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  • CLASSES

    Protein Kinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    An oral tyrosine kinase inhibitor that blocks the receptors for BCR-ABL, platelet-derived growth factor (PDGF), stem cell factor (SCF), and c-kit
    Used for Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia, myelodysplastic/myeloproliferative diseases, mastocytosis, hypereosinophilic syndrome and/or chronic eosinophilic leukemia, and c-kit (CD117)-positive gastrointestinal stromal tumors
    Serious hepatotoxicity has occurred; monitoring is required

    COMMON BRAND NAMES

    Gleevec

    HOW SUPPLIED

    Gleevec/Imatinib/Imatinib Mesylate Oral Tab: 100mg, 400mg

    DOSAGE & INDICATIONS

    For the treatment of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).
    For the treatment of newly diagnosed chronic-phase Ph+ CML.
    Oral dosage
    Adults

    400 mg PO once daily with food. Treatment is continued until disease progression or unacceptable toxicity. Avoid concomitant use of strong CYP3A4 inducers if possible; increase the imatinib dosage if concomitant use is necessary. Consider increasing to 600 mg PO once daily in the absence of severe adverse reactions and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory hematologic response after at least 3 months of treatment; loss of a previously achieved hematologic response or cytogenetic response; or failure to achieve a cytogenetic response after 6 to 12 months of treatment. In patients with newly diagnosed chronic-phase chronic myelogenous leukemia (CML), the complete cytogenic response (CCyR) rate was 74.7% in patients who received oral imatinib (n = 553) compared with 6.5% in patients who received subcutaneous cytarabine plus interferon (n = 553) in a multinational, randomized, phase III study. Imatinib dosage escalation (up to 800 mg/day) was permitted. The estimated progression-free survival rate at 30 months was 87.8% in the imatinib arm and 68.3% in the combination arm (p < 0.001). After a median follow-up of 60 months, 65% of patients in the cytarabine plus interferon crossed over to the imatinib arm; subsequent analyses of the patients in this trial focused only on those originally randomized to imatinib. The CCyR rate was 87%, the overall survival (OS) rate was 89%, and 93% of patients had not progressed to blast crisis or to the accelerated phase. The primary endpoint of major molecular response (MMR) rate at 12 months was significantly improved with nilotinib 300 mg twice daily (44%) and nilotinib 400 mg twice daily (43%) compared with imatinib 400 mg once daily (22%; p < 0.001 for both comparisons) in patients with newly diagnosed chronic phase Philadelphia chromosome-positive CML in a multicenter, randomized, phase III trial (the ENESTnd trial; n = 846). Additionally, the 12-month CCyR rates were significantly higher for nilotinib (600 mg/day, 80%; 800 mg/day, 78%) compared with imatinib (65%; p < 0.001 for both comparisons). At a minimum follow-up of 24 months, the 24-month MMR rates continued to be significantly higher for nilotinib (600 mg/day, 71%; 800 mg/day, 67%) compared with imatinib (44%; p < 0.0001 for both comparisons). At a follow-up of 60 months, the median OS time had not been reached in any study arm; the estimated OS rate was 93.7% in the nilotinib 600-mg/day arm and 91.7% in the imatinib arm. Additionally, the MMR rate continued to be higher in patients who received nilotinib therapy (77% vs. 60%).

    Children >= 1 year and Adolescents

    340 mg/m2/day orally; do not exceed 600 mg/day. The daily dose may be given as a single dose or split into 2 doses given once in the morning and once in the evening. Treatment is continued until disease progression or unacceptable toxicity. Avoid concomitant use of strong CYP3A4 inducers if possible. Treatment with imatinib led to an 8-week complete hematologic response rate of 78% and a complete cytogenetic response rate of 65% in pediatric patients with chronic phase, Philadelphia chromosome-positive chronic myelogenous leukemia in a multicenter, single-arm, phase II trial (n = 51).

    For the treatment of chronic-phase Ph+ CML after the failure of interferon-alfa therapy.
    Oral dosage
    Adults

    400 mg PO once daily. Consider increasing to 600 mg PO once daily in the absence of severe adverse reactions and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory hematologic response after at least 3 months; loss of a previously achieved hematologic response. Treatment is continued until disease progression or unacceptable toxicity. Avoid concomitant use of strong CYP3A4 inducers if possible; increase the imatinib dosage if concomitant use is necessary. Patients with chronic phase CML who have failed interferon alfa therapy demonstrated a hematologic response rate of 95%, with 60% of patients achieving a major cytogenetic response. Thirty-nine percent achieved a complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation performed at least one month after the initial bone marrow study. The median time to hematologic response was 1 month. In one report, patients with chronic phase CML post-interferon failure were treated with imatinib 400 mg PO twice daily. Of evaluable patients, 19/21 (90%) achieved a major cytogenetic response. Toxicities were similar to those reported with standard dose.

    For pediatric patients with chronic phase Ph+ CML whose disease has recurred after hematopoietic stem cell transplant or who are resistant to interferon-alfa therapy†.
    Oral dosage
    Children >= 3 years, Adolescents, and Adults <= 20 years

    260 mg/m2/day PO given as a single daily dose or the dose may be divided given once in the morning and once in the evening. Consider increasing to 340 mg/m2/day PO in the absence of severe adverse reactions and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory hematologic response after at least 3 months of treatment; loss of a previously achieved hematologic response or cytogenetic response; or failure to achieve a cytogenetic response after 6 to 12 months of treatment. In an open-label single-arm study, 14 pediatric patients with Ph+ chronic phase CML recurrent after stem cell transplant or resistant to interferon alfa therapy were treated with imatinib. In the 13 patients for whom cytogenetic information is available, 4 achieved a major cytogenetic response, 7 achieved a complete cytogenetic response, and 2 had minimal cytogenetic response. The cytogenetic response rate was similar at all dosage levels studied.

    For the treatment of accelerated-phase or blast crisis Ph+ CML after the failure of interferon-alfa therapy.
    Oral dosage
    Adults

    600 mg PO once daily. Consider increasing to 800 mg/day PO (400 mg PO twice daily) in the absence of severe adverse reactions and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory hematologic response after at least 3 months of treatment; loss of a previously achieved hematologic response or cytogenetic response; or failure to achieve a cytogenetic response after 6 to 12 months of treatment. Treatment is continued until disease progression or unacceptable toxicity. Avoid concomitant use of strong CYP3A4 inducers if possible; increase the imatinib dosage if concomitant use is necessary. In patients with CML in accelerated phase or blast crisis, the hematologic response (doses 400 to 600 mg/day) was 69% and 52%, respectively, with major cytogenic responses in 21% and 13.5%, respectively. Twenty-four percent of patients in accelerated phase and 19% in blast crisis returned to chronic phase CML. In blast crisis, the median duration of hematologic response is about 7 months, and in accelerated phase, the median duration is more than 6 months, but the specific median duration of response cannot yet be estimated.

    For the treatment of Philadelphia chromosome-positive (Ph+) acute lymphocytic leukemia (ALL).
    For the treatment of relapsed or refractory Ph+ ALL.
    Oral dosage
    Adults

    600 mg orally once daily. Treatment is continued until disease progression or unacceptable toxicity. Avoid concomitant use of strong CYP3A4 inducers if possible; increase the imatinib dosage if concomitant use is necessary. Single-agent imatinib therapy (median duration of 62 days; range, 14 to 343 days) resulted in a sustained hematologic response (lasting at least 4 weeks) in 27% of relapsed or refractory, Philadelphia chromosome-positive acute lymphocytic leukemia patients in a multicenter, phase II trial (n = 48; prior bone morrow transplant, n = 10 (21%)); a sustained complete hematologic response (CHR) was achieved in 6% of patients. Additionally, 17% of patients had a complete cytogenetic response. The estimated median time to progression was 2.2 months and the estimated median overall survival time was 4.9 months.

    For the treatment of newly diagnosed Ph+ ALL, in combination with chemotherapy.
    Oral dosage
    Children >= 1 year, Adolescents, and Adults <= 21 years

    340 mg/m2 orally once daily; do not exceed 600 mg/day. Avoid concomitant use of strong CYP3A4 inducers if possible. The 3-year event-free survival (EFS) rate was 80.5% +/- 11.2% (95% CI, 64.5%—89.8%) in a cohort of 50 patients aged 1 to 21 years (median age, 10 years) with very high-risk Philadelphia chromosome-positive acute lymphocytic leukemia (ALL) who received imatinib after 4 to 6 weeks of 3- or 4-drug induction therapy in a multicenter, nonrandomized trial (the COG AALL0031 trial). Most patients in this cohort (n = 44) received continuous imatinib therapy for 280 days prior to maintenance. High-risk ALL was defined as patients with an expected 5-year EFS of less than 45% with conventional chemotherapy. In this trial, patients received daily imatinib starting with the first course of post-induction chemotherapy and continued through maintenance chemotherapy cycles 1 to 4; imatinib was administered intermittently on a 2-week-on/2-week-off schedule during maintenance cycles 5 to 12. The 20 patients who underwent hematopoietic stem cell transplant (HSCT) received 42 days of imatinib prior to HSCT and 28 weeks (196 days) of imatinib after the immediate post transplant period. At a median follow-up time of 40.5 months, the estimated 4-year EFS of patients in this study was 70% (95% CI, 54% to 81%).

    For the treatment of Kit (CD117) positive gastrointestinal stromal tumors (GIST).
    NOTE: Imatinib has been designated an orphan drug by the FDA for this indication.
    For the treatment of Kit (CD117) positive unresectable and/or metastatic GIST.
    Oral dosage
    Adults

    400 mg by mouth once daily until disease progression or unacceptable toxicity. If patients show clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions, the dose may be increased up to 800 mg per day (given as 400 mg twice daily) as clinically indicated; however, the incidence of anemia and asthenia increases significantly at this dosage and the median time to progression after dose escalation is approximately 80 days. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In 2 multicenter, randomized, open-label clinical trials (n = 1,640), patients with unresectable or metastatic GIST were randomized to treatment with either 400 mg or 800 mg per day of imatinib; patients in the 400 mg arm were permitted to cross over to receive 800 mg daily upon disease progression. The primary outcome of progression-free survival (PFS) was 18.9 months compared with 23.2 months, respectively. Partial responses occurred in 46.1% of the 400-mg arm compared with 48.9% of the 800-mg arm, while complete responses were recorded in 5.3% versus 5% of patients, respectively. There were no differences in overall survival between treatment groups (p = 0.98). In another multicenter, open-label phase 2 clinical trial, there were no differences in response rates between patients treated with either 400 mg or 600 mg of imatinib per day.

    For the adjuvant treatment of Kit (CD117) positive GIST after complete gross resection.
    Oral dosage
    Adults

    400 mg by mouth once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. A treatment duration of 3 years in patients with tumor diameter greater than 5 cm and mitotic count greater than 5/50 high power fields (HPF), tumor diameter greater than 10 cam and any mitotic count, any tumor size with mitotic count greater than 10/50 HPF, or tumors ruptured into the peritoneal cavity. The optimal duration of treatment for other patients is unknown, but in clinical trials durations of both 1 year and 3 years have been studied. In a planned 15-month interim analysis of a multicenter, randomized, double-blind clinical trial, recurrence-free survival (RFS) was improved with 1-year of imatinib treatment (n = 359) compared with placebo (n = 354) (HR 0.398; p less than 0.0001). Twenty percent of placebo arm crossed over to receive imatinib after the interim analysis, and the updated RFS hazard ratio after 50 months was 0.718 (95% CI, 0.531 to 0.971). Overall survival was not significantly improved by adjuvant imatinib. In a second multicenter, randomized, open-label phase 3 clinical trial, 36 months of imatinib treatment significantly prolonged RFS compared with 12 months of imatinib treatment (HR 0.46; p less than 0.0001) in patients with tumor diameter greater than 5 cm with mitotic count greater than 5/50 high power fields (HPF), tumor diameter greater than 10 cam with any mitotic count, any tumor size with mitotic count greater than 10/50 HPF, or tumors ruptured into the peritoneal cavity. Overall survival was also significantly improved in the 36-month treatment arm (HR 0.45; p = 0.0187).

    For the treatment of hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIPL1L1-PDGFR alpha fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIPL1L-PDGFR alpha fusion kinase negative or unknown.
    Oral dosage
    Adults

    400 mg PO once daily in patients who are FIPL1L-PDGFR alpha fusion kinase negative or unknown. For HES/CEL patients with demonstrated FIP1L1-PDGFR alpha fusion kinase, a starting dose of 100 mg/day PO is recommended. Increase dose from 100 mg to 400 mg for these patients may be considered in those who have had an inadequate response to therapy in the absence of adverse drug reactions. Treatment should continue as long as the patient continues to benefit. Several small series of patients with HES have reported responses to imatinib at dosages of 100 to 400 mg/day PO. In one series, 9 of 11 patients treated with imatinib had responses lasting more than 3 months in which the eosinophil count returned to normal. In another series, patients whose disease did not respond to imatinib 100 mg/day PO after 4 weeks had their dosage increased to 400 mg/day PO. In 3 of the 4 without response, the disease failed to respond to an increase in dosage. The dosage of imatinib should be increased by at least 50% and clinical response closely monitored in patients receiving imatinib with a potent cytochrome P450 inducer such as rifampin or phenytoin.

    For the treatment of myelodysplastic syndrome (MDS)/myeloproliferative disease (MPD) associated with the PDGFR (platelet-derived growth factor receptor) gene rearrangements.
    Prior to starting therapy, test for platelet-derived growth factor receptor (PDGFR) gene re-arrangements using a FDA-approved test.
    Oral dosage
    Adults

    400 mg PO once daily. Treatment should continue as long as the patient continues to benefit. An open label phase 2 trial of patients with life-threatening conditions associated with Abl, Kit, or PDGFR protein tyrosine kinases included 7 patients with MDS/MPD who were treated with imatinib 400 mg/day. In addition, case reports and series describe an additional 24 patients with MDS/MPD treated with imatinib 400 mg/day. Of the total patients treated (n = 31), 14 (45%) achieved a complete hematologic response and 12 (39%) a major cytogenetic response (including 10 with a complete cytogenetic response). Response durations in the phase 2 trial ranged from 141+ days to 457+ days; median duration of response was 12.9 months.

    For the treatment of aggressive systemic mastocytosis (ASM) without D816V c-Kit mutation or with c-Kit mutation status unknown.
    Prior to starting therapy, test for D816V c-Kit mutation status using a FDA-approved test.
    Oral dosage
    Adults

    400 mg PO once daily in patients without the FIP1L1-PDGFR alpha c-Kit mutation. If c-Kit status is unknown or not available, treatment with 400 mg PO once daily may be considered for patients with ASM not responding to other therapies. For patients with ASM associated with eosinophilia, a starting dose of 100 mg/day PO is recommended. Dose increases from 100 mg to 400 mg for these patients may be considered in those who have had an inadequate response to therapy the absence of adverse drug reactions. Treatment should continue as long as the patient continues to benefit. An open label phase 2 trial of patients with life-threatening conditions associated with Abl, Kit, or PDGFR protein tyrosine kinases included 5 patients with ASM who were treated with imatinib 100 to 400 mg/day. In addition, case reports and series describe 23 other patients with ASM treated with imatinib 100 to 400 mg/day. Of the total patients treated (n = 28), 8 (29%) achieved a complete hematologic response and 9 (32%) a partial hematologic response (61% overall response rate). In the literature, the response duration ranged from 1+ to 30+ months.

    For the treatment of unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans (DFSP).
    NOTE: The dosage of imatinib should be increased by at least 50% and clinical response closely monitored in patients receiving imatinib with a potent cytochrome P450 inducer such as rifampin or phenytoin (see Drug Interactions).
    Oral dosage
    Adults

    400 mg PO twice daily (800 mg/day). Treatment should continue as long as the patient continues to benefit. An open label phase 2 trial of patients with life-threatening conditions associated with Abl, Kit, or PDGFR protein tyrosine kinases included 12 patients with DFSP who were treated with imatinib 800 mg/day. In addition, case reports and series describe 6 other patients with DFSP treated with imatinib either 400 or 800 mg/day. A single pediatric patient received 400 mg/m2/day increased to 520 mg/m2/day. Of the total 18 patients, 8 of them had metastatic disease. Response in those with DFSP included 7 (39%) complete responses and 8 (44%) partial responses with an overall response rate of 83%.

