INTERACTIONS
- CYP3A4 inducers may decrease imatinib mesylate tablets Cmax and area under curve (AUC). ( 2.12 , 7.1 , 12.3 )
- CYP3A4 inhibitors may increase imatinib mesylate tablets Cmax and AUC. ( 7.2 , 12.3 )
- Imatinib mesylate tablets are an inhibitor of CYP3A4 and CYP2D6 which may increase the Cmax and AUC of other drugs. ( 7.3 , 7.4 , 12.3 )
- Patients who require anticoagulation should receive low-molecular weight or standard heparin and not warfarin. ( 7.3 )
7.1 Agents Inducing CYP3A Metabolism Concomitant administration of imatinib mesylate tablets and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .
7.2 Agents Inhibiting CYP3A Metabolism Concomitant administration of imatinib mesylate tablets and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .
7.3 Interactions With Drugs Metabolized by CYP3A4 Imatinib mesylate tablets will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering imatinib mesylate tablets with CYP3A4 substrates that have a narrow therapeutic window. Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .
7.4 Interactions With Drugs Metabolized by CYP2D6 Use caution when administering imatinib mesylate tablets with CYP2D6 substrates that have a narrow therapeutic window.
Drug Interactions Agents
Inducing CYP3A Metabolism Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of imatinib mesylate tablets, increased imatinib mesylate tablets oral-dose clearance by 3.8-fold, which significantly (p less than 0.05) decreased mean C max and AUC. Similar findings were observed in patients receiving 400 to 1200 mg/day imatinib mesylate tablets concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the patients receiving EIAED’s decreased by 73% compared to patients not receiving EIAED. Concomitant administration of imatinib mesylate tablets and St. John’s Wort led to a 30% reduction in the AUC of imatinib. Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other CYP3A4 inducers are indicated. Imatinib mesylate tablets doses up to 1,200 mg/day (600 mg twice daily) have been given to patients receiving concomitant strong CYP3A4 inducers [see Dosage and Administration (2.12) ] .
Agents
Inhibiting CYP3A Metabolism There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40%, respectively) in healthy subjects when imatinib mesylate tablets were coadministered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering imatinib mesylate tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice may also increase plasma concentrations of imatinib and should be avoided. Interactions with Drugs Metabolized by CYP3A4 Imatinib mesylate tablets increase the mean C max and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by imatinib mesylate tablets. Particular caution is recommended when administering imatinib mesylate tablets with CYP3A4 substrates that have a narrow therapeutic window (e.g., alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, or tacrolimus). Imatinib mesylate tablets will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin. Interactions with Drugs Metabolized by CYP2D6 Imatinib mesylate tablets increased the mean C max and AUC of metoprolol by approximately 23% suggesting that imatinib mesylate tablets have a weak inhibitory effect on CYP2D6-mediated metabolism. No dose adjustment is necessary, however, caution is recommended when administering imatinib mesylate tablets with CYP2D6 substrates that have a narrow therapeutic window. Interactions with Acetaminophen In vitro, imatinib mesylate tablets inhibit the acetaminophen O-glucuronidate pathway (K i 58.5 μM). Coadministration of imatinib mesylate tablets (400 mg/day for 8 days) with acetaminophen (1,000 mg single dose on Day 8) in patients with CML did not result in any changes in the pharmacokinetics of acetaminophen. Imatinib mesylate tablets pharmacokinetics were not altered in the presence of single-dose acetaminophen. There is no pharmacokinetic or safety data on the concomitant use of imatinib mesylate tablets at doses greater than 400 mg/day or the chronic use of concomitant acetaminophen and imatinib mesylate tablets.
