The patient's list of medications reveals significant drug interactions to be addressed.
Patient Case: LS
LS is a male patient aged 54 years who has been coming to your pharmacy for the past 5 years. He received a diagnosis of stage IIIB colon cancer during a colonoscopy 2 months ago and has now completed surgical resection.
He comes to the pharmacy counter looking for a lotion recommended by his oncology team to prevent palmarplantar erythrodysesthesia, or hand-foot syndrome, an adverse effect (AE) of his chemotherapy. He states he will be initiating an adjuvant treatment in the coming weeks with capecitabine (Xeloda; Genentech, Inc) and oxaliplatin (Eloxatin; Sanofi-Aventis US LLC) in hopes of eliminating any residual disease. He also inquires whether there may be any drug interactions with his current medications list that he should be concerned about.
LS most recently received a diagnosis of stage IIIB colon cancer and previously received diagnoses of gastroesophagealvreflux disease, hypertension, gout, and type 2 diabetes.
LS is taking the proton pump inhibitor (PPI) pantoprazole sodium (Protonix; Pfizer Inc) at 40 mg/d, lisinopril at 20 mg/d, atenolol (Tenormin; Almatica Pharma LLC) at 50 mg/d, naproxen sodium (Aleve; Bayer) at 500 mg/d, allopurinol (Zyloprim; Casper Pharma) at 450 mg/d, and metformin at 500 mg twice a day.
Adjuvant treatment of stage III colon cancer includes 3 to 6 months of a fluoropyrimidine-based chemotherapeutic regimen. Patients with good performance status generally receive either modified FOLFOX-6 (fluorouracil [5-FU], leucovorin, and oxaliplatin on day 1) repeated every 2 weeks or CAPOX (oxaliplatin on day 1 and capecitabine twice daily for 14 days, followed by 7 days off) repeated every 3 weeks.1
Oxaliplatin, which is a platinum-based cytotoxic chemotherapy that inhibits DNA replication and transcription, can have toxicities such as myelosuppression, risks of hypersensitivity reaction, and peripheral sensory neuropathy, which may be transient or permanent.2 Additionally, capecitabine is an oral prodrug of 5-FU that exerts antitumor effects by interfering with DNA and RNA synthesis and inhibition of thymidylate synthase.3 Common AEs associated with use of capecitabine include palmar-plantar erythrodysesthesia, diarrhea, nausea, fatigue, and hyperbilirubinemia.
Palmar-plantar erythrodysesthesia is one of the more common dose-limiting toxicities associated with capecitabine. Presentation varies from mild dryness with or without erythema on palms and/or soles to more severe symptoms, such as significant pain that limits activities of daily living, blisters, edema, hyperkeratosis, and desquamation. To help prevent these symptoms, patients are recommended to avoid exposing their hands and feet to friction and hot temperatures (eg, soaking in hot baths). Additionally, patients are recommended to gently apply emollients to hands and feet several times per day, which should be reinforced with patients at each follow-up. Further, pharmacists should recommend the use of thick, alcohol-free moisturizers to patients, with urea-based creams providing additional benefit for prevention and treatment.4 Lastly, patients should be counseled to report discomfort as soon as it develops to allow for prompt symptom management to minimize the need for dose reduction and/or treatment interruption.
Upon review of LS’s current medication list, the pharmacist observes 2 significant drug interactions. First, allopurinol should not be combined with capecitabine because it may result in the decreased efficacy of capecitabine.3 Capecitabine is an oral prodrug that requires enzymatic metabolism to form 2 active metabolites, 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) and 5-fluorouridine 5'-triphosphate (FUTP). When capecitabine is administered with allopurinol, the conversion of capecitabine to 5-FU and then to FdUMP and FUTP may be reduced via inhibition of phosphorylation.
However, some studies have demonstrated a reduction of 5-FU–associated AEs and an increase in the maximum tolerated doses of capecitabine when administered with allopurinol,5,6 although the clinical impact of this has not been fully characterized. Given the potential for decreased antitumor activity of capecitabine, avoiding use of allopurinol in these patients is recommended.