    For the treatment of desmoid tumor† or aggressive fibromatosis† not amenable to surgery or radiotherapy.
    Oral dosage
    Adults

    Various dosage regimens ranging from 200 to 800 mg/day PO have been studied. 400 mg/day PO for up to 12 months (increased to 800 mg/day if disease progression occurred) resulted in a 3-month response rate (complete response [CR] + partial response [PR] + stable disease [SD]) of 91% (CR, 2.9%; PR, 8.6%) and a median progression-free survival time of 25 months in 35 evaluable patients in a phase II study. One patient in this study experienced grade 3 rhabdomyolysis. In another phase II study, the 4-month clinical benefit rate was 84% in 51 patients aged 12 to 67 years with AF who received imatinib 100 mg PO twice daily (BSA less than 1 m2), 200 mg PO twice daily (BSA 1 to 1.4 m2), or 300 mg PO twice daily (BSA more than 1.5 m2); additionally, 3 patients had a PR after 19, 22, and 26 months of therapy. In a phase II study in 19 heavily-pretreated patients, 800 mg/day PO resulted in 3 partial responses (15.7%) lasting greater than 1.5 years (range, 594 to 1494+ days), 4 patients with stable disease lasting greater than 1 year, and a median time to progression of 325 days. Dose reductions to 400 to 600 mg/day PO were required for most patients due to grade 3 or higher toxicity.

    Children >= 12 years and Adolescents

    100 mg PO twice daily (BSA less than 1 m2), 200 mg PO twice daily (BSA 1 to 1.4 m2), or 300 mg PO twice daily (BSA more than 1.5 m2) has been studied in a phase II study. The 4-month clinical benefit rate was 84% in 51 patients; additionally, 3 patients had a PR after 19, 22, and 26 months of therapy.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    800 mg/day PO; 1200 mg/day PO if taking a strong 3A4 inducer.

    Geriatric

    800 mg/day PO; 1200 mg/day PO if taking a strong 3A4 inducer.

    Adolescents

    600 mg/day PO.

    Children

    600 mg/day PO.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Dose Adjustments for Hepatotoxicity, Other Non-Hematologic Adverse Reactions, or Hematotoxicity
     
    Dosage Adjustments in Adults
    For severe non-hematologic reactions (e.g., severe hepatotoxicity or fluid retention): Hold imatinib until reaction has resolved. Treatment can be resumed as appropriate depending upon the severity of the initial event.
     
    For bilirubin levels > 3-times the upper limit of normal (ULN) or transaminases > 5-times the ULN: Hold imatinib until bilirubin levels are < 1.5-times ULN and transaminase levels are < 2.5-times ULN. Treatment with imatinib may then be continued at a reduced dose; in adults reduce 400 mg/day to 300 mg/day or reduce 600 mg/day to 400 mg/day, in children reduce 260 mg/m2/day to 200 mg/m2/day or 340 mg/m2/day to 260 mg/m2/day
     
    For absolute neutrophil count (ANC) < 1000/mm3 and/or platelets < 50,000/mm3 with a starting adult dose of 100 mg/day in patients with ASM associated with eosinophilia and HES/CEL with FIPL1-PDGR alpha fusion kinase: Hold imatinib until ANC >= 1500/mm3 and platelets >= 75,000/mm3. Resume therapy at original dose
     
    For absolute neutrophil count (ANC) < 1000/mm3 and/or platelets < 50,000/mm3 with a starting adult dose of 400 mg/day in patients with chronic phase CML, MDS/MPD, ASM, and HES/CEL or 400—600 mg/day in GIST: Hold imatinib until ANC >= 1500/mm3 and platelets >= 75,000/mm3. Resume therapy at original dose (400 or 600 mg/day). If recurrence of ANC < 1000/mm3 and/or platelets < 50,000/mm3, hold imatinib as above, then reduce dose: to 300 mg/day if the starting dose was 400 mg/day or, if the starting dose was 600 mg/day, reduce dose to 400 mg/day
     
    For absolute neutrophil count (ANC) < 500/mm3 and/or platelets < 10,000/mm3 in patients with CML in accelerated phase or blast crisis or Ph+ ALL at a starting dose of 600 mg/day: Determine if the cytopenia is related to leukemia. If unrelated to leukemia, reduce dose to 400 mg/day. If cytopenia persists for 2 weeks, further reduce dose to 300 mg/day. If cytopenia persists 4 weeks and is still unrelated to leukemia, hold imatinib until ANC >= 1000/mm3 and platelets >= 20,000/mm3 and then resume treatment at 300 mg/day
     
    For absolute neutrophil count (ANC) < 1000/mm3 and/or platelets < 50,000/mm3 with a starting adult dose of 800 mg/day in patients with DFSP: Hold imatinib until ANC >= 1500/mm3 and platelets >= 75,000/mm3. Resume therapy at 600 mg/day PO. If recurrence of ANC < 1000/mm3 and/or platelets < 50,000/mm3, hold imatinib as above, then reduce dose to 400 mg/day PO
     
    Dosage Adjustments in Children
    For severe non-hematologic reactions (e.g., severe hepatotoxicity or fluid retention): Hold imatinib until reaction has resolved. Treatment can be resumed as appropriate depending upon the severity of the initial event
     
    For bilirubin levels > 3-times the upper limit of normal (ULN) or transaminases > 5-times the ULN: Hold imatinib until bilirubin levels are < 1.5-times ULN and transaminase levels are < 2.5-times ULN. Treatment with imatinib may then be continued at a reduced dose; in children reduce 260 mg/m2/day to 200 mg/m2/day or 340 mg/m2/day to 260 mg/m2/day
     
    For absolute neutrophil count (ANC) < 1000/mm3 and/or platelets < 50,000/mm3 with a starting 340 mg/m2 in newly diagnosed pediatric patients with chronic phase CML: Hold imatinib until ANC >= 1500/mm3 and platelets >= 75,000/mm3. Resume therapy at same dose. If recurrence of ANC < 1000/mm3 and/or platelets < 50,000/mm3, hold imatinib as above, then reduce dose to 260 mg/m2/day PO
     
    For absolute neutrophil count (ANC) < 1000/mm3 and/or platelets < 50,000/mm3 with a starting 260 mg/m2 in pediatric patients with chronic phase CML recurring after transplant or resistant to interferon: Hold imatinib until ANC >= 1500/mm3 and platelets >= 75,000/mm3. Resume therapy at same dose. If recurrence of ANC < 1000/mm3 and/or platelets < 50,000/mm3, hold imatinib as above, then reduce dose to 200 mg/m2/day PO

    Hepatic Impairment

    Total bilirubin 1.5—3x ULN and any AST concentration: Decrease the initial dose to 400 mg/day PO
    Total bilirubin > 3x ULN and any AST concentration: Decrease the initial dose to 300 mg/day PO

    Renal Impairment

    CrCl >= 60 mL/min: No adjustment needed
    CrCl 40—59 mL/min: Doses > 600 mg/day PO are not recommended
    CrCl 20—39 mL/min: Decrease initial dose by 50% and increase as tolerated; doses > 400 mg/day PO are not recommended
    CrCl < 20 mL/min: Use with caution. A dose of 100 mg/day PO has been tolerated; drug exposure is similar to 400 mg/day PO in a patient with normal renal function

    ADMINISTRATION

    Oral Administration

    Imatinib should be taken with food and a large glass of water to decrease the risk of GI irritation.
    Do not take with grapefruit juice.
    Doses of 400 or 600 mg should be taken once daily; the 800 mg/day dosage should be taken in as 400 mg twice daily.
    If a dose is missed, take it as soon as possible. If it is almost time for the next dose, skip the dose; do not take a double dose.
    Follow procedures for proper handling and disposal of anticancer drugs. Avoid exposure to crushed or broken tablets.

    Oral Solid Formulations

    400 mg tablets are scored; however, do not crush tablets.
    If a daily dose of 800 mg or greater is required, use the 400 mg tablets instead of the 100 mg tablets to limit the patient's iron exposure.

    Extemporaneous Compounding-Oral

    For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice.
    Use approximately 50 mL of liquid for a 100-mg tablet and 200 ml of liquid for a 400-mg tablet.
    The required number of tablets should be placed in the appropriate volume of liquid and stirred with a spoon.
    If a daily dose of 800 mg or greater is required, use the 400 mg tablets instead of the 100 mg tablets to limit the patient's iron exposure.
    The suspension should be administered immediately after complete disintegration of the tablets.

    STORAGE

    Gleevec:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Diabetes mellitus, hypertension, nephrotoxicity, renal impairment

    Nephrotoxicity including a decline in renal function has been reported with imatinib therapy. Evaluate renal function (e.g., serum creatinine/BUN levels) prior to starting and during imatinib therapy. Use imatinib with caution in patients with renal impairment. Dose reductions are necessary in patients with moderate (creatinine clearance (CrCl) of 20 to 39 mL/min) or severe (CrCl of less than 20 mL/min) renal impairment. Patients with pre-existing renal impairment, cardiac failure, diabetes mellitus, and hypertension are at increased risk for developing nephrotoxicity.

    Cardiac disease, heart failure, renal disease, ventricular dysfunction

    Severe congestive heart failure and left ventricular dysfunction have been reported in patients who received imatinib in clinical trials; patients with advanced age, a prior history of cardiac disease, or other co-morbidities (e.g., renal disease) may be at increased risk. Monitor patients with cardiac disease or risk factors for heart failure for signs and symptoms of cardiac or kidney failure. Evaluate and treat patients according to current standards of practice.

    Bleeding, bone marrow suppression, fungal infection, GI bleeding, herpes infection, immunosuppression, infection, neutropenia, thrombocytopenia, varicella, viral infection

    Bone marrow suppression often occurs during imatinib therapy and is dependent upon the stage of the underlying disease. Complete blood counts should be performed at least weekly for the first month, biweekly the second month, and periodically thereafter, as clinically indicated. Dosage adjustments for neutropenia and thrombocytopenia are recommended. In patients with chronic myeloid leukemia (CML), the occurrence of cytopenias is dependent upon the stage of disease and is more frequent in patients with accelerated or blast crisis than in patients with chronic phase CML. Patients should be closely monitored for any signs or symptoms of bleeding, especially GI bleeding. Gastrointestinal tumor sites may have been the source of GI bleeds in patients treated with imatinib. Patients with an active infection should be treated prior to receiving imatinib when possible. Opportunistic infection, including viral infection and fungal infection, may occur in some patients due to severe immunosuppression. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy. Patients should immediately report any symptoms of severe myelosuppression such as fever, sore throat, or abnormal bleeding.

    Hepatic disease, jaundice

    Although patients with mild to moderate hepatic impairment experience similar exposure to imatinib and its metabolite as patients with normal hepatic function, patients with severe underlying hepatic disease may have increased exposure to imatinib and should be closely monitored. The recommended initial dose of imatinib is also dependent upon the degree of hepatic impairment. When imatinib is combined with chemotherapy, cases of hepatotoxicity have occurred including reports of acute liver failure. In addition to the consideration of pre-existing hepatic disease, hepatotoxicity, which can be severe, may occur with single-agent imatinib. Liver function should be monitored before starting therapy and monthly or as clinically indicated. Treatment interruption and/or imatinib dosage adjustments are recommended for changes in liver function tests, hyperbilirubinemia, or jaundice.

    Hemochromatosis

    Patients with hemochromatosis may not be appropriate candidates for imatinib. Each 100 mg tablet of imatinib contains 0.813 mg of elemental iron, and each 400 mg tablet of imatinib contains 1.944 mg of elemental iron. The iron is from ferric oxide, red and ferric oxide, yellow, which are contained in the tablet coating. Patients who need a total daily imatinib dose of 800 mg or greater should use the 400 mg tablets instead of the 100 mg tablets to obtain their dose and to limit iron exposure.

    Children, growth inhibition, infants, neonates

    Growth inhibition has been reported in children and preadolescents receiving imatinib. Close monitoring of growth in children and adolescents who have not completed puberty and growth is advised, as the long term effects of prolonged imatinib treatment on growth in pediatric patients are unknown. The safety and efficacy of imatinib in pediatric patients (infants and neonates) less than 1 year of age have not been established.

    Driving or operating machinery

    Imatinib may cause dizziness, blurred vision, or somnolence, and, thus, caution may be warranted for recipients driving or operating machinery. Although most reports of motor vehicle accidents are not suspected to be caused by imatinib, reports have been received in patients receiving imatinib.

    Ascites, edema, geriatric, pericardial effusion, pleural effusion, pulmonary edema

    Severe fluid retention/edema (e.g., pleural effusion, pericardial effusion, ascites, and pulmonary edema) has been reported in patients who received imatinib in clinical trials; geriatric patients and treatment with imatinib 600 mg/day in patients with blast- or accelerated-phase chronic myelogenous leukemia may be at increased risk. Monitor patients for signs of fluid retention such as rapid weight gain and manage patients as medically indicated (e.g., diuretics and other supportive care measures). Interrupting therapy may be necessary.

    Pregnancy

    Imatinib may cause fetal harm when administered during pregnancy based on human and animal data; postmarketing reports of spontaneous abortions and of infant congenital anomalies have been reported following imatinib use in pregnancy women. Advise females of reproductive potential to avoid pregnancy while taking imatinib. Discuss the potential hazard to the fetus if imatinib is used during pregnancy or if a patient becomes pregnant while taking this drug. In animal studies in rats, imatinib was teratogenic when given during organogenesis at doses approximately equal to the maximum imatinib dose of 800 mg/day based on body surface area.

    Contraception requirements, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during imatinib treatment. Pregnancy testing should be performed prior to starting imatinib in female patients of reproductive potential. These patients should use effective contraception (i.e., contraceptive methods that result in < 1% pregnancy rates) and avoid pregnancy during and for at least 14 days after stopping imatinib therapy. Women who become pregnant while receiving imatinib should be apprised of the potential hazard to the fetus.