AND PRECAUTIONS Fluid Retention and Edema: Edema and severe fluid retention have occurred. Weigh patients regularly and manage unexpected rapid weight gain by drug interruption and diuretics. ( 5.1 , 6.1 )
Hematologic
Toxicity: Cytopenias, particularly anemia, neutropenia, and thrombocytopenia, have occurred. Manage with dose reduction, dose interruption, or discontinuation of treatment. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter. ( 5.2 )
Congestive Heart
Failure and Left Ventricular Dysfunction: Severe congestive heart failure and left ventricular dysfunction have been reported, particularly in patients with comorbidities and risk factors. Monitor and treat patients with cardiac disease or risk factors for cardiac failure. ( 5.3 ) Hepatotoxicity: Severe hepatotoxicity, including fatalities may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. ( 5.4 ) Hemorrhage: Grade 3/4 hemorrhage has been reported in clinical studies in patients with newly diagnosed CML and with GIST. GI tumor sites may be the source of GI bleeds in GIST. ( 5.5 )
Gastrointestinal
Disorders: Gastrointestinal (GI) perforations, some fatal, have been reported. ( 5.6 )
Hypereosinophilic Cardiac
Toxicity: Cardiogenic shock/left ventricular dysfunction has been associated with the initiation of Imkeldi in patients with conditions associated with high eosinophil levels (e.g., HES, MDS/MPD, and ASM). ( 5.7 )
Dermatologic
Toxicities: Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have been reported with the use of Imkeldi. ( 5.8 ) Hypothyroidism: Hypothyroidism has been reported in thyroidectomy patients undergoing levothyroxine replacement. Closely monitor TSH levels in such patients. ( 5.9 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus, and to use effective contraception. ( 5.10 , 8.1 )
Growth
Retardation in Children and Adolescents: Growth retardation occurring in children and pre-adolescents receiving Imkeldi has been reported. Close monitoring of growth in children under Imkeldi treatment is recommended. ( 5.11 , 6.2 )
Tumor Lysis
Syndrome: Close monitoring is recommended. ( 5.12 )
Impairments
Related to Driving and Using Machinery: Motor vehicle accidents have been reported in patients receiving imatinib. Caution patients about driving a car or operating machinery. ( 5.13 )
Renal
Toxicity: A decline in renal function may occur in patients receiving Imkeldi. Evaluate renal function at baseline and during therapy, with attention to risk factors for renal dysfunction. ( 5.14 )
Measuring
Device: Advise patients to measure IMKELDI with an accurate milliliter measuring device. Inform patients that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions. Advise patients to ask their pharmacist to recommend an appropriate press-in bottle adapter and oral dispensing syringe and for instructions for measuring the correct dose. ( 5.15 )
5.1 Fluid Retention and Edema Imatinib can cause edema and occasionally serious fluid retention <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Weigh and monitor patients regularly for signs and symptoms of fluid retention. Investigate unexpected rapid weight gain carefully and provide appropriate treatment. The probability of edema was increased with higher imatinib dose and age greater than 65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking imatinib, and in 2% to 6% of other adult CML patients taking imatinib. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking imatinib, and in 2% to 6% of other adult CML patients taking imatinib. Severe fluid retention was reported in 9% to 13.1% of patients taking imatinib for GIST <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib and nilotinib, severe (Grade 3 or 4) fluid retention occurred in 2.5% of patients receiving imatinib and in 3.9% of patients receiving nilotinib 300 mg twice daily. Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema were observed in 2.1% (none were Grade 3 or 4) of patients in the imatinib arm and 2.2% (0.7% Grade 3 or 4) of patients in the nilotinib 300 mg twice daily arm.
5.2 Hematologic Toxicity Treatment with imatinib can cause anemia, neutropenia, and thrombocytopenia. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2 to 3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias, including neutropenia, thrombocytopenia, and anemia. These generally occur within the first several months of therapy <span class="opacity-50 text-xs">[see Dosage and Administration (2.14) ]</span>.
5.3 Congestive Heart Failure and Left Ventricular Dysfunction Congestive heart failure and left ventricular dysfunction have been reported in patients taking imatinib. Cardiac adverse reactions were more frequent in patients with advanced age or co-morbidities, including previous medical history of cardiac disease. In an international randomized Phase 3 study in 1106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking imatinib compared to 0.9% of patients taking IFN + Ara-C. In another randomized trial with newly diagnosed Ph+ CML patients in chronic phase that compared imatinib and nilotinib, cardiac failure was observed in 1.1% of patients in the imatinib arm and 2.2% of patients in the nilotinib 300 mg twice daily arm and severe (Grade 3 or 4) cardiac failure occurred in 0.7% of patients in each group. Carefully monitor patients with cardiac disease or risk factors for cardiac or history of renal failure. Evaluate and treat any patient with signs or symptoms consistent with cardiac or renal failure.
