From Warning to Action: Implementing DPYD Testing Following the FDA-Approved Capecitabine Label Update

In October 2025, the FDA approved an updated label update for capecitabine (Xeloda; Genentech) mandating DPYD genetic testing before initiating treatment, unless urgent. The update emphasizes that patients with complete dihydropyrimidine dehydrogenase (DPD) deficiency are at risk of severe toxicity or death. The label update now requires clinicians to test for DPYD variants in order to identify poor metabolizers (an estimated 7% of people) who break down the drug too slowly, allowing for dose adjustments or alternative treatments.¹

In a Q&A with Pharmacy Times, Serena Mitaly, PharmD, a system clinical pharmacogenomics pharmacist with Ochsner Health, discussed what this label update means for practicing pharmacists and their patients.

Q: Can you explain the clinical rationale behind the FDA’s new boxed warning for capecitabine, and how DPYD testing helps prevent severe fluoropyrimidine toxicity?

Serena Mitaly, PharmD: The new capecitabine boxed warning reflects a growing recognition that severe fluoropyrimidine toxicity is not a random event—it’s often biologically predictable. Fluorouracil (5-FU) and capecitabine remain staples in many cancer regimens, yet a significant portion of patients still experience serious, sometimes life-threatening toxicities early in treatment. A key driver behind these reactions is reduced activity of dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for metabolizing most of the administered drug. When patients carry certain DPYD variants that diminish or eliminate DPD function, their systemic exposure to the drug rises dramatically which can lead to severe and sometimes fatal overdoses.

DPYD testing gives us the ability to identify these patients before therapy begins. Poor metabolizers—those with essentially no DPD activity—should not receive capecitabine or 5-FU because no safe dose has been established. Intermediate metabolizers, who have partial deficiency, can be started at a significantly reduced dose and then titrated as tolerated. Prospective studies have shown that adjusting therapy based on DPYD genotype substantially reduces the risk of severe toxicity and hospitalization without compromising anticancer efficacy. In that sense, the boxed warning reinforces something that Ochsner has felt since our implementation of required DPYD testing in 2022: this isn’t optional anymore; it’s a core patient-safety step.

Q: From a pharmacy operations standpoint, what are the biggest barriers health systems face in implementing DPYD genotyping before therapy, and how can pharmacists help overcome them?

Mitaly: The biggest barriers tend to fall into operational, financial, and cultural categories. One challenge is reimbursement—coverage for pharmacogenomic testing has historically been inconsistent, and health systems often hesitate to absorb the up-front cost even though preventing severe toxicity is ultimately cost-saving. Another challenge is workflow integration. If results aren’t discrete, searchable, and tied to clinical decision support in the electronic medical record, they won’t reliably influence prescribing. There’s also concern among clinicians about potential treatment delays, even though most results come back within a week and can easily be ordered early in the planning phase. And finally, there’s the comfort level issue: many providers simply haven’t felt confident interpreting pharmacogenomic results or fail to see testing as “essential” vs “optional” given lack of strong [National Comprehensive Cancer Network] guidance, despite wide adoption from international regulatory bodies.

Pharmacists are uniquely positioned to tackle each of these barriers. We can help build the business case by illustrating the true downstream costs of unmanaged toxicity, work closely with IT teams to design smart electronic medical record (EMR) alerts and safety checks, and provide education that makes prescribers feel supported rather than overwhelmed. When pharmacists take the lead in designing clear workflows and offering accessible expertise, DPYD testing becomes much easier to operationalize.

Q: How does preemptive DPYD testing impact workflow in oncology pharmacy practice, including treatment initiation timelines and patient counseling?

Mitaly: What we’ve found is that preemptive DPYD testing adds a small step early on but streamlines everything that follows. If the test is ordered at the time the treatment plan is being developed, results are almost always back by the time the first cycle is ready to start, so there’s typically no meaningful delay. In the background, pharmacists verify orders with the support of EMR decision tools that automatically flag patients who require dose reductions or alternative therapy based on their DPYD phenotype.