    Breast-feeding

    According to the manufacturer, women should discontinue breast-feeding during imatinib therapy and for 1 month after the last dose because of the potential for serious adverse reactions in nursing infants. Imatinib and its active metabolite are excreted into human milk. Based on data from three breast feeding women taking imatinib, the milk:plasma ratio is roughly 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and its active metabolite, a breast-fed infant could receive up to 10% of the maternal therapeutic dose based on body weight.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 3.1-64.0
    thrombocytopenia / Delayed / 1.0-63.0
    anemia / Delayed / 3.0-53.0
    bleeding / Early / 0-19.0
    abdominal pain / Early / 0.3-13.8
    edema / Delayed / 0-13.1
    fluid retention / Delayed / 2.5-13.1
    lethargy / Early / 0-12.2
    malaise / Early / 0-12.2
    asthenia / Delayed / 0-12.2
    fatigue / Early / 0.5-12.2
    anasarca / Delayed / 1.0-10.0
    pericardial effusion / Delayed / 1.0-10.0
    ocular hemorrhage / Delayed / 0.1-10.0
    pancytopenia / Delayed / 1.0-10.0
    vomiting / Early / 0.5-9.2
    nausea / Early / 0.5-9.0
    diarrhea / Early / 0.5-9.0
    intracranial bleeding / Delayed / 0.2-9.0
    musculoskeletal pain / Early / 2.0-9.0
    hypoxia / Early / 0-9.0
    rash / Early / 0.9-8.9
    GI bleeding / Delayed / 1.4-8.0
    elevated hepatic enzymes / Delayed / 0.2-8.0
    infection / Delayed / 0-8.0
    fever / Early / 0-8.0
    dyspnea / Early / 0.5-7.0
    weight gain / Delayed / 0-7.0
    pulmonary edema / Early / 0.1-6.9
    pleural effusion / Delayed / 0.1-6.9
    anorexia / Delayed / 0-6.6
    arthralgia / Delayed / 0-6.0
    headache / Early / 0-5.7
    myalgia / Early / 0-5.6
    stomatitis / Delayed / 0.6-5.4
    pruritus / Rapid / 0-5.4
    pharyngitis / Delayed / 0-5.4
    constipation / Delayed / 0.4-5.1
    chills / Rapid / 0-4.6
    cough / Delayed / 0-4.5
    alopecia / Delayed / 0-4.3
    hyperbilirubinemia / Delayed / 0-4.0
    hypoalbuminemia / Delayed / 0-4.0
    hypokalemia / Delayed / 0.8-4.0
    muscle cramps / Delayed / 0.4-2.2
    chest pain (unspecified) / Early / 0.4-2.0
    lymphopenia / Delayed / 0.7-1.9
    leukopenia / Delayed / 0.3-1.6
    bone pain / Delayed / 1.6-1.6
    heart failure / Delayed / 0.7-1.1
    flatulence / Early / 0.2-1.0
    hematemesis / Delayed / 0.1-1.0
    peptic ulcer / Delayed / 0.1-1.0
    pancreatitis / Delayed / 0.1-1.0
    dyspepsia / Early / 0-1.0
    dizziness / Early / 0-1.0
    peripheral edema / Delayed / 0-1.0
    increased intracranial pressure / Early / 0.1-1.0
    papilledema / Delayed / 0.1-1.0
    retinal hemorrhage / Delayed / 0.1-1.0
    exfoliative dermatitis / Delayed / 0.1-1.0
    erythema multiforme / Delayed / 0.1-1.0
    night sweats / Early / 0.2-1.0
    back pain / Delayed / 0.6-1.0
    hypertension / Early / 0-1.0
    hearing loss / Delayed / 0.1-1.0
    macular edema / Delayed / 0.1-1.0
    blurred vision / Early / 0-1.0
    hyperglycemia / Delayed / 0-1.0
    hypocalcemia / Delayed / 0-1.0
    hyperkalemia / Delayed / 0.1-1.0
    renal failure (unspecified) / Delayed / 0.1-1.0
    insomnia / Early / 0-0.9
    anxiety / Delayed / 0-0.8
    depression / Delayed / 0-0.8
    influenza / Delayed / 0-0.8
    xerosis / Delayed / 0-0.5
    paresthesias / Delayed / 0-0.5
    sinusitis / Delayed / 0.2-0.4
    ileus / Delayed / 0-0.1
    cerebral edema / Early / 0-0.1
    cardiac tamponade / Delayed / 0-0.1
    aplastic anemia / Delayed / 0-0.1
    hemolytic anemia / Delayed / 0-0.1
    acute generalized exanthematous pustulosis (AGEP) / Delayed / 0-0.1
    vasculitis / Delayed / 0-0.1
    Stevens-Johnson syndrome / Delayed / 0-0.1
    atrial fibrillation / Early / 0-0.1
    arrhythmia exacerbation / Early / 0-0.1
    myocardial infarction / Delayed / 0-0.1
    cardiac arrest / Early / 0-0.1
    hepatic necrosis / Delayed / 0-0.1
    hepatic failure / Delayed / 0-0.1
    pulmonary fibrosis / Delayed / 0-0.1
    pulmonary hypertension / Delayed / 0-0.1
    optic neuritis / Delayed / 0-0.1
    angioedema / Rapid / 0-0.1
    GI perforation / Delayed / Incidence not known
    GI obstruction / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    pseudoporphyria / Delayed / Incidence not known
    avascular necrosis / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    osteonecrosis / Delayed / Incidence not known
    pericarditis / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    nephrotoxicity / Delayed / Incidence not known

    Moderate

    gastritis / Delayed / 1.0-10.0
    peripheral neuropathy / Delayed / 1.0-10.0
    eosinophilia / Delayed / 1.0-10.0
    erythema / Early / 1.0-10.0
    palpitations / Early / 1.0-10.0
    conjunctivitis / Delayed / 1.0-10.0
    hyperamylasemia / Delayed / 1.0-10.0
    dysphagia / Delayed / 0.1-1.0
    oral ulceration / Delayed / 0.1-1.0
    esophagitis / Delayed / 0.1-1.0
    dehydration / Delayed / 0.1-1.0
    melena / Delayed / 0.1-1.0
    memory impairment / Delayed / 0.1-1.0
    migraine / Early / 0.1-1.0
    ascites / Delayed / 0.1-1.0
    subdural hematoma / Early / 0.1-1.0
    lymphadenopathy / Delayed / 0.1-1.0
    psoriasis / Delayed / 0.1-1.0
    hematoma / Early / 0.1-1.0
    bullous rash / Early / 0.1-1.0
    gout / Delayed / 0.1-1.0
    hyperuricemia / Delayed / 0.1-1.0
    sinus tachycardia / Rapid / 0.1-1.0
    hypotension / Rapid / 0.1-1.0
    jaundice / Delayed / 0.1-1.0
    hepatitis / Delayed / 0.1-1.0
    blepharitis / Early / 0.1-1.0
    cataracts / Delayed / 0.1-1.0
    impotence (erectile dysfunction) / Delayed / 0.1-1.0
    testicular swelling / Early / 0.1-1.0
    hyponatremia / Delayed / 0.1-1.0
    hypercalcemia / Delayed / 0.1-1.0
    hypomagnesemia / Delayed / 0.1-1.0
    hypophosphatemia / Delayed / 0-1.0
    hematuria / Delayed / 0.1-1.0
    colitis / Delayed / 0-0.1
    confusion / Early / 0-0.1
    angina / Early / 0-0.1
    pneumonitis / Delayed / 0-0.1
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    growth inhibition / Delayed / Incidence not known
    myopathy / Delayed / Incidence not known
    clastogenesis / Delayed / Incidence not known
    hypothyroidism / Delayed / Incidence not known