5.4 Hepatotoxicity Hepatotoxicity, occasionally severe, may occur with Imkeldi <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of imatinib. Monitor liver function (transaminases, bilirubin, and alkaline phosphatase) before initiation of treatment and monthly, or as clinically indicated. Manage laboratory abnormalities with Imkeldi interruption and/or dose reduction <span class="opacity-50 text-xs">[see Dosage and Administration (2.13) ]</span>. When imatinib is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended.
5.5 Hemorrhage In a trial of imatinib versus IFN+Ara-C in patients with the newly diagnosed CML, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies, 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study, 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib and nilotinib, GI hemorrhage occurred in 1.4% of patients in the imatinib arm, and in 2.9% of patients in the nilotinib 300 mg twice daily arm. None of these events were Grade 3 or 4 in the imatinib arm; 0.7% were Grade 3 or 4 in the nilotinib 300 mg twice daily arm. In addition, gastric antral vascular ectasia has been reported in postmarketing experience.
5.6 Gastrointestinal Disorders Imatinib can cause GI irritation. Imkeldi should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of GI perforation.
5.7 Hypereosinophilic Cardiac Toxicity In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of Imkeldi therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Imkeldi. Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Consider performing an echocardiogram and determining serum troponin in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, consider prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Imkeldi at the initiation of therapy.
5.8 Dermatologic Toxicities Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of imatinib. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon rechallenge. Several foreign postmarketing reports have described cases in which patients tolerated the reintroduction of imatinib therapy after resolution or improvement of the bullous reaction. In these instances, imatinib was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.
5.9 Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib. Monitor TSH levels in such patients.
5.10 Embryo-Fetal Toxicity Imkeldi can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area (BSA). Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on BSA. Advise females of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using Imkeldi and for 14 days after stopping Imkeldi. Advise pregnant women of the potential risk to a fetus <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span> .
5.11 Growth Retardation in Children and Adolescents Growth retardation has been reported in children and pre-adolescents receiving imatinib. The long-term effects of prolonged treatment with Imkeldi on growth in children are unknown. Therefore, monitor growth in children under Imkeldi treatment <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>.
5.12 Tumor Lysis Syndrome Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL, and eosinophilic leukemia receiving imatinib. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. Monitor these patients closely and take appropriate precautions. Due to possible occurrence of TLS, correct clinically significant dehydration and treat high uric acid levels prior to initiation of Imkeldi.
5.13 Impairments Related to Driving and Using Machinery Motor vehicle accidents have been reported in patients receiving imatinib. Advise patients that they may experience side effects, such as dizziness, blurred vision, or somnolence during treatment with Imkeldi. Recommend caution when driving a car or operating machinery.
5.14 Renal Toxicity A decline in renal function may occur in patients receiving Imkeldi. Median estimated glomerular filtration rate (eGFR) values in patients on imatinib 400 mg daily for newly-diagnosed CML (four randomized trials) and malignant GIST (one single-arm trial) declined from a baseline value of 85 mL/min/1.73 m 2 (N = 1190) to 75 mL/min/1.73 m 2 at 12 months (N = 1082) and 69 mL/min/1.73 m 2 at 60 months (N = 549). Evaluate renal function prior to initiating Imkeldi and monitor during therapy, with attention to risk factors for renal dysfunction, such as preexisting renal impairment, diabetes mellitus, hypertension, and congestive heart failure.
5.15 Measuring Device Advise patients to measure Imkeldi with an accurate milliliter measuring device. Inform patients that a household teaspoon is not an accurate measuring device and could lead to overdosage, which can result in serious adverse reactions. Advise patients to ask their pharmacist to recommend an appropriate press-in bottle adapter and oral dispensing syringe and for instructions for measuring the correct dose <span class="opacity-50 text-xs">[see Instructions for Use ]</span>.