From a counseling standpoint, preemptive testing actually improves the quality of our conversations with patients. Instead of reacting to toxicity after it occurs, we can explain upfront that we’re using a genetic test to help tailor their chemotherapy dose for safety. When a patient has a decreased-function variant, the conversation shifts from “why are we lowering the dose?” to “we’re personalizing this dose to reduce your risk of severe side effects.” Patients understand that message immediately—it feels proactive, thoughtful, and individualized. Even patients with normal results benefit because we can provide clearer expectations and reinforce early toxicity monitoring.

Q: What role can pharmacists play in educating prescribers and patients about the significance of DPYD variants and dose adjustments for safety?

Mitaly: Pharmacists are often the bridge between complex genetic information and real-world clinical decisions. Because we understand both the science and the practical implications, we naturally become the point people for educating prescribers on how to use DPYD results in day-to-day practice. At Ochsner, for example, pharmacists helped develop educational sessions, quick-reference tools, and consult pathways so that oncologists and advanced practice providers felt supported from the moment testing was introduced. Pharmacists also helped shape the clinical decision support language in the EMR to make sure recommendations were clear, actionable, and aligned with guidelines.

When it comes to patients, pharmacists play an equally important role. We’re often the ones explaining why a patient may not be receiving the “standard dose,” and framing that adjustment as a personalized safety measure rather than a step backward in treatment.

Clear pharmacist-led communication helps normalize genetic testing as part of routine cancer care and empowers patients to participate in their own safety.

Q: Can you share practice insights from Ochsner Health’s experience, such as how pharmacy teams integrated testing into existing EMR and verification systems?

Mitaly: Ochsner’s experience offers a really practical model. The health system built a structured governance process for pharmacogenomics under the Pharmacy and Therapeutics committee, which allowed pharmacists, physicians, genetic counselors, and informatics specialists to collaborate on policies and workflows. Pharmacists were heavily involved in translating guideline recommendations into EMR-based rules, creating interruptive alerts for high-risk scenarios and inline dosing recommendations for intermediate metabolizers.

One of the most impactful steps was ensuring that DPYD results flowed into the EMR as discrete data, not just scanned reports. This allowed pharmacists to see the patient’s metabolizer status directly during verification and ensured that clinical decision support could automatically trigger the appropriate recommendations. This infrastructure supported the 929 critical pharmacogenomics (PGx) safety alerts that have already been triggered and enabled the 154 medication changes that prevented serious harm. The volume of testing—more than 5000 oncology tests to date—shows that once the workflow is designed well, adoption becomes seamless, and pharmacists can consistently intervene at the point of care. Ochsner also established a pharmacogenomics consult service and a PGx “hotline,” making it easy for clinicians to get help with interpretation or dosing questions, and to date, over 800 of these PGx consultations have been completed.

By pairing strong operational infrastructure with accessible pharmacist expertise, the system has made DPYD pretesting part of the standard safety process rather than an optional add-on.

Q: Looking ahead, how might broader adoption of pharmacogenomic testing like DPYD screening shape the pharmacist’s role in precision oncology care?

Mitaly: As pharmacogenomic testing becomes increasingly routine, I think pharmacists will move even more firmly into the center of precision oncology care. We’re already seen as medication-therapy experts; adding genomics to that skillset allows us to guide decisions on which drugs, at what dose, and for which patients based on inherited and tumor-specific biomarkers. DPYD is a great example of how a single genetic test can fundamentally shift the safety profile of a widely used drug class. As more genes and gene–drug pairs become clinically actionable, pharmacists will be essential for ensuring that these tools are integrated into workflows in a meaningful, sustainable way.

I also expect pharmacists to take on larger roles in system-level initiatives—building cross-departmental PGx programs, shaping EMR decision support, leading provider education, and ensuring equitable access to testing. Ultimately, pharmacogenomics allows us to personalize therapy in ways that truly matter to patients, and pharmacists are uniquely equipped to make that personalization both safe and practical in real clinical environments.

REFERENCE

Xeloda (capecitabine) tablets label update. FDA. October 3, 2025. Accessed January 15, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2025/020896Orig1s052ltr.pdf