    Mild

    lacrimation / Early / 9.8-25.0
    rhinitis / Early / 16.7-16.7
    dysgeusia / Early / 6.5-12.6
    weight loss / Delayed / 10.1-10.1
    xerostomia / Early / 1.0-10.0
    gastroesophageal reflux / Delayed / 1.0-10.0
    epistaxis / Delayed / 1.0-10.0
    purpura / Delayed / 1.0-10.0
    photosensitivity / Delayed / 1.0-10.0
    flushing / Rapid / 1.0-10.0
    weakness / Early / 0.1-10.0
    xerophthalmia / Early / 1.0-10.0
    cheilitis / Delayed / 0.1-1.0
    appetite stimulation / Delayed / 0.1-1.0
    eructation / Early / 0.1-1.0
    libido decrease / Delayed / 0.1-1.0
    tremor / Early / 0.1-1.0
    syncope / Early / 0.1-1.0
    petechiae / Delayed / 0.1-1.0
    skin hypopigmentation / Delayed / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    hyperhidrosis / Delayed / 0.1-1.0
    ecchymosis / Delayed / 0.1-1.0
    folliculitis / Delayed / 0.1-1.0
    skin hyperpigmentation / Delayed / 0.1-1.0
    restless legs syndrome (RLS) / Delayed / 0.1-1.0
    drowsiness / Early / 0.1-1.0
    vertigo / Early / 0.1-1.0
    tinnitus / Delayed / 0.1-1.0
    ocular irritation / Rapid / 0.1-1.0
    ocular pain / Early / 0.1-1.0
    gynecomastia / Delayed / 0.1-1.0
    menstrual irregularity / Delayed / 0.1-1.0
    menorrhagia / Delayed / 0.1-1.0
    breast enlargement / Delayed / 0.1-1.0
    increased urinary frequency / Early / 0.1-1.0
    nail discoloration / Delayed / 0-0.1
    vesicular rash / Delayed / 0-0.1
    lichen planus-like eruption / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with imatinib is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
    Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with imatinib. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors. Additionally, acalabrutinib may increase imatinib exposure and increase the risk of imatinib toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Imatinib is a BCRP substrate.
    Acetaminophen: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib.
    Acetaminophen; Aspirin, ASA; Caffeine: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib.
    Acetaminophen; Butalbital: (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates. (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib.
    Acetaminophen; Butalbital; Caffeine: (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates. (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates. (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Moderate) Concomitant use of codeine with imatinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of imatinib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If imatinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Imatinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Moderate) Imatinib is an inhibitor of CYP2D6 and may cause increased serum concentrations of dihydrocodeine leading to toxicity. Monitor for enhanced sedation or respiratory depression.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib.
    Acetaminophen; Codeine: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Moderate) Concomitant use of codeine with imatinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of imatinib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If imatinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Imatinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Acetaminophen; Dextromethorphan: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Acetaminophen; Dextromethorphan; Doxylamine: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib.
    Acetaminophen; Diphenhydramine: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib.
    Acetaminophen; Guaifenesin; Phenylephrine: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib.
    Acetaminophen; Hydrocodone: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Acetaminophen; Oxycodone: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Moderate) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including oxycodone.
    Acetaminophen; Pentazocine: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib.
    Acetaminophen; Propoxyphene: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Moderate) Propoxyphene is a substrate and an inhibitor of CYP2D6. Increased serum concentrations of propoxyphene would be expected from concurrent use of a CYP2D6 inhibitor, such as imatinib.
    Acetaminophen; Pseudoephedrine: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib.
    Acetaminophen; Tramadol: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Moderate) Since tramadol is primarily metabolized by cytochrome P450 isoenzyme CYP2D6, agents that inhibit this enzyme, such as imatinib, decrease the metabolism of tramadol. Concomitant use of these agents and tramadol may increase plasma levels of tramadol and decrease concentration of the active metabolite leading to decreased analgesic effects and possibly increased side effects due to higher tramadol concentrations.
    Alfentanil: (Moderate) Alfentanil is metabolized by the cytochrome P450 3A4 isoenzyme present in the liver. Inhibitors of CYP3A4, such as imatinib, may decrease systemic clearance of alfentanil leading to increased or prolonged effects.
    Alfuzosin: (Moderate) Alfuzosin is primarily metabolized by CYP3A4 hepatic enzymes; inhibitors of CYP3A4, such as imatinib, are expected to inhibit alfuzosin metabolism and increase systemic exposure to alfuzosin.
    Aliskiren; Amlodipine: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as imatinib, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when imatinib is coadministered with amlodipine; therapeutic response should be monitored.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as imatinib, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when imatinib is coadministered with amlodipine; therapeutic response should be monitored.
    Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Alprazolam: (Major) In patients taking CYP3A inhibitors such as imatinib, STI-571 use alprazolam with caution and consider alprazolam dose reduction (up to 50% dose reduction may be needed).
    Amiodarone: (Moderate) Consider serial measurement of amiodarone serum concentration during concomitant use of imatinib. Concurrent use may increase amiodarone exposure. Higher antiarrhythmic plasma concentrations increase the potential risk of QT prolongation, torsade de pointes (TdP) or other proarrhythmias. Amiodarone is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor.
    Amitriptyline: (Major) Imatinib is a potent inhibitor of CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme, such as the tricyclic antidepressants (TCAs). An increase in serum concentrations may increase the risk for TCA-related side effects, such as constipation, dizziness, difficulty with urination, xerostomia, fast or irregular heartbeat, and very rarely, QT prolongation.
    Amitriptyline; Chlordiazepoxide: (Major) Imatinib is a potent inhibitor of CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme, such as the tricyclic antidepressants (TCAs). An increase in serum concentrations may increase the risk for TCA-related side effects, such as constipation, dizziness, difficulty with urination, xerostomia, fast or irregular heartbeat, and very rarely, QT prolongation. (Moderate) CYP3A4 inhibitors, such as imatinib, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
    Amlodipine: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as imatinib, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when imatinib is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Atorvastatin: (Major) The risk of developing myopathy during therapy with atorvastatin, a CYP3A4 substrate, is increased if coadministered with imatinib, STI-571, a CYP3A4 inhibitor. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and imatinib, STI-571 therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as imatinib, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when imatinib is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Benazepril: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as imatinib, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when imatinib is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as imatinib, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when imatinib is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as imatinib, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when imatinib is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Olmesartan: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as imatinib, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when imatinib is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Telmisartan: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as imatinib, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when imatinib is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Valsartan: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as imatinib, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when imatinib is coadministered with amlodipine; therapeutic response should be monitored.
    Amobarbital: (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates.
    Amoxapine: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including amoxapine.
    Amoxicillin; Clarithromycin; Lansoprazole: (Minor) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes and should be used cautiously with CYP3A4 substrates, such as imatinib, due to the potential for reduced metabolism and drug accumulation.
    Amoxicillin; Clarithromycin; Omeprazole: (Minor) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes and should be used cautiously with CYP3A4 substrates, such as imatinib, due to the potential for reduced metabolism and drug accumulation.
    Anagrelide: (Moderate) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Antithrombin III: (Major) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Monitor closely for bleeding.
    Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Apalutamide: (Major) Avoid coadministration of imatinib with apalutamide if possible due to decreased plasma concentrations of imatinib. If concomitant use is unavoidable, increase the dose of imatinib by at least 50%, carefully monitoring clinical response; imatinib doses up to 1,200 mg per day (600 mg twice daily) have been given to patients receiving concomitant strong CYP3A4 inducers. Imatinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer increased imatinib clearance by 3.8-fold, which significantly decreased the mean Cmax and AUC of imatinib.
    Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of imatinib with aprepitant due to substantially increased exposure of aprepitant. Fosaprepitant is rapidly converted to aprepitant; therefore, a similar interaction is likely with imatinib. Imatinib is a moderate CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of another moderate CYP3A4 inhibitor with aprepitant increased the aprepitant AUC by 2-fold.
    Aripiprazole: (Major) Because aripiprazole is metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving inhibitors of both CYP3A4 and CYP2D6 such as imatinib, STI-571. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 and CYP2D6 inhibitor.
    Artemether; Lumefantrine: (Moderate) Imatinib, STI-571 is a substrate/inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Imatinib, STI-571 is a substrate/inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates. (Moderate) Concomitant use of codeine with imatinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of imatinib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If imatinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Imatinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Imatinib is an inhibitor of CYP2D6 and may cause increased serum concentrations of dihydrocodeine leading to toxicity. Monitor for enhanced sedation or respiratory depression.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with imatinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of imatinib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If imatinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Imatinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Aspirin, ASA; Dipyridamole: (Moderate) Due to the thrombocytopenic effects of antineoplastics an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Aspirin, ASA; Oxycodone: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including oxycodone.
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with imatinib, STI-571 as there is a potential for elevated imatinib and/or cobicistat concentrations. Imatinib is a CYP3A4 substrate and moderate iinhibitor, a weak inhibitor of CYP2D6, and a breast cancer resistance protein (BCRP) substrate. Cobicistat is a strong inhibitor of CYP3A4, a BCRP inhibitor, and a substrate of CYP2D6 and CYP3A4.
    Atomoxetine: (Major) Administer atomoxetine and imatinib, STI-571 with caution. Because atomoxetine is primarily metabolized by CYP2D6, concurrent use of strong CYP2D6 inhibitors such as imatinib may theoretically increase the risk of atomoxetine-induced adverse effects. In children and adolescents up to 70 kg receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers (PMs), atomoxetine should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. In children and adolescents over 70 kg and adults receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers, atomoxetine should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. If concurrent use is necessary, monitor for adverse effects, such as dizziness, drowsiness, nervousness, insomnia, and cardiac effects (e.g., hypertension, increased pulse rate, QT prolongation) during concurrent use.
    Atorvastatin: (Major) The risk of developing myopathy during therapy with atorvastatin, a CYP3A4 substrate, is increased if coadministered with imatinib, STI-571, a CYP3A4 inhibitor. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and imatinib, STI-571 therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Atorvastatin; Ezetimibe: (Major) The risk of developing myopathy during therapy with atorvastatin, a CYP3A4 substrate, is increased if coadministered with imatinib, STI-571, a CYP3A4 inhibitor. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and imatinib, STI-571 therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates.
    Avanafil: (Major) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including imatinib, STI-571, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Bacillus Calmette-Guerin Vaccine, BCG: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Barbiturates: (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates.
    Bedaquiline: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as imatinib, STI-571, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, imatinib may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Severe) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme Coadministration of ergotamine with potent inhibitors of CYP3A4 is considered contraindicated due to the risk of acute ergot toxicity. (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates.
    Bepridil: (Major) Imatinib, STI-571 inhibits cytochrome P450 3A4 and may result in increased levels of bepridil.
    Bicalutamide: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Substances that are potent inhibitors of CYP3A4 activity, such as imatinib, decrease the metabolism of bicalutamide and increase bicalutamide concentrations. This increase may be clinically relevant as adverse reactions to bicalutamide are related to dose and exposure.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering imatinib, STI-571 with boceprevir due to an increased potential for imatinib-related adverse events. If imatinib dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of imatinib and boceprevir. Both imatinib and boceprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4. When used in combination, the plasma concentrations of both medications may be elevated.
    Bortezomib: (Minor) Agents that inhibit cytochrome P450 3A4, such as imatinib, may increase the exposure to bortezomib and increase the risk for toxicity; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with CYP3A4 inhibitors is not known.
    Bosutinib: (Major) Avoid concomitant use of bosutinib and imatinib, STI-571; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
    Brexpiprazole: (Major) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Imatinib, STI-571 is a potent inhibitor of both CYP3A4 and CYP2D6. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. A reduction of the brexpiprazole dose to 25% of the usual dose is also recommended in patients who are poor metabolizers of CYP2D6 and are receiving a strong CYP3A4 inhibitor.
    Brigatinib: (Moderate) Monitor for decreased efficacy of imatinib if coadministration is necessary. Imatinib is a CYP3A substrate and brigatinib induces CYP3A in vitro. Coadministration with a strong CYP3A4 inducer increased oral clearance of imatinib by 3.8-fold, which significantly decreased the mean Cmax and AUC; brigatinib may also decrease imatinib exposure.
    Brimonidine; Timolol: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 2D6 and might decrease the hepatic metabolism of timolol. This interaction may be more pronounced in extensive metabolizers. Clinicians should be alert to exaggerated beta-blocker effects if the timolol is given with these drugs.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of imatinib. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; imatinib is a moderate inhibitor of CYP3A4. Administration of bromocriptine with a moderate inhibitor of CYP3A4 increased the bromocriptine mean AUC and Cmax by 3.7-fold and 4.6-fold, respectively.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Bupivacaine Liposomal: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as imatinib, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Bupivacaine: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as imatinib, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine-related toxicity when administering with imatinib; lidocaine exposure may increase. Imatinib is a moderate CYP3A4 inhibitor; lidocaine is a CYP3A4 substrate. (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as imatinib, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Buprenorphine: (Major) Since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a CYP3A4 inhibitor such as imatinib, STI-571 may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
    Buprenorphine; Naloxone: (Major) Since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a CYP3A4 inhibitor such as imatinib, STI-571 may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
    Buspirone: (Moderate) CYP3A4 inhibitors, such as imatinib, may decrease systemic clearance of buspirone leading to increased or prolonged effects. If buspirone is to be administered concurrently with significant CYP3A4 inhibitors, a low dose of buspirone is recommended initially.
    Butabarbital: (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates.
    Caffeine; Ergotamine: (Severe) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme Coadministration of ergotamine with potent inhibitors of CYP3A4 is considered contraindicated due to the risk of acute ergot toxicity.
    Carbamazepine: (Major) Carbamazepine is a substrate and inducer of CYP3A4. Imatinib, STI-571 is a substrate and inhibitor of CYP3A4. A complex interaction could occur if these drugs are coadministered. Carbamazepine metabolism could be decreased, resulting in increased concentrations; closely monitor concentrations and reduce the dose if necessary. Metabolism of imatinib could be increased, resulting in decreased concentrations and clinical effects; closely monitor for efficacy and increase the dose if necessary.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Cariprazine: (Moderate) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Imatinib is a moderate inhibitor of CYP3A4 and may reduce the hepatic metabolism of CYP3A4 substrates, although the impact of moderate CYP3A4 inhibitors on cariprazine metabolism has not been studied. Monitoring for adverse effects, such as CNS effects and extrapyramidal symptoms, is advisable during coadministration.
    Carvedilol: (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including carvedilol. Caution is recommended when administering imatinib with carvedilol.
    Ceritinib: (Moderate) Monitor for imatinib-related adverse reactions if coadministered with ceritinib; imatinib exposure may increase. Ceritinib is a CYP3A4 inhibitor and imatinib is primarily metabolized by CYP3A4.
    Cevimeline: (Moderate) Cevimeline is metabolized by cytochrome P450 3A4 and CYP2D6. Inhibitors of these isoenzymes, such as imatinib, would be expected to lead to an increase in cevimeline plasma concentrations.
    Chlordiazepoxide: (Moderate) CYP3A4 inhibitors, such as imatinib, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
    Chlordiazepoxide; Clidinium: (Moderate) CYP3A4 inhibitors, such as imatinib, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with imatinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of imatinib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If imatinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Imatinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Chlorpheniramine; Dextromethorphan: (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Imatinib is an inhibitor of CYP2D6 and may cause increased serum concentrations of dihydrocodeine leading to toxicity. Monitor for enhanced sedation or respiratory depression.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Imatinib is an inhibitor of CYP2D6 and may cause increased serum concentrations of dihydrocodeine leading to toxicity. Monitor for enhanced sedation or respiratory depression.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Cilostazol: (Major) Imatinib is a potent inhibitor of cytochrome P450 (CYP) 3A4 and may increase concentrations of other drugs metabolized by this enzyme, inlcuding cilostazol. Consider up to a 50% reduction in cilostazol dosage when coadministered with imatinib. The combination may also cause an additive risk of bleeding.
    Cimetidine: (Minor) Imatinib, STI-571 is metabolized by cytochrome P450 3A4, which can be inhibited by cimetidine. During concurrent use, clinicians should be aware of the potential increase risk of imatinib toxicity.
    Ciprofloxacin: (Moderate) Increased imatinib serum levels and toxicity may result with concurrent use of ciprofloxacin. Close monitor patients for any signs of toxicity, such as meylosuppression, fluid retention, and bleeding. Ciprofloxacin may inhibit the metabolism of imatinib via CYP3A4 inhibition.
    Cisapride: (Severe) Imatinib is a potent inhibitor of cytochrome P450 CYP 3A4 and may increase concentrations of cisapride if coadministered. Increased concentrations of cisapride have lead to QT prolongation and ventricular arrhythmias, including torsade de pointes and death. Because of the potential severity of this drug interaction, imatinib should not be used with cisapride.
    Clarithromycin: (Minor) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes and should be used cautiously with CYP3A4 substrates, such as imatinib, due to the potential for reduced metabolism and drug accumulation.
    Clindamycin: (Moderate) Concomitant use of clindamycin and imatinib may decrease clindamycin clearance and increase the risk of adverse reactions. Clindamycin is a CYP3A4 substrate; imatinib is a moderate inhibitor of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    Clomipramine: (Major) Imatinib is a potent inhibitor of CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme, such as the tricyclic antidepressants (TCAs). An increase in serum concentrations may increase the risk for TCA-related side effects, such as constipation, dizziness, difficulty with urination, xerostomia, fast or irregular heartbeat, and very rarely, QT prolongation.
    Clonazepam: (Moderate) CYP3A4 inhibitors, such as imatinib, may reduce the metabolism of clonazepam and increase the potential for benzodiazepine toxicity.
    Clopidogrel: (Moderate) The therapeutic effectiveness of clopidogrel should be monitored when used concomitantly with imatinib. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps. The CYP3A4 isoenzyme is involved in one of the metabolic steps. Imatinib is an inhibitor of CYP3A4 and may decrease the hepatic metabolism of clopidogrel to its active metabolite.
    Clorazepate: (Moderate) Imatinib, STI-571 may inhibit the metabolism of clorazepate and leading to increased levels and potential toxicity. Monitor patients closely who receive concurrent therapy.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. Additionally, clozapine is a CYP2D6 substrate and imatinib, STI-571 is a potent inhibitor of CYP2D6, Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP2D6 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with imatinib, STI-571 as there is a potential for elevated imatinib and/or cobicistat concentrations. Imatinib is a CYP3A4 substrate and moderate iinhibitor, a weak inhibitor of CYP2D6, and a breast cancer resistance protein (BCRP) substrate. Cobicistat is a strong inhibitor of CYP3A4, a BCRP inhibitor, and a substrate of CYP2D6 and CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with imatinib, STI-571 as there is a potential for elevated imatinib and/or cobicistat concentrations. Imatinib is a CYP3A4 substrate and moderate iinhibitor, a weak inhibitor of CYP2D6, and a breast cancer resistance protein (BCRP) substrate. Cobicistat is a strong inhibitor of CYP3A4, a BCRP inhibitor, and a substrate of CYP2D6 and CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with imatinib, STI-571 as there is a potential for elevated imatinib and/or cobicistat concentrations. Imatinib is a CYP3A4 substrate and moderate iinhibitor, a weak inhibitor of CYP2D6, and a breast cancer resistance protein (BCRP) substrate. Cobicistat is a strong inhibitor of CYP3A4, a BCRP inhibitor, and a substrate of CYP2D6 and CYP3A4.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with chronic imatinib, STI-571 therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of imatinib is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of imatinib, resume cobimetinib at the previous dose. Use an alternative to imatinib in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a CYP3A substrate in vitro, and imatinib is a moderate inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
    Codeine: (Moderate) Concomitant use of codeine with imatinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of imatinib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If imatinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Imatinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with imatinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of imatinib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If imatinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Imatinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with imatinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of imatinib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If imatinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Imatinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with imatinib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of imatinib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If imatinib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Imatinib is a moderate inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and imatinib unless the use of both agents is imperative. Imatinib can inhibit colchicine's metabolism via CYP3A4, resulting in increased colchicine exposure. If coadministration cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken a moderate CYP3A4 inhibitor like imatinib in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg twice daily or 0.6 mg once daily or if the original dose is 0.6 mg once daily, decrease the dose to 0.3 mg once daily; for treatment of gout flares, give 1.2 mg as a single dose and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed 1.2 mg/day.