Furthermore, pharmacists can facilitate discussion between the patient and the prescriber regarding whether allopurinol may be safely interrupted or discontinued for gout prophylaxis or whether gout should be managed with an alternative agent such as febuxostat (Uloric; Takeda Pharmaceuticals America, Inc) or probenecid (Benemid; Lannett Company, Inc). Careful considerations should also be made in patients with preexisting cardiovascular disease because both febuxostat and capecitabine have been associated with an increased risk of cardiovascular events.3,7
The second drug interaction warranting consideration is the coadministration of capecitabine with gastric acid suppression (eg, a PPI). Some evidence suggests that an increase in gastric pH may reduce dissolution and absorption of capecitabine after oral administration.8,9 Although there are no prospective studies adequately evaluating the clinical impact of this potential interaction, several retrospective studies suggest a reduction in progression-free survival and/or overall survival with the combination.8,10
However, a recent study evaluated the probability of this interaction using available retrospective studies and both in vitro and in vivo evidence, with the results showing an overall low probability of a true interaction that would limit the clinical significance in patients receiving palliative chemotherapy.11 Given that the goal of LS’s therapy is to cure, it would be recommended to trial discontinuation of the PPI or to trial the use of an alternative such as short-acting antacids or a histamine-2 receptor antagonist for management of the gastroesophageal reflux disease during the course of adjuvant chemotherapy.
In addition to providing guidance on drug interactions, the pharmacist can support LS in his treatment by reviewing the importance of continued good glycemic control to minimize risk of neuropathy. As described previously, oxaliplatin is commonly associated with peripheral sensory neuropathy that, in some cases, may be permanent and debilitating. This is of particular importance in younger, curative patients who may be saddled with symptoms for the remainder of their lives. A retrospective study demonstrated that the cumulative dose at which patients with diabetes developed peripheral neuropathy was lower compared with patients without diabetes.12 Because of this, LS should be counseled to report neuropathic symptoms such as persistent cold sensitivity, numbness, and tingling to his oncologist.
Summary of Pharmacist's Recommendations for LS
1. NCCN. Clinical Practice Guidelines in Oncology. Colon cancer, Version 2.2021. Accessed June 10, 2022. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
2. Oxaliplatin. Package insert. Cipla Ltd; 2020. Accessed November 11, 2022. https://labeling.pfizer.com/ShowLabeling.aspx?id=4558
3. Capecitabine. Package insert. Genentech USA Inc; 2021. Accessed November 11, 2022. https://www.gene.com/download/pdf/xeloda_prescribing.pdf
4. Kwakman JJM, Elshot YS, Punt CJA, Koopman M. Management of cytotoxic chemotherapy-induced hand-foot syndrome. Oncol Rev. 2020;14(1):442. doi:10.4081/oncol.2020.442
5. Tsavaris N, Karagiaouris P, Vonorta K, et al. Concomitant administration of 4-hydroxypyrazolopyrimidine (allopurinol) and high-dose continuous infusion 5-fluorouracil. Oncology. 1990;47(1):70-74. doi:10.1159/000226788
6. Woolley PV, Ayoob MJ, Smith FP, et al. A controlled trial of the effect of 4-hydroxypyrazolopyrimidine (allopurinol) on the toxicity of a single bolus dose of 5-fluorouracil. J Clin Oncol. 1985;3(1):103-109. doi:10.1200/JCO.19220.127.116.11
7. Febuxosat. Package insert. Takeda Pharmaceuticals; 2021. Accessed November 11, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021856s013lbl.pdf
8. Sun J, Ilich AI, Kim CA, et al. Concomitant administration of proton pump inhibitors and capecitabine is associated with increased recurrence risk in early stage colorectal cancer patients. Clin Colorectal Cancer. 2016;15(3):257-263. doi:10.1016/j.clcc.2015.12.008
9. Sontag SJ. The medical management of reflux esophagitis. role of antacids and acid inhibition. Gastroenterol Clin North Am. 1990;19(3):683-712. doi:10.1016/S0889-8553(21)00664-6
10. Reinhardt HE, Phillips MA, Wade N, Baran A. Evaluation of the clinical impact of concomitant acid suppression in colorectal cancer patients treated with capecitabine monotherapy. J Oncol Pharm Pract. 2019;25(8):1839-1845. doi:10.1177/1078155218818237
11. Cheng V, de Lemos M, Hunter N, Badry N, de Lemos J. Concomitant use of capecitabine and proton pump inhibitors - is it safe? J Oncol Pharm Practice. 2019;25(7):1705-1711. doi:10.1177/1078155219846952
12. Uwah AN, Ackley J, Leighton JC Jr, Pomerantz S, Tester W. The effect of diabetes on oxaliplatin-induced peripheral neuropathy. Clin Colorectal Cancer. 2012;11(4):275-279. doi:10.1016/j.clcc.2012.05.002
About the Author
Michelle Phillips, PharmD, BCOP, is a clinical oncology pharmacy specialist with a focus on gastrointestinal and neuro-oncology at the Wilmot Cancer Institute at the University of Rochester Medical Center in New York.