Oral Anticancer Therapy: Management of Drug Interactions

Britny G. Rogala, PharmD; Margaret M. Charpentier, PharmD; Michelle K. Nguyen, PharmD; Kaitlin M. Landolf, PharmD; Lamya Hamad, RPh; Kelly M. Gaertner, PharmD

Disclosures

J Oncol Pract. 2019;15(2):81-90. 

In This Article

Pharmacodynamic Interactions

QTc Prolongation

Corrected QT interval (QTc) prolongation occurs in approximately 6% of patients with cancer before the initiation of therapy.[7] The incidence of QTc prolongation greater than 500 ms is more commonly reported with targeted therapy than with traditional therapy. Fortunately, the reported incidence of arrhythmia or sudden cardiac death as a result of QTc prolongation is less than 0.1%.[8] Patients with cancer who receive chemotherapy are at risk for electrolyte disturbances leading to QT prolongation, particularly due to the development of mucositis, emesis, diarrhea, or inadequate nutrition. Commonly coprescribed drug classes of greatest QT-prolonging risk include antidepressants, antipsychotics, anti-infectives, high-dose loperamide, select pain medications (ie, buprenorphine, methadone, and tramadol), and antiemetics. Finally, drugs that inhibit the metabolism of oral anticancer therapies can increase the likelihood of QT prolongation.

Patients initiating oral anticancer therapy with the potential to prolong the QT interval (Table 1) should have baseline and follow-up ECGs.[8,9] Electrolyte repletion and discontinuation of concomitant QT-prolonging medications, if possible, will also minimize risks. If, following the initiation of oral anticancer therapy, the patient's QTc interval is greater than 500 ms, or increases by 60 ms from baseline, the offending agent should be discontinued.

Bleeding

Patients with cancer have a four- to eightfold higher risk of venous thromboembolism development compared with the general population.[10,11] This hypercoagulable state in patients with cancer is attributable to factors such as older age, advanced disease, obesity, smoking, poor performance status, major surgery, and certain therapies.[12,13] In addition, patients with cancer have a higher risk for recurrent venous thromboembolism.[13]

Low-molecular-weight heparin is associated with a significantly reduced risk of recurrent venous thromboembolism compared with warfarin and is the preferred strategy for short-term anticoagulation.[12] When lowmolecular- weight heparin is not a viable option for long-term anticoagulation, edoxaban is preferred, and warfarin or other direct oral anticoagulants are reasonable alternatives.

Exposure to direct oral anticoagulants can be altered by pharmacodynamic parameters requiring dose adjustment, including renal and hepatic function, age, and weight.[12] In addition, several pharmacokinetic interactions exist between oral anticoagulants and oral anticancer therapies. All direct oral anticoagulants are metabolized by CYP3A4, P-glycoprotein (Pgp), or both, and require dose adjustment or therapy modification when coadministered with inducers and/or inhibitors of these enzymes.

Warfarin is a major substrate of CYP2C9 and a minor CYP1A2, CYP2C19, and CYP3A4 substrate. Tamoxifen, capecitabine, abiraterone, bicalutamide, ceritinib, dasatinib, gefitinib, and imatinib are CYP2C9/19 and/or CYP3A4 inhibitors that have been documented to increase warfarin exposure. Concomitant use of tamoxifen with warfarin is contraindicated in certain indications. Otherwise, proactive dose reduction of warfarin before tamoxifen initiation can be considered. Warfarin is often avoided in patients taking capecitabine because of the sporadic dosing schedule of capecitabine and less predictable international normalized ratio (INR) changes.[13]

In patients who will be initiating any other oral anticancer therapies that may increase warfarin exposure, careful monitoring of INR until stabilization is recommended. Patients should also receive additional counseling, with special attention given to the signs and symptoms of bleeding. This approach is likely only appropriate for reliable patients who demonstrate thorough understanding of the risks and monitoring.

The use of anticoagulation with ibrutinib remains a controversial topic. Ibrutinib selectively inhibits platelet signaling and glycoprotein VI function, thereby blocking platelet aggregation; thus, ibrutinib independently carries an increased bleeding risk.[14] Before the realization of significant bleeding risks with ibrutinib therapy, clinical trials allowed the use of warfarin concomitantly, but this was limited to a small subset of patients and for a short duration.[15,16]

Minimizing additive bleeding risk factors may help avoid potential risk. A prospective trial in 85 patients receiving ibrutinib revealed that 55% of patients experienced grade 2 or less bleeding over a median follow-up of 24 months.[17] In patients who experienced bleeding, the relative risk of an event for patients taking aspirin, nonsteroidal anti-inflammatory drugs, fish oil, or an anticoagulant was 1.45. Although the increased risk of bleeding was not statistically significant in this trial, an increased risk of bleeding has been previously reported with fish oil, aspirin-containing products, nonsteroidal anti-inflammatory drugs, and anticoagulants, as well as with vitamin E.[18]

For patients requiring anticoagulation, some recommend avoiding warfarin altogether, as a result of negative early trial results.[18] Use of alternative anticoagulation should be performed cautiously, with consideration of availability of reversal agents and data in patients with cancer.

When aspirin therapy is indicated (ie, after a recentmyocardial infarction or stroke), consider use of aspirin 81 mg daily instead of higher doses.[18] At this time, it is recommended to avoid use of ibrutinib with dual antiplatelet therapy and in patients who have a high bleeding-risk.[18,19] In the instance of atrial fibrillation and need for anticoagulation, some recommend calculating the HAS-BLED (hypertension; abnormal renal and liver function; stroke; bleeding; labile INR; elderly; drugs or alcohol) bleeding risk score and avoiding ibrutinib in patients with a score greater than 3.[19] Discontinuation of medications with additive bleeding risks and avoidance of medications that will affect ibrutinib metabolism via CYP3A4 may minimize the bleeding risk associated with ibrutinib.

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