    Conivaptan: (Major) Avoid concomitant use of conivaptan, a strong CYP3A4 inhibitor and a sensitive CYP3A4 substrate, and imatinib, STI-571, a CYP3A4 substrate and moderate CYP3A4 inhibitor. Coadministration may result in elevated concentrations of conivaptan and/or imatinib, STI-571. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Conjugated Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as imatinib, STI-571 may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Conjugated Estrogens; Bazedoxifene: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as imatinib, STI-571 may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Conjugated Estrogens; Medroxyprogesterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as imatinib, STI-571 may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Crizotinib: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with imatinib is necessary. Crizotinib is a CYP3A substrate and imatinib is a moderate CYP3A inhibitor.
    Cyclobenzaprine: (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including cyclobenzaprine.
    Cyclophosphamide: (Moderate) Use caution if cyclophosphamide is used concomitantly with imatinib and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide, including neutropenia, neurotoxicity, and risk of infection. Imatinib is a moderate 3A4 inhibitor; conversion of cyclophosphamide to its active metabolites or to its neurotoxic metabolites may be affected. The significance of this potential interaction is not clear given the complexity of cyclophosphamide pharmacokinetics. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional CYP450 enzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites of cyclophosphamide are then inactivated by aldehyde dehydrogenase-mediated oxidation.
    Cyclosporine: (Major) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme. Concurrent administration of cyclosporine and imatinib may result in increased concentrations of cyclosporine due to decreased metabolism. Monitoring of cyclosporine concentrations is warranted.
    Dabigatran: (Major) Due to the thrombocytopenic effects of imatinib, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Monitor closely for bleeding.
    Daclatasvir: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with imatinib, a moderate CYP3A4 inhibitor, may increase daclatasvir. In addition, the therapeutic effects of imatinib, a substrate for the breast cancer resistant protein (BCRP), may be increased by daclatasvir, a BCRP inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Dalfopristin; Quinupristin: (Moderate) Dalfopristin; quinupristin is a major inhibitor of cytochrome P450 3A4 and may decrease the elimination of drugs metabolized by this enzyme including imatinib.
    Dalteparin: (Major) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Monitor closely for bleeding.
    Danaparoid: (Major) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Monitor closely for bleeding.
    Dapagliflozin; Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and imatinib, STI-571 are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as imatinib, STI-571.
    Dapsone: (Minor) Imatinib, STI-571 may inhibit the metabolism of dapsone and leading to increased levels and potential toxicity. Monitor patients closely who receive concurrent therapy.
    Darifenacin: (Moderate) Clinicians should monitor patients for increased anticholinergic effects when CYP2D6 inhibitors, such as imatinib, are coadministered with darifenacin; the dosage of darifenacin should be adjusted, if necessary.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with imatinib, STI-571 as there is a potential for elevated imatinib and/or cobicistat concentrations. Imatinib is a CYP3A4 substrate and moderate iinhibitor, a weak inhibitor of CYP2D6, and a breast cancer resistance protein (BCRP) substrate. Cobicistat is a strong inhibitor of CYP3A4, a BCRP inhibitor, and a substrate of CYP2D6 and CYP3A4.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with imatinib, STI-571 as there is a potential for elevated imatinib and/or cobicistat concentrations. Imatinib is a CYP3A4 substrate and moderate iinhibitor, a weak inhibitor of CYP2D6, and a breast cancer resistance protein (BCRP) substrate. Cobicistat is a strong inhibitor of CYP3A4, a BCRP inhibitor, and a substrate of CYP2D6 and CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Coadministration of dasabuvir and imatinib may result in increased plasma concentrations of dasabuvir and/or imatinib. Dasabuvir is a CYP3A substrate and a BCRP inhibitor; imatinib is a moderate CYP3A4 inhibitor and a BCRP substrate. (Moderate) Coadministration of paritaprevir and imatinib may result in increased plasma concentrations of paritaprevir and/or imatinib. Paritaprevir is a CYP3A substrate and a BCRP inhibitor; imatinib is a moderate CYP3A4 inhibitor and a BCRP substrate.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with imatinib. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; imatinib is a moderate inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
    Delavirdine: (Moderate) Coadministration may result in elevated plasma concentrations of both drugs. Imatinib is a CYP3A4 substrate and moderate CYP3A4 inhibitor. Delavirdine is a CYP3A4 substrate and strong CYP3A4 inhibitor.
    Desipramine: (Major) Imatinib is a potent inhibitor of CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme, such as the tricyclic antidepressants (TCAs). An increase in serum concentrations may increase the risk for TCA-related side effects, such as constipation, dizziness, difficulty with urination, xerostomia, fast or irregular heartbeat, and very rarely, QT prolongation.
    Desirudin: (Major) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Monitor closely for bleeding.
    Dexamethasone: (Minor) Any drug that induces cytochrome P450 3A4, such as dexamethasone, may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Dextromethorphan: (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Dextromethorphan; Guaifenesin: (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Dextromethorphan; Promethazine: (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Dextromethorphan; Quinidine: (Major) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may inhibit quinidine metabolism leading to increased concentrations and risk of adverse reactions. (Minor) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including dextromethorphan.
    Diazepam: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including diazepam.
    Diclofenac: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Diclofenac; Misoprostol: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Dienogest; Estradiol valerate: (Minor) As imatinib inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Imatinib is an inhibitor of CYP2D6 and may cause increased serum concentrations of dihydrocodeine leading to toxicity. Monitor for enhanced sedation or respiratory depression.
    Dihydroergotamine: (Severe) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme Coadministration of ergotamine with potent inhibitors of CYP3A4 is considered contraindicated due to the risk of acute ergot toxicity.
    Diltiazem: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including diltiazem.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Diphenhydramine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Diphenhydramine; Naproxen: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Dipyridamole: (Moderate) Due to the thrombocytopenic effects of antineoplastics an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Disopyramide: (Major) Imatinib is a potent inhibitor of cytochrome P450 CYP 3A4. Disopyramide is a CYP3A4 substrate and coadministration with imatinib may increase serum plasma concentrations of disopyramide.
    Docetaxel: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including docetaxel.
    Dofetilide: (Major) Imatinib could significantly inhibit the CYP3A4 metabolism of dofetilide. The resultant increase in serum dofetilide concentrations could increase the risk of torsade de pointes.
    Dolutegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering imatinib, STI-571 with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Imatinib is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Donepezil: (Moderate) Imatinib, STI-571 is a potent inhibitor of CYP3A4 and 2D6, the two isoenzymes involved in the metabolism of donepezil. The clinical effect of these interactions on the response to donepezil have not been determined.
    Donepezil; Memantine: (Moderate) Imatinib, STI-571 is a potent inhibitor of CYP3A4 and 2D6, the two isoenzymes involved in the metabolism of donepezil. The clinical effect of these interactions on the response to donepezil have not been determined.
    Dorzolamide; Timolol: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 2D6 and might decrease the hepatic metabolism of timolol. This interaction may be more pronounced in extensive metabolizers. Clinicians should be alert to exaggerated beta-blocker effects if the timolol is given with these drugs.
    Doxepin: (Major) Imatinib is a potent inhibitor of CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme, such as the tricyclic antidepressants (TCAs). An increase in serum concentrations may increase the risk for TCA-related side effects, such as constipation, dizziness, difficulty with urination, xerostomia, fast or irregular heartbeat, and very rarely, QT prolongation.
    Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, such as imatinib, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy.
    Doxorubicin: (Major) Imatinib, STI-571 is an inhibitor of CYP2D6 and CYP3A4; doxorubicin is a major CYP2D6 and CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6 and/or CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of imatinib and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Dronabinol: (Major) Use caution if coadministration of dronabinol with imatinib is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Concomitant use may result in elevated plasma concentrations of dronabinol. Dronabinol is a 3A4 substrate; imatinib is a moderate inhibitor of 3A4.
    Drospirenone; Estradiol: (Minor) As imatinib inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Dutasteride: (Moderate) Monitor for common side effects of dutasteride, such as libido decrease, breast tenderness, or erectile dysfunction when chronic, potent inhibitors of CYP3A4 like imatinib are used concomitantly. The effect of potent CYP3A4 inhibitors on the metabolism of dutasteride has not been studied. However, because dutasteride is metabolized by CYP3A4 and CYP3A5 isoenzymes, chronic coadministration with potent CYP3A4 enzyme inhibitors may result in elevated concentrations of dutasteride.
    Dutasteride; Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of imatinib, STI-571. Tamsulosin is extensively metabolized by CYP2D6 and CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Therefore, concomitant use with drugs that inhibit both CYP2D6 and CYP3A4, such as imatinib, STI-571, should be avoided. (Moderate) Monitor for common side effects of dutasteride, such as libido decrease, breast tenderness, or erectile dysfunction when chronic, potent inhibitors of CYP3A4 like imatinib are used concomitantly. The effect of potent CYP3A4 inhibitors on the metabolism of dutasteride has not been studied. However, because dutasteride is metabolized by CYP3A4 and CYP3A5 isoenzymes, chronic coadministration with potent CYP3A4 enzyme inhibitors may result in elevated concentrations of dutasteride.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to immunosuppressant drugs like imatinib. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Efavirenz: (Moderate) Due to the complex interaction that may occur between efavirenz and imatinib, STI-571, close monitoring of the antiviral and antineoplastic responses are recommended. Efavirenz is a CYP3A4 inducer and imatinib is a CYP3A4 inhibitor; both drugs are metabolized by this enzyme. Although no specific studies have been conducted, caution is recommended when administering these drugs together.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Due to the complex interaction that may occur between efavirenz and imatinib, STI-571, close monitoring of the antiviral and antineoplastic responses are recommended. Efavirenz is a CYP3A4 inducer and imatinib is a CYP3A4 inhibitor; both drugs are metabolized by this enzyme. Although no specific studies have been conducted, caution is recommended when administering these drugs together.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Due to the complex interaction that may occur between efavirenz and imatinib, STI-571, close monitoring of the antiviral and antineoplastic responses are recommended. Efavirenz is a CYP3A4 inducer and imatinib is a CYP3A4 inhibitor; both drugs are metabolized by this enzyme. Although no specific studies have been conducted, caution is recommended when administering these drugs together.
    Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with imatinib, STI-571 may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Imatinib is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. In addition, imatinib is a substrate for the breast cancer resistance protein (BCRP), while both elbasvir and grazoprevir are BCRP inhibitors. If these drugs are used together, closely monitor for signs of hepatotoxicity.
    Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with imatinib. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A4, and imatinib is a moderate CYP3A4 inhibitor. Coadministration of other moderate CYP3A4 inhibitors increased the eletriptan AUC by 2 to 4-fold.
    Eliglustat: (Major) Coadministration of imatinib, STI-571 and eliglustat is contraindicated in extensive and intermediate CYP2D6 metabolizers (EMs or IMs) and not recommended in CYP26 poor metabolizers (PMs). Imatinib is an inhibitor of both CYP2D6 and CYP3A4. Eliglustat is a CYP2D6 and CYP3A substrate that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Coadministration of imatinib and eliglustat may result in significantly increased plasma concentrations of eliglustat, increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
    Eltrombopag: (Moderate) Use caution and monitor for adverse reactions if eltrombopag and imatinib, STI-571 are coadministered. Eltrombopag is an inhibitor of Breast Cancer Resistance Protein (BCRP). Drugs that are substrates for this transporter, such as imatinib, may exhibit an increase in systemic exposure if coadministered with eltrombopag.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering imatinib, STI-571 with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Imatinib is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Close clinical monitoring is advised when administering imatinib, STI-571 with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Imatinib is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Enalapril; Felodipine: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including felodipine.
    Encainide: (Severe) Encainide is significantly metabolized by CYP2D6 isoenzymes. Caution is recommended when administering encainide with CYP2D6 inhibitors, such as imatinib, since encainide exhibits a narrow therapeutic range and large increases in serum concentrations may be associated with severe adverse reactions.
    Encorafenib: (Major) Avoid coadministration of encorafenib and imatinib due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of imatinib. If imatinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of imatinib. Encorafenib is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Enoxaparin: (Major) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Monitor closely for bleeding.
    Enzalutamide: (Major) Avoid coadministration of imatinib with enzalutamide if possible due to decreased plasma concentrations of imatinib. If concomitant use is unavoidable, increase the dose of imatinib by at least 50%, carefully monitoring clinical response; imatinib doses up to 1,200 mg per day (600 mg twice daily) have been given to patients receiving concomitant strong CYP3A4 inducers. Imatinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer increased imatinib clearance by 3.8-fold, which significantly decreased the mean Cmax and AUC of imatinib.
    Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Imatinib is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Eptifibatide: (Moderate) Due to the thrombocytopenic effects of antineoplastics an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Ergoloid Mesylates: (Severe) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme Coadministration of ergotamine with potent inhibitors of CYP3A4 is considered contraindicated due to the risk of acute ergot toxicity.
    Ergonovine: (Severe) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme Coadministration of ergotamine with potent inhibitors of CYP3A4 is considered contraindicated due to the risk of acute ergot toxicity.
    Ergot alkaloids: (Severe) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme Coadministration of ergotamine with potent inhibitors of CYP3A4 is considered contraindicated due to the risk of acute ergot toxicity.
    Ergotamine: (Severe) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme Coadministration of ergotamine with potent inhibitors of CYP3A4 is considered contraindicated due to the risk of acute ergot toxicity.
    Erythromycin: (Moderate) Any agent that inhibits cytochrome P450 3A4, such as erythromycin, may decrease the metabolism of imatinib and increase imatinib concentrations leading to an increased incidence of adverse reactions.
    Erythromycin; Sulfisoxazole: (Moderate) Any agent that inhibits cytochrome P450 3A4, such as erythromycin, may decrease the metabolism of imatinib and increase imatinib concentrations leading to an increased incidence of adverse reactions.
    Esomeprazole; Naproxen: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Estazolam: (Moderate) Imatinib is a CYP3A4 inhibitor and may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity.
    Esterified Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as imatinib, STI-571 may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Esterified Estrogens; Methyltestosterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as imatinib, STI-571 may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) As imatinib inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol: (Minor) As imatinib inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Levonorgestrel: (Minor) As imatinib inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Norethindrone: (Minor) As imatinib inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Norgestimate: (Minor) As imatinib inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estropipate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as imatinib, STI-571 may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Eszopiclone: (Moderate) Although data are not available, CYP3A4 inhibitors, such as imatinib, may decrease systemic clearance of eszopiclone leading to prolonged effects. If eszopiclone is to be administered concurrently with significant CYP3A4 inhibitors, a decreased dose of eszopiclone may be warranted. Subsequent dosage adjustments should be based on clinical response.
    Ethinyl Estradiol; Etonogestrel: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as imatinib may increase the serum concentration of etonogestrel.
    Etodolac: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as etodolac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Etonogestrel: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as imatinib may increase the serum concentration of etonogestrel.
    Etoposide, VP-16: (Major) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with imatinib, STI-571. Imatinib is an inhibitor of CYP3A4 and etoposide, VP-16 is a CYP3A4 substrate. Coadministration may increase etoposide concentrations.
    Etravirine: (Moderate) Monitor for evidence of increased etravirine-related adverse effects if coadministered with imatinib. Etravirine exposure may be increased during concurrent use. Etravirine is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor.
    Everolimus: (Major) A dose adjustment of everolimus is necessary when prescribed with imatinib due to increased plasma concentrations of everolimus. For patients with breast cancer, neuroendocrine tumors, renal cell carcinoma, and renal angiolipoma with tubular sclerosis complex (TSC), reduce the dose of Afinitor to 2.5 mg once daily; consider increasing the dose to 5 mg based on patient tolerance. If imatinib is discontinued, increase everolimus to its original dose after 3 days. For patients with subependymal giant cell astrocytoma (SEGA) with TSC or TSC-associated partial-onset seizures, reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. If imatinib is discontinued, increase everolimus to its original dose after 3 days. Zortress dosing for prophylaxis of organ rejection should be guided by TDM. Everolimus is a CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor.
    Ezetimibe; Simvastatin: (Major) Imatinib, STI-571 inhibits the metabolism of simvastatin via CYP3A4. Concurrent use of simvastatin and imatinib resulted in 2- and 3.5-fold increases in simvastatin Cmax and AUC values, respectively. Increases in serum concentrations of simvastatin may lead to myopathy and rhabdomyolysis.
    Famotidine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Felodipine: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including felodipine.
    Fenoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as fenoprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Fentanyl: (Moderate) Concurrent use of fentanyl with imatinib may increase the risk of increased fentanyl-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of fentanyl until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of imatinib in a patient taking fentanyl may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to fentanyl. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Fentanyl is a substrate for CYP3A4, and imatinib is an inhibitor of CYP3A4.
    Fesoterodine: (Moderate) Fesoterodine is rapidly hydrolyzed to its active metabolite, 5-hydroxymethyltolterodine, which is metabolized via hepatic CYP3A4. Imatinib, STI-571, a potent inhibitor of CYP3A4 and CYP2D6, may impair both CYP metabolic pathways of 5-hydroxymethyltolterodine. Fesoterodine doses greater than 4 mg/day are not recommended during concurrent use of potent 3A4 inhibitors.
    Flecainide: (Major) Flecainide is significantly metabolized by CYP2D6 isoenzymes. Caution is recommended when administering flecainide with CYP2D6 inhibitors including imatinib; flecainide exhibits a narrow therapeutic range and large increases in serum concentrations may be associated with severe adverse reactions.
    Flibanserin: (Severe) The concomitant use of flibanserin and moderate CYP3A4 inhibitors, such as imatinib, STI-571, is contraindicated. Moderate CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a moderate CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a moderate CYP3A4 inhibitor following flibanserin use, start the moderate CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
    Fluconazole: (Moderate) Fluconazole may inhibit the metabolism of imatinib, STI-571 via cytochrome P450 3A4. Increased imatinib serum levels and toxicity may result with concurrent use of fluconazole. Close monitor patients for any signs of toxicity.
    Fluoxetine: (Moderate) Agents that inhibit cytochrome P450 3A4, such as fluoxetine, may decrease imatinib, STI-571 metabolism and increase concentrations leading to toxicity.
    Fluoxetine; Olanzapine: (Moderate) Agents that inhibit cytochrome P450 3A4, such as fluoxetine, may decrease imatinib, STI-571 metabolism and increase concentrations leading to toxicity.
    Flurazepam: (Moderate) Imatinib, STI-571 may inhibit the metabolism of flurazepam and leading to increased levels and potential toxicity. Monitor patients closely who receive concurrent therapy.
    Flurbiprofen: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as flurbiprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Fluvastatin: (Moderate) Monitor for evidence of fluvastatin-related toxicity including myopathy and rhabdomyolysis if fluvastatin is coadministered with imatinib. Concurrent use may result in clinically significant increased levels of fluvastatin. Imatinib is a moderate CYP3A4 inhibitor; fluvastatin is a CYP3A4 substrate.
    Fondaparinux: (Major) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Monitor closely for bleeding.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with imatinib, STI-571. Imatinib is an inhibitor of CYP2C9 and CYP3A4, two isoenzymes responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with imatinib the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Fostamatinib: (Moderate) Monitor for imatinib toxicities that may require imatinib dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a BCRP substrate may increase the concentration of the BCRP substrate. The active metabolite of fostamatinib, R406, is a BCRP inhibitor; imatinib is a substrate for BCRP. Coadministration of fostamatinib with another BCRP substrate increased the substrate AUC by 95% and Cmax by 88%.
    Galantamine: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including galantamine.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and imatinib as coadministration may increase serum concentrations of imatinib and increase the risk of adverse effects. Imatinib is a substrate of the breast cancer resistance protein (BCRP) transporter; glecaprevir is an inhibitor of BCRP. (Moderate) Caution is advised with the coadministration of pibrentasvir and imatinib as coadministration may increase serum concentrations of imatinib and increase the risk of adverse effects. Imatinib is a substrate of the breast cancer resistance protein (BCRP) transporter; pibrentasvir is an inhibitor of BCRP.
    Glimepiride: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like imatinib. Monitor serum glucose concentrations if glimepiride is coadministered with imatinib. Dosage adjustments may be necessary.
    Glimepiride; Pioglitazone: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like imatinib. Monitor serum glucose concentrations if glimepiride is coadministered with imatinib. Dosage adjustments may be necessary.
    Glimepiride; Rosiglitazone: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like imatinib. Monitor serum glucose concentrations if glimepiride is coadministered with imatinib. Dosage adjustments may be necessary.
