (range, 5 to 17 years); 68% were male; 81% were white and 14% were Black/African American.
In the chronic phase Ph+ CML with resistance or intolerance to prior therapy group, the medianage was 11.5 years (range, 1 to 17 years); 57% were male; 43% were white, 7% were Black/African American, and 14%were Asian. The major and complete cytogenetic responses among newly diagnosed patients were 76.2%
and 71.4%, respectively. The major molecular response was 28.6%.
The median duration of follow-up was 14.2 months (range, 1.1 to 26.3 months)in this group. For patients in the prior treatment failure group, the major and complete cytogenetic responses were 82.1%
and 78.6%, respectively. The major molecular responsewas 50.0%.
Among 14 patients who achieved major molecular response, 2 lost this response after 13.6 months and 24.7 months ontreatment, respectively .
The median duration of follow-up for overall survival was 23.2 months (range, 1.0 to 61.5 months) in this patient group. Safety and efficacy of bosutinib in pediatric patients>=1 year of age with newly diagnosed chronic phase Ph+ CML or who had chronic phase Ph+ CML with prior treatment failure has been established.
. Use of bosutinib for these indications is based on data from a clinical study that included pediatric patients with newly diagnosed chronic phase Ph+ CML in the following age groups: 1 to <6 yearsof age (2 patients), 6 to <12 years of age (3 patients), and 12 to <17 years ofage (10 patients). The study also included pediatric patients with chronic phase Ph+ CML with prior treatment failure inthe following age groups: 1 to <6 years of age (4 patients), 6 to <12 years of age (10 patients), and 12 to <17 years of age (10 patients).
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Patients in the prior treatment failure group received bosutinib at doses of 300 to 400 mg/m2 orally once daily and those in the newly diagnosed group were administered bosutinib 300 mg/m2 orally once daily. Efficacy outcomes included complete cytogenetic response, major cytogenetic response, and major molecular response. Patients with newly diagnosed chronic phase Ph+ CML had a median age of 14 years (range, 5 to 17 years); 68% were male; 81% were white and 14% were Black/African American.
In the chronic phase Ph+ CML with resistance or intolerance to prior therapy group, the medianage was 11.5 years (range, 1 to 17 years); 57% were male; 43% were white, 7% were Black/African American, and 14%were Asian. The major and complete cytogenetic responses among newly diagnosed patients were 76.2%
and 71.4%, respectively. The major molecular response was 28.6%.
The median duration of follow-up was 14.2 months (range, 1.1 to 26.3 months)in this group. For patients in the prior treatment failure group, the major and complete cytogenetic responses were 82.1%
and 78.6%, respectively. The major molecular responsewas 50.0%.
Among 14 patients who achieved major molecular response, 2 lost this response after 13.6 months and 24.7 months ontreatment, respectively .
The median duration of follow-up for overall survival was 23.2 months (range, 1.0 to 61.5 months) in this patient group. Safety and efficacy of bosutinib in pediatric patients>=1 year of age with newly diagnosed chronic phase Ph+ CML or who had chronic phase Ph+ CML with prior treatment failure has been established.
. Use of bosutinib for these indications is based on data from a clinical study that included pediatric patients with newly diagnosed chronic phase Ph+ CML in the following age groups: 1 to <6 yearsof age (2 patients), 6 to <12 years of age (3 patients), and 12 to <17 years ofage (10 patients). The study also included pediatric patients with chronic phase Ph+ CML with prior treatment failure inthe following age groups: 1 to <6 years of age (4 patients), 6 to <12 years of age (10 patients), and 12 to <17 years of age (10 patients).
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Based on findings from animal studies and its mechanism of action, bosutinib may cause fetal harm when administered to a pregnant patient. If used during pregnancy or if the patient becomes pregnant while receiving the drug, inform the patient of the potential fetal hazard.
No data are available regarding the presence of bosutinib or its metabolites in human milk, its effects on a breast-fed child, or its effects on milk production. However, bosutinib is present in the milk of lactating rats. Breast-feeding during bosutinib treatment is not recommended due to the potential for serious adverse reactions; breast-feeding should be avoided during bosutinib therapy and for2 weeks following the last bosutinib dose.
The manufacturer makes no specific dosage recommendations for geriatric patients. In clinical trials evaluating bosutinib in patients with Ph+ CML who were resistant or intolerant to prior therapy, 20% of patients were >=65 years of age and 4% were >=75 years of age. In clinical trials evaluating bosutinib for newly diagnosed CML, 20% of patients were >=65 years of age and 5% were >=75 years of age.
No overall differences in safety or efficacy were observed between geriatric and younger adults. However, the possibility of increased sensitivity to the drug in some geriatric patients cannot be ruled out.
No overall differences in safety or efficacy were observed between geriatric and younger adults. However, the possibility of increased sensitivity to the drug in some geriatric patients cannot be ruled out.
The following prioritized warning is available for BOSULIF (bosutinib):
No warning message for this drug.
No warning message for this drug.
The following icd codes are available for BOSULIF (bosutinib)'s list of indications:
| Accelerated phase philadelphia chromosome (+) CML | |
| C92.1 | Chronic myeloid leukemia, BCr/ABl-positive |
| C92.10 | Chronic myeloid leukemia, BCr/ABl-positive, not having achieved remission |
| C92.12 | Chronic myeloid leukemia, BCr/ABl-positive, in relapse |
| Chronic phase philadelphia chromosome (+) CML | |
| C92.1 | Chronic myeloid leukemia, BCr/ABl-positive |
| C92.10 | Chronic myeloid leukemia, BCr/ABl-positive, not having achieved remission |
| C92.12 | Chronic myeloid leukemia, BCr/ABl-positive, in relapse |
| Lymphoid blast phase philadelphia chromosome (+) CML | |
| C92.1 | Chronic myeloid leukemia, BCr/ABl-positive |
| C92.10 | Chronic myeloid leukemia, BCr/ABl-positive, not having achieved remission |
| C92.12 | Chronic myeloid leukemia, BCr/ABl-positive, in relapse |
| Myeloid blast phase philadelphia chromosome (+) CML | |
| C92.1 | Chronic myeloid leukemia, BCr/ABl-positive |
| C92.10 | Chronic myeloid leukemia, BCr/ABl-positive, not having achieved remission |
| C92.12 | Chronic myeloid leukemia, BCr/ABl-positive, in relapse |
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