    Grapefruit juice: (Major) Any agent that inhibits cytochrome P450 CYP 3A4, such as grapefruit juice, may decrease the metabolism of imatinib and increase imatinib concentrations leading to an increased incidence of adverse reactions. Monitor patient closely.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Guanfacine: (Major) Imatinib may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon imatinib discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and imatinib is a moderate CYP3A4 inhibitor.
    Halofantrine: (Moderate) Drugs which significantly inhibit cytochrome CYP3A4, may lead to an inhibition of halofantrine metabolism, placing the patient at risk for halofantrine cardiac toxicity. If concurrent use of halofantrine and a CYP3A4 inhibitor is warranted, it would be prudent to use caution and monitor the ECG periodically.
    Haloperidol: (Moderate) Imatinib, STI-571 is an inhibitor of CYP2D6 and CYP3A4, the isoenzymes responsible for the metabolism of haloperidol. Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and inhibitors of CYP3A4 or CYP2D6. Until more data are available, it is advisable to closely monitor for adverse events when these medications are co-administered.
    Heparin: (Major) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. The manufacturer recommends that patients who require anticoagulation while receiving imatinib should receive low-molecular weight heparin or standard heparin instead of warfarin.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Hydrochlorothiazide, HCTZ; Losartan: (Minor) Imatinib, STI-571 is a potent inhibitor of the hepatic CYP2C9 isoenzyme and may inhibit the conversion of losartan to its more active metabolite E-3174. Monitor patients response to therapy closely if imatinib is added or discontinued in a patient receiving losartan.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration. A dosage reduction for metoprolol may be needed based on response. Concurrent use may increase metoprolol exposure. Metoprolol is a CYP2D6 substrate; imatinib is a moderate CYP2D6 inhibitor. In the presence of another moderate CYP2D6 inhibitor, the AUC of metoprolol was increased by 3.29-fold with no effect on the cardiovascular response to metoprolol.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Propranolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as imatinib, could theoretically impair propranolol metabolism; the clinical significance of such interactions is unknown.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Hydrocodone; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with imatinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of imatinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If imatinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Imatinib is a moderate inhibitor of CYP3A4 and is also an inhibitor of CYP2D6.
    Ibrutinib: (Major) If coadministered with imatinib, reduce the ibrutinib dose to 280 mg/day PO for the treatment of B-cell malignancies. Resume ibrutinib at the previous dose if imatinib is discontinued. Initiate ibrutinib at the recommended dose of 420 mg/day PO for the treatment of chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); interruption of ibrutinib therapy or a dose reduction may be necessary in patients who develop severe toxicity. Ibrutinib is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ibuprofen; Oxycodone: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding. (Moderate) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including oxycodone.
    Ibuprofen; Pseudoephedrine: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with imatinib, STI-571, a CYP3A substrate, as imatinib, STI-571 toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with imatinib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Imatinib is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Imipramine: (Major) Imatinib is a potent inhibitor of CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme, such as the tricyclic antidepressants (TCAs). An increase in serum concentrations may increase the risk for TCA-related side effects, such as constipation, dizziness, difficulty with urination, xerostomia, fast or irregular heartbeat, and very rarely, QT prolongation.
    Indomethacin: (Major) An increased risk of bleeding may occur when NSAIDs, such as indomethacin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Interferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b; Ribavirin: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfacon-1: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Intranasal Influenza Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with imatinib, STI-571 may result in increased serum concentrations of both drugs. Imatinib is a substrate and inhibitor of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Any drug that induces cytochrome P450 CYP3A4 may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with rifamycins. The dosage of imatinib should be increased by at least 50% and clinical response closely monitored in patients concurrently receiving a potent cytochrome P450 inducer such as rifamycins.
    Isoniazid, INH; Rifampin: (Major) Any drug that induces cytochrome P450 CYP3A4 may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with rifamycins. The dosage of imatinib should be increased by at least 50% and clinical response closely monitored in patients concurrently receiving a potent cytochrome P450 inducer such as rifamycins.
    Isradipine: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including isradipine.
    Itraconazole: (Moderate) Use caution if coadministration of itraconazole and imatinib is necessary due to increased imatinib exposure and adverse effects. Imatinib is a CYP3A4 and breast cancer resistance protein (BCRP) substrate; and itraconazole is a BCRP inhibitor and strong CYP3A4 inhibitor. Coadminsitration of another CYP3A4 inhibitor increased imatinib exposure by 40%.
    Ivabradine: (Major) Avoid coadministration of ivabradine and imatinib, STI-571 as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; imatinib inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ivacaftor: (Major) If imatinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and imatinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with imatinib due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
    Ixabepilone: (Major) Ixabepilone is a CYP3A4 substrate, and concomitant use of ixabepilone with strong CYP3A4 inhibitors such as imatinib, STI-571 should be avoided. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. If concurrent treatment with a strong CYP3A4 inhibitor is necessary, strongly consider an ixabepilone dose reduction. Closely monitor patients for ixabepilone-related toxicities. If a strong CYP3A4 inhibitor is discontinued, allow 7 days to elapse before increasing the ixabepilone dose.
    Ketoconazole: (Major) Agents that inhibit cytochrome P450 3A4, such as ketoconazole, decrease imatinib, STI-571 metabolism and increase concentrations leading to toxicity. There was a significant increase in imatinib Cmax and AUC (26% and 40%, respectively) in healthy subjects when imatinib was given with a single dose of ketoconazole.
    Ketoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ketoprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ketorolac: (Major) An increased risk of bleeding may occur when NSAIDs, such as ketorolac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Lansoprazole; Naproxen: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Lapatinib: (Moderate) Imatinib, an inhibitor of CYP3A4, may increase the serum concentrations of lapatinib. Use lapatinib and imatinib together with caution, and monitor patients closely.
    Lesinurad: (Moderate) Use lesinurad and imatinib, STI-571 together with caution; imatinib may increase the systemic exposure of lesinurad. Imitinab is an inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
    Lesinurad; Allopurinol: (Moderate) Use lesinurad and imatinib, STI-571 together with caution; imatinib may increase the systemic exposure of lesinurad. Imitinab is an inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
    Letermovir: (Moderate) Plasma concentrations of imatinib could be significantly elevated when administered concurrently with letermovir. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. If these drugs are given together, closely monitor for imatinib-related adverse events. Imatinib is primarily metabolized by CYP3A4. Letermovir is a moderate inhibitor of CYP3A4; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor significantly increased the mean Cmax and AUC of imatinib by 26% and 40%, respectively.
    Levobupivacaine: (Minor) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including levobupivacaine.
    Levomethadyl: (Major) Imatinib inhibits hepatic cytochrome P450 CYP3A4 and may decrease the metabolism of levomethadyl, increase levomethadyl levels, and may precipitate severe arrhythmias including torsade de pointes.
    Lidocaine: (Moderate) Monitor for lidocaine-related toxicity when administering with imatinib; lidocaine exposure may increase. Imatinib is a moderate CYP3A4 inhibitor; lidocaine is a CYP3A4 substrate.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Lomitapide: (Severe) Concomitant use of imatinib, STI-571 and lomitapide is contraindicated. If treatment with imatinib is unavoidable, lomitapide should be stopped during the course of treatment. Imatinib is a moderate CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor. Although concomitant use of moderate CYP3A4 inhibitors with lomitapide has not been studied, a significant increase in lomitapide exposure is likely during concurrent use.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4 and CYP2D6 substrate, may be increased when administered concurrently with imatinib, STI-571, an inhibitor of CYP3A4 and CYP2D6. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4 and CYP2D6 substrate, may be increased when administered concurrently with imatinib, STI-571, an inhibitor of CYP3A4 and CYP2D6. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Losartan: (Minor) Imatinib, STI-571 is a potent inhibitor of the hepatic CYP2C9 isoenzyme and may inhibit the conversion of losartan to its more active metabolite E-3174. Monitor patients response to therapy closely if imatinib is added or discontinued in a patient receiving losartan.
    Lovastatin: (Major) Imatinib, STI-571 is a potent inhibitor of the cytochrome P450 3A4 isoenzyme. Concurrent use of lovastatin and imatinib may result in increased levels of lovastatin and potential toxicity. Concurrent use of simvastatin and imatinib resulted in 2- and 3.5-fold increases in simvastatin Cmax and AUC values, respectively.
    Lovastatin; Niacin: (Major) Imatinib, STI-571 is a potent inhibitor of the cytochrome P450 3A4 isoenzyme. Concurrent use of lovastatin and imatinib may result in increased levels of lovastatin and potential toxicity. Concurrent use of simvastatin and imatinib resulted in 2- and 3.5-fold increases in simvastatin Cmax and AUC values, respectively.
    Lumacaftor; Ivacaftor: (Major) Concomitant use of lumacaftor; ivacaftor and imatinib should be avoided; if coadministration is necessary, increase the imatinib dosage by at least 50% and monitor clinical response closely. The net effect of lumacaftor; ivacaftor is strong CYP3A induction; imatinib is a CYP3A4 substrate and a moderate CYP3A4 inhibitor. Dosage adjustment of lumacaftor; ivacaftor is not required. Coadministration of other strong CYP3A inducers have decreased imatinib exposure (AUC) by 73% and 30%, respectively. (Major) If imatinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and imatinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Lumacaftor; Ivacaftor: (Major) Concomitant use of lumacaftor; ivacaftor and imatinib should be avoided; if coadministration is necessary, increase the imatinib dosage by at least 50% and monitor clinical response closely. The net effect of lumacaftor; ivacaftor is strong CYP3A induction; imatinib is a CYP3A4 substrate and a moderate CYP3A4 inhibitor. Dosage adjustment of lumacaftor; ivacaftor is not required. Coadministration of other strong CYP3A inducers have decreased imatinib exposure (AUC) by 73% and 30%, respectively.
    Lurasidone: (Major) Imatinib is a moderate inhibitor of CYP3A4 and has the potential for interactions with substrates of CYP3A4 such as lurasidone. Concurrent use of these medications may lead to an increased risk of lurasidone-related adverse reactions. If a moderate inhibitor of CYP3A4 is being prescribed and lurasidone is added in an adult patient, the recommended starting dose of lurasidone is 20 mg/day and the maximum recommended daily dose of lurasidone is 80 mg/day. If a moderate CYP3A4 inhibitor is added to an existing lurasidone regimen, reduce the lurasidone dose to one-half of the original dose. Patients should be monitored for efficacy and toxicity.
    Maprotiline: (Major) Imatinib, STI-571 is a potent inhibitor of CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering imatinib with other CYP2D6 substrates, such as maprotiline, that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions.
    Maraviroc: (Moderate) Use caution if coadministration of maraviroc with imatinib is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A substrate and imatinib is a CYP3A4 inhibitor. Monitor for an increase in adverse effects with concomitant use.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Meclofenamate Sodium: (Major) An increased risk of bleeding may occur when NSAIDs, such as meclofenamate sodium, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Mefenamic Acid: (Major) An increased risk of bleeding may occur when NSAIDs, such as mefenamic acid, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Mefloquine: (Moderate) Mefloquine is metabolized by CYP3A4. Imatinib is an inhibitor of this enzyme and may decrease the clearance of mefloquine and increase mefloquine systemic exposure.
    Meloxicam: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. However, meloxicam may be associated with less risk than other NSAIDs due to its relative minimal platelet inhibitory effects and gastric ulceration or hemorrhagic potential. Monitor closely for bleeding.
    Mephobarbital: (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates.
    Metformin; Repaglinide: (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Imatinib, STI-571 is an inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
    Metformin; Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and imatinib, STI-571 are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as imatinib, STI-571.
    Methadone: (Moderate) The concurrent administration of methadone and inhibitors of cytochrome P450 3A4, such as imatinib, may result in increased concentrations of methadone. Inhibition of methadone metabolism can lead to toxicity including CNS adverse effects and potential for QT prolongation and torsades de pointes when high doses of methadone are used.
    Methamphetamine: (Major) Imatinib is a potent inhibitor of cytochrome P450 (CYP) 2D6 and may increase concentrations of methamphetamine.
    Methohexital: (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates.
    Methylergonovine: (Severe) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme Coadministration of ergotamine with potent inhibitors of CYP3A4 is considered contraindicated due to the risk of acute ergot toxicity.
    Methysergide: (Severe) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme Coadministration of ergotamine with potent inhibitors of CYP3A4 is considered contraindicated due to the risk of acute ergot toxicity.
    Metoprolol: (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration. A dosage reduction for metoprolol may be needed based on response. Concurrent use may increase metoprolol exposure. Metoprolol is a CYP2D6 substrate; imatinib is a moderate CYP2D6 inhibitor. In the presence of another moderate CYP2D6 inhibitor, the AUC of metoprolol was increased by 3.29-fold with no effect on the cardiovascular response to metoprolol.
    Mexiletine: (Major) Because mexiletine is metabolized by CPY 2D6, imatinib, STI-571, a potent inhibitor of cytochrome P450 2D6, might decrease the metabolism of mexiletine. Clinicians should be aware of the potential for severe adverse reactions.
    Midazolam: (Major) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may inhibit midazolam metabolism leading to increased levels and potential toxicity. Monitor patients closely who receive concurrent therapy.
    Mifepristone: (Major) Coadministration of mifepristone, a CYP3A inhibitor, may lead to an increase in serum levels of drugs that are CYP3A4 substrates, such as imatinib, and that have a narrow therapeutic index. The risk for imatinib side effects, such as fluid retention, gastrointestinal or liver toxicity, and/or hematologic toxicity may increase when mifepristone is administered for chronic conditions, such as Cushing's syndrome. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration. Medications that inhibit CYP3A, like imatinib, could increase plasma mifepristone concentrations and dose reduction of mifepristone may be required.
    Mitotane: (Major) Avoid the concomitant use of mitotane with imatinib, STI-571. If coadministration cannot be avoided, the dosage of imatinib should be increased by at least 50% and clinical response closely monitored. Mitotane is a strong CYP3A4 inducer and imatinib is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of imatinib. In a study of healthy volunteers treated with multiple doses of another strong CYP3A inducer, rifampin (600mg), followed by a single dose of imatinib 400mg, oral clearance of imatinib was increased by 3.8-fold, which represents significant mean decreases in Cmax, AUC(0 to 24), and AUC(0 to infinity) by 54%, 68%, and 74%, of the respective values without rifampin treatment.
    Nabumetone: (Moderate) An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. However, nabumetone may be associated with less risk than other NSAIDs due to its relative minimal platelet inhibitory effects and gastric ulceration or hemorrhagic potential. Monitor closely for bleeding.
    Naloxegol: (Major) Avoid concomitant administration of naloxegol and imatinib due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
    Naproxen: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen; Pseudoephedrine: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen; Sumatriptan: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with imatinib, STI-571. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as imatinib, STI-571, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with imatinib, STI-571. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as imatinib, STI-571, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Nefazodone: (Moderate) Inhibitors of cytochrome P450 3A4, such as nefazodone, may decrease metabolism and increase imatinib, STI-571 concentrations leading to adverse reactions. However, interactions have not been studied.
    Neratinib: (Major) Avoid concomitant use of imatinib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as imatinib, STI-571. The plasma concentrations of CYP3A4 substrates can increase when co-administered with netupitant. The inhibitory effect on CYP3A4 can last for multiple days. If coadministration is necessary, use caution and monitor for chemotherapeutic related adverse reactions.
    Nevirapine: (Major) Imatinib, STI-571 is metabolized by CYP3A4. Nevirapine induces CYP3A4. Use caution if these drugs are coadministered; decreased imatinib concentrations should be expected with concurrent use.
    Niacin; Simvastatin: (Major) Imatinib, STI-571 inhibits the metabolism of simvastatin via CYP3A4. Concurrent use of simvastatin and imatinib resulted in 2- and 3.5-fold increases in simvastatin Cmax and AUC values, respectively. Increases in serum concentrations of simvastatin may lead to myopathy and rhabdomyolysis.
    Nicardipine: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including nicardipine.
    Nifedipine: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including nifedipine.
    Nilotinib: (Major) The concomitant use of nilotinib and imatinib resulted in increased levels of both drugs in a phase I study. Both nilotinib and imatinib are a substrates and moderate inhibitors of CYP3A4. Following the administration of nilotinib 400 mg twice daily in combination with imatinib 400 mg once daily or imatinib 400 mg twice daily in a phase I study, the AUC values were increased by 30 to 50% for nilotinib and by about 20% for imatinib. These agents may be used together; monitor patients for nilotinib or imatinib toxicity including QT interval prolongation.
    Nimodipine: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including nimodipine.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with imatinib due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and imatinib is a CYP3A4 inhibitor.
    Nortriptyline: (Major) Imatinib is a potent inhibitor of CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme, such as the tricyclic antidepressants (TCAs). An increase in serum concentrations may increase the risk for TCA-related side effects, such as constipation, dizziness, difficulty with urination, xerostomia, fast or irregular heartbeat, and very rarely, QT prolongation.
    Olaparib: (Major) Avoid coadministration of olaparib with imatinib and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and imatinib is a moderate CYP3A4 inhibitor.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Coadministration of paritaprevir and imatinib may result in increased plasma concentrations of paritaprevir and/or imatinib. Paritaprevir is a CYP3A substrate and a BCRP inhibitor; imatinib is a moderate CYP3A4 inhibitor and a BCRP substrate.
    Oritavancin: (Moderate) Coadministration of oritavancin and imatinib, STI-571 may result in increases or decreases in imatinib exposure and may increase side effects or decrease efficacy of imatinib. Imatinib is primarily metabolized by CYP3A4, but is also metabolized by CYP2D6, CYP2C9, and CYP2C19. Oritavancin weakly induces CYP3A4 and CYP2D6, while weakly inhibiting CYP2C9 and CYP2C19. If these drugs are administered concurrently, monitor the patient for signs of toxicity or lack of efficacy.
    Osimertinib: (Moderate) Monitor for an increase in imatinib-related adverse reactions if coadministration with osimertinib is necessary. Imatinib is a BCRP substrate and osimertinib is a BCRP inhibitor.
    Oxaprozin: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as oxaprozin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Oxybutynin: (Moderate) Oxybutynin is metabolized by CYP3A4. Serum concentrations of oxybutynin may be increased if coadministered with inhibitors of CYP3A4 including imatinib. The manufacturer recommends that caution when oxybutynin is co-administered with CYP3A4 inhibitors.
    Oxycodone: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme including oxycodone.
    Paclitaxel: (Minor) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering imatinib with other CYP3A4 substrates including paclitaxel.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Paricalcitol: (Moderate) Paricalcitol is partially metabolized by CYP3A4. Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as imatinib. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
    Paroxetine: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 2D6, and may theoretically decrease paroxetine metabolism leading to increased adverse reactions.
    Pazopanib: (Moderate) Pazopanib is a weak inhibitor of and substrate for CYP3A4. Imatinib is an inhibitor of and substrate for CYP3A4. Concurrent administration may result in increased pazopanib concentrations and/or increased imatinib, STI-571 concentrations. Dose reduction of pazopanib may be necessary when coadministration of pazopanib and imatinib is required.
    Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentobarbital: (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates.
    Pentosan: (Major) Pentosan is a weak anticoagulant. Pentosan has 1/15 the anticoagulant activity of heparin. An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with pentosan.
    Pergolide: (Severe) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme Coadministration of ergotamine with potent inhibitors of CYP3A4 is considered contraindicated due to the risk of acute ergot toxicity.
    Perindopril; Amlodipine: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as imatinib, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when imatinib is coadministered with amlodipine; therapeutic response should be monitored.
    Perphenazine: (Moderate) Imatinib is a potent inhibitor of cytochrome P4502D6 and might decrease perphenazine metabolism leading to increased adverse reactions.
    Perphenazine; Amitriptyline: (Major) Imatinib is a potent inhibitor of CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme, such as the tricyclic antidepressants (TCAs). An increase in serum concentrations may increase the risk for TCA-related side effects, such as constipation, dizziness, difficulty with urination, xerostomia, fast or irregular heartbeat, and very rarely, QT prolongation. (Moderate) Imatinib is a potent inhibitor of cytochrome P4502D6 and might decrease perphenazine metabolism leading to increased adverse reactions.
    Phenobarbital: (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates.
    Phentermine; Topiramate: (Moderate) Imatinib is a potent inhibitors of cytochrome P450 2C9 and might decrease topiramate metabolism leading to increased topiramate serum concentrations and a risk of adverse reactions.
    Pimozide: (Severe) Concurrent use of pimozide and imatinib, STI-571 should be avoided. Pimozide is metabolized primarily through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. Imatinib, STI-571 is an inhibitor of CYP3A4 and CYP2D6. Elevated pimozide concentrations occurring through inhibition of CYP3A4, CYP2D6, and/or CYP1A2 can lead to QT prolongation, ventricular arrhythmias, and sudden death. Concurrent use of CYP3A4 inhibitors or potent CYP2D6 inhibitors and pimozide is contraindicated by the manufacturer of pimozide.
    Piroxicam: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as piroxicam, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ponatinib: (Moderate) Concomitant use of ponatinib and imatinib may increase the exposure of ponatinib and/or imatinib. Ponatinib is a CYP3A4 substrate and a breast cancer resistance protein (BCRP) inhibitor in vitro; imatinib is a moderate CYP3A4 inhibitor and a BCRP substrate in vitro. The manufacturer recommends a reduced starting ponatinib dose when use of a strong CYP3A4 inhibitor cannot be avoided; however, no dosage guidance is provided for use with moderate CYP3A4 inhibitors.
    Posaconazole: (Moderate) Posaconazole and imatinib, STI-571 should be coadministered with caution due to an increased potential for adverse events. Both posaconazole and imatinib are inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of imatinib. Further, both imatinib and posaconazole are substrates of the drug efflux protein, P-glycoprotein, which when administered together may increase the absorption or decrease the clearance of the other drug. This complex interaction may cause alterations in the plasma concentrations of both posaconazole and imatinib, ultimately resulting in an increased risk of adverse events.
    Prednisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Primidone: (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates.
    Propafenone: (Major) Imatinib is a potent inhibitor of cytochrome P450 2D6 and may increase concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering imatinib with CYP2D6 substrates that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions including propafenone.
    Propoxyphene: (Moderate) Propoxyphene is a substrate and an inhibitor of CYP2D6. Increased serum concentrations of propoxyphene would be expected from concurrent use of a CYP2D6 inhibitor, such as imatinib.
    Propranolol: (Moderate) Propranolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as imatinib, could theoretically impair propranolol metabolism; the clinical significance of such interactions is unknown.
    Protease inhibitors: (Major) Protease Inhibitors inhibit cytochrome P450 CYP3A4 and may decrease the metabolism of imatinib and increase imatinib concentrations leading to an increased incidence of adverse reactions. In addition, because imatinib inhibits CYP2C9, CYP2D6, and CYP3A4/5, the metabolism of protease inhibitors may be decreased by imatinib. Close monitoring of the antiviral and antineoplastic responses is recommended.
    Protriptyline: (Major) Imatinib is a potent inhibitor of CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme, such as the tricyclic antidepressants (TCAs). An increase in serum concentrations may increase the risk for TCA-related side effects, such as constipation, dizziness, difficulty with urination, xerostomia, fast or irregular heartbeat, and very rarely, QT prolongation.
    Quazepam: (Moderate) CYP3A4 inhibitors, such as imatinib, may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity.
    Quetiapine: (Moderate) The cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine. Imatinib, STI-571 may increase plasma concentrations of quetiapine through CYP3A4 inhibition. The manufacturer of quetiapine recommends a reduced dosage during concurrent administration of CYP3A4 inhibitors.
    Quinidine: (Major) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 3A4 and may inhibit quinidine metabolism leading to increased concentrations and risk of adverse reactions.
    Ramelteon: (Moderate) Coadministration of ramelteon with inhibitors of CYP3A4, such as imatinib, may lead to increases in the serum concentrations of ramelteon.
    Ranolazine: (Severe) Ranolazine is metabolized mainly by CYP3A. According to the manufacturer, ranolazine is contraindicated in patients receiving drugs known to be strong CYP3A inhibitors. Inhibition of ranolazine metabolism could lead to increased ranolazine plasma concentrations and associated QTc prolongation. Although not specifically mentioned by the manufacturer of ranolazine, imatinib, STI-571 is known to be a strong inhibitor of CYP3A4. In addition, ranolazine is metabolized to a lesser extent by CYP2D6; imatinib, STI-571 is a known CYP2D6 inhibitor.
    Regorafenib: (Moderate) Use caution if coadministration of regorafenib with imatinib, STI-571 is necessary, and monitor for an increase in imatinib- and regorafenib-related adverse reactions. Imatinib is a BCRP substrate and CYP3A4 inhibitor. Regorafenib is metabolized primarily by CYP3A4 and UGT1A9, and it is a BCRP inhibitor. Administration of regorafenib for 14 days prior to a single dose of rosuvastatin, another BCRP substrate, increased the mean AUC and Cmax of rosuvastatin by 3.8-fold and a 4.6-fold, respectively; regorafenib-mediated BCRP inhibition may also increase exposure to imatinib. Ketoconazole, a strong CYP3A4 inhibitor, increased the mean AUC of regorafenib by 33%, and decreased the mean AUC of active metabolites M-2 and M-5 by 93%; information is not available for coadministration of regorafenib with moderate CYP3A4 inhibitors such as imatinib, but regorafenib exposure may increase. Coadministration of imatinib with another CYP3A4 substrate, simvastatin, increased the simvastatin Cmax and AUC by 2-fold and 3.5-fold, respectively. Imatinib is also a CYP2C9 substrate. Regorafenib and active metabolite, M-2, are CYP2C9 inhibitors in vitro. Regorafenib increased the mean AUC of a sensitive CYP2C9 substrate, warfarin, by 25% (n = 8); this may also affect exposure to imatinib.
    Repaglinide: (Moderate) Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Imatinib, STI-571 is an inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may be necessary.
    Ribociclib: (Moderate) Monitor for an increase in imatinib-related adverse reactions if coadministration with ribociclib is necessary. Imatinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased imatinib exposure by 40%.
    Ribociclib; Letrozole: (Moderate) Monitor for an increase in imatinib-related adverse reactions if coadministration with ribociclib is necessary. Imatinib is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased imatinib exposure by 40%.
    Rifabutin: (Major) Any drug that induces cytochrome P450 CYP3A4 may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with rifamycins. The dosage of imatinib should be increased by at least 50% and clinical response closely monitored in patients concurrently receiving a potent cytochrome P450 inducer such as rifamycins.
    Rifampin: (Major) Any drug that induces cytochrome P450 CYP3A4 may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with rifamycins. The dosage of imatinib should be increased by at least 50% and clinical response closely monitored in patients concurrently receiving a potent cytochrome P450 inducer such as rifamycins.
    Rifamycins: (Major) Any drug that induces cytochrome P450 CYP3A4 may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with rifamycins. The dosage of imatinib should be increased by at least 50% and clinical response closely monitored in patients concurrently receiving a potent cytochrome P450 inducer such as rifamycins.
    Rifapentine: (Major) Any drug that induces cytochrome P450 CYP3A4 may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with rifamycins. The dosage of imatinib should be increased by at least 50% and clinical response closely monitored in patients concurrently receiving a potent cytochrome P450 inducer such as rifamycins.
    Rilpivirine: (Moderate) Close clinical monitoring is advised when administering imatinib, STI-571 with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Imatinib is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Rivaroxaban: (Major) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Coadministration of rivaroxaban and imatinib, STI-571 may also result in increases in rivaroxaban exposure, which may increase bleeding risk. Imatinib is an inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Rolapitant: (Moderate) Monitor for imatinib-related adverse reactions if coadministration of these drugs is required. Imatinib is a substrate of the breast cancer resistance protein (BCRP) transporter; rolapitant is a BCRP inhibitor.
    Romidepsin: (Moderate) Romidepsin is a substrate for CYP3A4. Imatinib, STI-571 is an inhibitor of CYP3A4. Concurrent administration of romidepsin with an inhibitor of CYP3A4 may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Rotavirus Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rufinamide: (Minor) Rufinamide is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as imatinib, STI-571, may occur during concurrent use with rufinamide.
    Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as imatinib, STI-571, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Safinamide: (Moderate) Safinamide at the 100 mg dose and its major metabolite may inhibit intestinal breast cancer resistance protein (BCRP), which could increase plasma concentrations of BCRP substrates such as imatinib. Monitor patients for increased pharmacologic or adverse effects of BCRP substrates during concurrent use of safinamide, particularly the 100 mg dose.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and imatinib, STI-571 as coadministration may result in increased systemic exposure of imatinib. Imatinib is a substrate for the drug transporter breast cancer resistance protein (BCRP); in vitro data show that sapropterin may inhibit BCRP in the gut at the therapeutic doses. If these drugs are used together, closely monitor for increased side effects of imatinib.
    Saxagliptin: (Minor) Monitor patients for hypoglycemia if saxagliptin and imatinib, STI-571 are used together. The metabolism of saxagliptin is primarily mediated by CYP3A4/5; saxagliptin plasma concentrations may increase in the presence of moderate CYP 3A4/5 inhibitors such as imatinib, STI-571.
    Secobarbital: (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates.
    Sertraline: (Major) Sertraline is a substrate for the CYP isoenzymes 3A4, 2D6 and 2C19. Imatinib is a potent inhibitor of cytochrome P450 2D6 and 3A4 and might decrease sertraline metabolism leading to increased adverse reactions.
    Sibutramine: (Major) Avoid concomitant use of imatinib, a strong CYP3A inhibitor, with sibutramine, a CYP3A substrate. Strong CYP3A4 inhibitors may moderately increase sibutramine Cmax and AUC, which might increase the risk for sibutramine-related side effects.
    Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with imatinib is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor.
    Silodosin: (Moderate) Silodosin is extensively metabolized by hepatic cytochrome P450 3A4. In theory, drugs that inhibit CYP3A4 such as imatinib, STI-571 may cause significant increases in silodosin plasma concentrations.
    Simeprevir: (Major) Avoid the concomitant use of simeprevir and imatinib; increased plasma concentration of simeprevir and/or imatinib may occur. Simeprivir is CYP3A4 substrate and a breast cancer resistance protein (BCRP) inhibitor; imatinib is a moderate CYP3A4 inhibitor and a BCRP substrate.
    Simvastatin: (Major) Imatinib, STI-571 inhibits the metabolism of simvastatin via CYP3A4. Concurrent use of simvastatin and imatinib resulted in 2- and 3.5-fold increases in simvastatin Cmax and AUC values, respectively. Increases in serum concentrations of simvastatin may lead to myopathy and rhabdomyolysis.
    Simvastatin; Sitagliptin: (Major) Imatinib, STI-571 inhibits the metabolism of simvastatin via CYP3A4. Concurrent use of simvastatin and imatinib resulted in 2- and 3.5-fold increases in simvastatin Cmax and AUC values, respectively. Increases in serum concentrations of simvastatin may lead to myopathy and rhabdomyolysis.
    Sirolimus: (Minor) Imatinib is a potent inhibitor of cytochrome P450 CYP3A4 and may increase concentrations of other drugs metabolized by this enzyme including sirolimus.
    Smallpox Vaccine, Vaccinia Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with imatinib. Taking these medications together may increase the plasma concentrations of imatinib, potentially resulting in adverse events. Imatinib is a substrate for the drug transporter Breast Cancer Resistance Protein (BCRP). Velpatasvir is an inhibitor of BCRP.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concurrent administration of voxilaprevir and imatinib. Taking these medications together may increase the plasma concentrations of imatinib, potentially resulting in adverse events. Imatinib is a substrate for the drug transporter Breast Cancer Resistance Protein (BCRP). Voxilaprevir is an inhibitor of BCRP. (Moderate) Use caution when administering velpatasvir with imatinib. Taking these medications together may increase the plasma concentrations of imatinib, potentially resulting in adverse events. Imatinib is a substrate for the drug transporter Breast Cancer Resistance Protein (BCRP). Velpatasvir is an inhibitor of BCRP.
    Solifenacin: (Moderate) Solifenacin is significantly metabolized via the CYP3A4 pathway. Patients receiving CYP3A4 inhibitors, such as imatinib, should not receive solifenacin doses greater than 5 mg per day. Patients should be monitored for increased anticholinergic effects.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and imatinib, STI-571; sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
    St. John's Wort, Hypericum perforatum: (Major) Drugs that are inducers of CYP3A4 activity, such as St. John's wort, will decrease the plasma concentrations of imatinib, STI-571 (CYP3A4 substrate). St. John's wort has been found to reduce imatinib AUC and maximum concentrations by roughly 30%, which could lead to loss of imatinib efficacy. In patients receiving imatinib, St. John's wort should be avoided.
    Streptogramins: (Moderate) Dalfopristin; quinupristin is a major inhibitor of cytochrome P450 3A4 and may decrease the elimination of drugs metabolized by this enzyme including imatinib.
    Sufentanil: (Moderate) Sufentanil is metabolized by the cytochrome P450 CYP3A4 isoenzyme. Agents that inhibit CYP3A4 activity, such as imatinib, may decrease systemic clearance of sufentanil leading to increased or prolonged effects.
    Sulindac: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as sulindac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Suvorexant: (Major) A dose reduction to 5 mg of suvorexant is recommended during concurrent use with imatinib. The suvorexant dose may be increased to 10 mg if needed for efficacy. Suvorexant is a CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased the suvorexant AUC by 2-fold.
    Tacrolimus: (Major) Tacrolimus is metabolized via the hepatic cytochrome P-450 CYP3A4. Drugs that inhibit this isoenzyme, such as imatinib, can decrease the metabolism of tacrolimus. Subsequent increased whole blood concentrations of tacrolimus may lead to nephrotoxicity or other side effects.
    Tadalafil: (Major) Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as imatinib, STI-571, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the 'as needed' dose for erectile dysfunction should not exceed 10 mg within a 72 hour time period, and the 'once-daily' dose for erectile dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4. When used for pulmonary arterial hypertension, tadalafil should not be co-administered with potent CYP3A inhibitors.
    Tamoxifen: (Major) Concomitant use of imatinib and tamoxifen may result decreased concentrations of the active metabolites of tamoxifen, which may compromise efficacy. Monitor patients for increased imatinib side effects and changes in the therapeutic effect of tamoxifen. Imatinib, STI-571 is a CYP2D6 and CYP3A4 inhibitor. Tamoxifen is metabolized by CYP3A4, CYP2D6, and to a lesser extent by both CYP2C9 and CYP2C19, to other potent, active metabolites including endoxifen, which have up to 33 times more affinity for the estrogen receptor than tamoxifen. These metabolites are then inactivated by sulfotransferase 1A1 (SULT1A1). Imatinib may inhibit the metabolism of tamoxifen to these metabolites. Some data suggest that the efficacy of tamoxifen is reduced when coadministered with CYP2D6 inhibitors. A trial of 1,298 patients with breast cancer compared the rate of breast cancer recurrence in patients treated with tamoxifen with or without a CYP2D6 inhibitor. Patients who received tamoxifen in combination with a CYP2D6 inhibitor had a significantly higher rate of breast cancer recurrence at 2 years (13.9% v. 7.5%, p < 0.001). A separate observational study of 1,990 patients assessed event free time with adjuvant tamoxifen treatment for breast cancer. Only 215 of these patients were administered a CYP2D6 inhibitor, however no clinically significant differences were observed with the addition of a CYP2D6 inhibitor.
    Tamsulosin: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of imatinib, STI-571. Tamsulosin is extensively metabolized by CYP2D6 and CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Therefore, concomitant use with drugs that inhibit both CYP2D6 and CYP3A4, such as imatinib, STI-571, should be avoided.
    Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and imatinib, STI-571. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as imatinib, may increase exposure to tasimelteon with the potential for adverse reactions.
    Tedizolid: (Moderate) If possible, stop use of imatinib temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for imatinib-associated adverse events. Imatinib, STI-571 plasma concentrations may be increased when administered concurrently with oral tedizolid. Imatinib is a substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering imatinib, STI-571 with telaprevir due to an increased potential for imatinib-related adverse events. If imatinib dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of imatinib and telaprevir. Both imatinib and telaprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4. When used in combination, the plasma concentrations of both medications may be elevated.
    Telithromycin: (Moderate) Concentrations of telithromycin and imatinib, STI-571 may be increased with coadministration, as both agents are CYP3A4 substrates and inhibitors. Additionally, imatninib is a substrate for P-glycoprotein (PGP) and telithromycin is a potential PGP inhibitor. Patients should be monitored for increased side effects.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and imatinib is necessary, as the systemic exposure of imatinib may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of imatinib; consider increasing the dose of imatinib if necessary. Imatinib is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering imatinib, STI-571. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C9 and CYP3A4; imatinib is an inhibitor of these enzymes. Monitor patients for adverse reactions if these drugs are coadministered.
    Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with imatinib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor 100 mg/ivacaftor 150 mg tablet every other day in the morning and 1 ivacaftor 150 mg tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor 150 mg should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); imatinib is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If imatinib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Ivacaftor is a CYP3A substrate and imatinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
    Thiopental: (Major) Barbiturates induce CYP3A4 and may increase the metabolism of imatinib and decrease imatinib concentrations and clinical effects. Caution is recommended when imatinib is given in combination with barbiturates.
    Thioridazine: (Severe) Imatinib, is a potent inhibitor of cytochrome P450 2D6 and may decrease thioridazine metabolism leading to increased adverse reactions. Since this may lead to QT prolongation, the use of these drugs concurrently is not recommended.
    Ticlopidine: (Moderate) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Timolol: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 2D6 and might decrease the hepatic metabolism of timolol. This interaction may be more pronounced in extensive metabolizers. Clinicians should be alert to exaggerated beta-blocker effects if the timolol is given with these drugs.
    Tinzaparin: (Major) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Monitor closely for bleeding.
    Tirofiban: (Moderate) Due to the thrombocytopenic effects of antineoplastics an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Tolbutamide: (Major) Imatinib is a potent inhibitor of cytochrome P450 2C9 and might decrease the metabolism of tolbutamide leading to hypoglycemia. Blood glucose concentration should be monitored in patients requiring concurrent treatment with these agents.
    Tolmetin: (Moderate) An increased risk of bleeding may occur when NSAIDs, such as tolmetin sodium, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Tolterodine: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 CYP2D6 and 3A4. Tolterodine is metabolized primarily by CYP2D6 and alternatively, CYP3A4 in those patients who are poor metabolizers of tolterodine via CYP2D6. It is not known if dosage adjustments are required in patients requiring concurrent therapy, but patients should be monitored for increased anticholinergic effects.
    Tolvaptan: (Major) Avoid coadministration of imatinib when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with imatinib. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Topiramate: (Moderate) Imatinib is a potent inhibitors of cytochrome P450 2C9 and might decrease topiramate metabolism leading to increased topiramate serum concentrations and a risk of adverse reactions.
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and imatinib, STI-571 is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and imatinib is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Tramadol: (Moderate) Since tramadol is primarily metabolized by cytochrome P450 isoenzyme CYP2D6, agents that inhibit this enzyme, such as imatinib, decrease the metabolism of tramadol. Concomitant use of these agents and tramadol may increase plasma levels of tramadol and decrease concentration of the active metabolite leading to decreased analgesic effects and possibly increased side effects due to higher tramadol concentrations.
    Trandolapril; Verapamil: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including verapamil.
    Triazolam: (Major) Triazolam is a primary substrate of CYP3A4, and use with moderate inhibitors of CYP3A4, such as imatinib, may increase systemic exposure to triazolam. Serious adverse effects of triazolam, including significant and prolonged sedation and respiratory depression, are possible.
    Tricyclic antidepressants: (Major) Imatinib is a potent inhibitor of CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme, such as the tricyclic antidepressants (TCAs). An increase in serum concentrations may increase the risk for TCA-related side effects, such as constipation, dizziness, difficulty with urination, xerostomia, fast or irregular heartbeat, and very rarely, QT prolongation.
    Trimetrexate: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may decrease trimetrexate metabolism leading to increased concentrations and toxicity.
    Trimipramine: (Major) Imatinib is a potent inhibitor of CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme, such as the tricyclic antidepressants (TCAs). An increase in serum concentrations may increase the risk for TCA-related side effects, such as constipation, dizziness, difficulty with urination, xerostomia, fast or irregular heartbeat, and very rarely, QT prolongation.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Typhoid Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and imatinib, STI-571 is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
    Vardenafil: (Major) Imatinib is a potent inhibitor of CYP3A4. Vardenafil is metabolized by hepaticCYP3A4 and to a lesser extent CYP2C9. Inhibitors of CYP3A4 can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. In vivo studies report that several strong CYP3A4 inhibitors can significantly increase the AUC and Cmax of vardenafil when coadministered with vardenafil. Vardenafil dose adjustments are required when vardenafil is administered with such agents. The vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, do not use the orally disintegrating tablets with moderate or potent CYP3A4 inhibitors, such as erythromycin. Other potent CYP3A4 inhibitors such as, imatinib, STI-571, would be expected to have effects on vardenafil clearance when coadministered.
    Varicella-Zoster Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and imatinib, STI-571 may result in altered concentrations of imatinib and increased concentrations of vemurafenib. Vemurafenib is a substrate/inducer of CYP3A4, an inhibitor of CYP2C9, and a substrate/inhibitor P-glycoprotein (PGP). Imatinib is a substrate/inhibitor of CYP3A4 and a substrate of CYP2C9 and PGP. Use caution and monitor patients for toxicity and efficacy.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and imatinib, STI-571. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day). If imatinib is discontinued, wait 2 to 3 days, and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. Venetoclax is a substrate of CYP3A4 and imatinib is a moderate CYP3A4 inhibitor.
    Venlafaxine: (Moderate) Imatinib, STI-571 is a potent inhibitor of cytochrome P450 2D6 and might decrease venlafaxine metabolism leading to increased adverse reactions.
    Verapamil: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including verapamil.
    Vinblastine: (Moderate) Use vinblastine and imatinib together with caution; concomitant use may result in increased vinblastine plasma concentrations and increased vinblastine toxicity. Imatinib is a CYP3A4 inhibitor that may increase the plasma concentration of vinblastine, a CYP3A4 substrate.
    Vincristine Liposomal: (Moderate) Imatinib, STI-571, inhibits CYP3A4, and vincristine is a CYP3A substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Vincristine: (Moderate) Imatinib, STI-571, inhibits CYP3A4, and vincristine is a CYP3A substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with imatinib is necessary. Vinorelbine is a CYP3A4 substrate and imatinib is a moderate CYP3A4 inhibitor.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and imatinib. Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with imatinib, STI-571, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Voriconazole: (Moderate) Voriconazole may inhibit the metabolism of imatinib, STI-571 via cytochrome P450 3A4. Increased imatinib serum levels and toxicity may result with concurrent use of voriconazole. Closely monitor patients for any signs of toxicity. In addition, because imatinib inhibits CYP3A4, the metabolism of voriconazole may be decreased by imatinib.
    Warfarin: (Major) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, as well as thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. The manufacturer recommends that patients who require anticoagulation while receiving imatinib should receive low-molecular weight heparin or standard heparin instead of warfarin. Coagulation parameters should be monitored closely if warfarin therapy is continued during imatinib therapy. Imatinib is a moderate inhibitor of cytochrome P450 (CYP) 3A4 and CYP2C9, and therefore has potential to increase serum concentrations of warfarin. Since both imatinib and warfarin are highly protein bound (95% and 99%, respectively), displacement from plasma proteins may also occur. In a phase II trial of imatinib, a patient with Philadelphia positive chronic myelogenous leukemia in chronic phase developed cerebral and urinary tract bleeding while receiving imatinib 400 mg daily in combination with warfarin (dose not available). Although a significantly prolonged prothrombin time may have been the result of an increase in the patient's warfarin dose in the days preceding the bleeding, a drug interaction cannot be excluded.
    Yellow Fever Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Ziprasidone: (Major) Ziprasidone is partially metabolized via the hepatic CYP3A4 isoenzyme system. The concurrent use of ziprasidone with CYP3A4 inhibitors, such as imatinib, may lead to decreased metabolism of ziprasidone.
    Zolpidem: (Major) It is advisable to closely monitor zolpidem tolerability and safety during co-administration of CYP3A4 inhibitors, such as imatinib, STI-571, and consider using a lower dose of zolpidem to minimize the potential for adverse CNS effects. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.

    PREGNANCY AND LACTATION

    Pregnancy

    Imatinib may cause fetal harm when administered during pregnancy based on human and animal data; postmarketing reports of spontaneous abortions and of infant congenital anomalies have been reported following imatinib use in pregnancy women. Advise females of reproductive potential to avoid pregnancy while taking imatinib. Discuss the potential hazard to the fetus if imatinib is used during pregnancy or if a patient becomes pregnant while taking this drug. In animal studies in rats, imatinib was teratogenic when given during organogenesis at doses approximately equal to the maximum imatinib dose of 800 mg/day based on body surface area.

    According to the manufacturer, women should discontinue breast-feeding during imatinib therapy and for 1 month after the last dose because of the potential for serious adverse reactions in nursing infants. Imatinib and its active metabolite are excreted into human milk. Based on data from three breast feeding women taking imatinib, the milk:plasma ratio is roughly 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and its active metabolite, a breast-fed infant could receive up to 10% of the maternal therapeutic dose based on body weight.

    MECHANISM OF ACTION

    Mechanism of Action: Imatinib is a protein tyrosine kinase inhibitor. Inhibition of the bcr-abl tyrosine kinase results in inhibition of proliferation and induces apoptosis in bcr-able positive cell lines and in fresh leukemic cells from Philadelphia chromosome positive chronic myelogenous leukemia. The activity of protein tyrosine kinases is tightly regulated since they function as mediators of cell growth, differentiation, and death. Numerous protein kinase genes have been identified as oncogenes associated with transforming retroviruses or human tumors. Protein tyrosine kinases are grouped based on structural similarities and cellular function as receptor tyrosine kinases and non-receptor tyrosine kinases. Receptor tyrosine kinases have an extracellular and a cytoplasmic portion. The receptor tyrosine kinases include the receptors for epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), stem-cell factor (SCF), vascular endothelial growth factor (VEGF), and nerve growth factor (NGF). Non-receptor tyrosine kinases lack receptor-like features, but mediate critical cell signals of many cell surface receptors (e.g., growth factor receptor kinases, G-protein coupled receptors, B-cell receptor, T-cell receptor, and interferon gamma receptor). In addition, non-receptor tyrosine kinases interact with other proteins, lipids, and DNA. Non-receptor tyrosine kinases include Scr, the Janus kinases (Jaks), and Abl. Protein tyrosine kinases catalyze the transfer of phosphate from adenosine triphosphate (ATP) to the hydroxyl group of a tyrosine residue in the protein substrate. Imatinib competitively inhibits the ATP binding site on Abl, PDGF, SCF, and c-Kit tyrosine kinases and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells, which express an activating c-kit mutation.Chronic myelogenous leukemia is characterized by a genetic abnormality, the Philadelphia chromosome (Ph), resulting from the reciprocal translocation between the long arms of chromosomes 9 and 22. The resultant fusion protein, bcr-abl, is a constitutively active tyrosine kinase that is responsible for the development of CML. Imatinib causes growth arrest or apoptosis in cells that express bcr-abl but does not affect normal cells. Resistance to imatinib and subsequent disease relapse seem to be associated with a failure to maintain effective inhibition of Bcr-Abl activity. Resistance has been reported due to bcr-abl gene amplification or alteration of the amino acids of bcr-abl resulting in high levels of kinase activity even in the presence of imatinib.

    PHARMACOKINETICS

    Imatinib is administered orally. It is approximately 95% bound to plasma proteins, primarily albumin and a1-acid glycoprotein, at clinically relevant concentrations. Imatinib is metabolized via CYP450 isoenzymes, primarily CYP3A4. Its major active metabolite, N-demethylated piperazine derivative (CGP74588), has similar potency as the parent drug. In healthy volunteers, the elimination half-lives of imatinib CGP74588 were approximately 18 and 40 hours, respectively. In a 50 year old patient, the clearance of imatinib is predicted to be 8 L/hour in patients weighing 50 kg and 14 L/hour in patients weighing 100 kg; this represents an inter-patient variability of about 40%. Following an oral 14C-labeled dose of imatinib, approximately 81% of the dose (feces, 68%; urine, 14%) was eliminated within 7 days. Unchanged imatinib accounted for 25% of the dose (feces, 20%; urine, 5%) with the remainder excreted as metabolites.
     
    Affected cytochrome P450 isoenzymes and transporters: CYP3A4, CYP2D6, BCRP
    Imatinib is primarily metabolized via CYP3A4; it is metabolized via CYP1A2, CYP2D6, CYP2C9, and CYP2C19 to a lesser extent. Avoid the concomitant use of strong CYP3A4 inducers; consider at least a 50% dose increase if coadministration is unavoidable. Use imatinib cautiously in combination with strong CYP3A4 inhibitors. In vitro, imatinib is a potent competitive inhibitor of CYP2C9, CYP2D6, and CYP3A4/5. In drug interaction studies, imatinib was a moderate inhibitor of CYP3A4 and a weak inhibitor of CYP2D6; use caution if imatinib is coadministered with CYP3A4 and CYP2D6 substrates that have a narrow therapeutic index. Imatinib was a substrate for the breast cancer resistance protein (BCRP) transporter in an in vitro study.

    Oral Route

    Imatinib is well absorbed following oral administration; the mean absolute bioavailability is 98%. Peak plasma concentrations are reached within 2 to 4 hours of imatinib dosing. The mean imatinib AUC values increase proportionally over the dose range of 25 to 1,000 mg. When given once daily, imatinib accumulation is 1.5-to 2.5-fold at steady state. The plasma AUC for imatinib’s major active metabolite, N-demethylated metabolite (CGP74588), is about 15% of the AUC value for imatinib.