Xeljanz XR Drug Interactions: What to Avoid and What to Tell Your Doctor

Xeljanz XR (tofacitinib) is metabolized primarily by the liver enzyme CYP3A4 and to a lesser extent by CYP2C19. This means many common medications can affect how much tofacitinib is in your bloodstream — either increasing it to potentially toxic levels or reducing it so much that your treatment loses effectiveness. Tofacitinib also has serious interactions with other immunosuppressive drugs. Here's what you need to know.

Drug Interactions to Avoid Completely

The following combinations are contraindicated or carry the highest interaction risks:

Biologic DMARDs (adalimumab, etanercept, abatacept, tocilizumab, sarilumab, secukinumab, ustekinumab, etc.): Combining Xeljanz XR with biologic DMARDs is contraindicated. The combination significantly increases the risk of serious infections.

Other JAK inhibitors (upadacitinib/Rinvoq, baricitinib/Olumiant): Combining two JAK inhibitors is contraindicated due to additive immunosuppression and infection risk.

Strong CYP3A4 inducers (rifampin/rifampicin): Rifampin is used for TB and other infections. It dramatically decreases tofacitinib blood levels, potentially making the drug ineffective. Avoid this combination.

Live vaccines: Do not receive live vaccines while taking Xeljanz XR. This includes nasal spray flu vaccine, MMR, yellow fever, varicella, and others. A patient receiving tofacitinib developed a disseminated varicella vaccine-strain infection in a clinical case.

Drug Interactions Requiring Dose Adjustment

These drugs don't prohibit use of Xeljanz XR but require your doctor to adjust your dose:

Strong CYP3A4 inhibitors (ketoconazole, itraconazole, voriconazole, clarithromycin, ritonavir): These antifungal and antibiotic drugs block the enzyme that breaks down tofacitinib, increasing its blood levels. Your doctor will reduce your Xeljanz XR dose (typically to 5 mg once daily).

Moderate CYP3A4 inhibitors + strong CYP2C19 inhibitors (fluconazole): Fluconazole inhibits both pathways that metabolize tofacitinib. Your doctor will reduce your dose when fluconazole is needed (e.g., for a yeast infection).

Drug Interactions Requiring Extra Caution

These interactions are clinically significant and require monitoring, even if they don't always require a dose change:

Potent immunosuppressants (azathioprine, cyclosporine, tacrolimus, mycophenolate): These drugs increase immunosuppression when combined with tofacitinib. The combination is generally not recommended.

Oral contraceptives and certain hormone therapies: Some hormonal medications use CYP3A4 pathways; discuss with your doctor if you're on hormonal contraceptives.

Corticosteroids (prednisone, methylprednisolone): Short-term steroid use during flares is common while on Xeljanz XR. Long-term combined use adds to infection risk — minimize corticosteroid exposure when possible.

Grapefruit and Xeljanz XR

Grapefruit and grapefruit juice inhibit CYP3A4 in the gut, which can increase tofacitinib blood levels. While no specific dose adjustment is recommended for grapefruit alone, it's best to limit grapefruit intake while on Xeljanz XR or avoid it entirely if you're also taking a CYP3A4 inhibitor drug.

Supplements and Herbal Products

Always tell your doctor about all supplements and herbal products. Key concerns:

St. John's Wort: A strong CYP3A4 inducer — can significantly reduce tofacitinib blood levels, potentially causing treatment failure. Avoid.

Echinacea and immune-stimulating supplements: May partially counteract the immunosuppressive effect of Xeljanz XR.

What to Tell Every Doctor and Pharmacist

Every time you see a new provider, dentist, or pharmacist — or before any procedure or surgery — mention that you take Xeljanz XR. This is especially important when:

Starting any new prescription or over-the-counter medication

Getting any vaccines (only inactivated vaccines are safe; no live vaccines)

Undergoing surgery (may need to hold tofacitinib around the time of the procedure)

Treating a new infection with antibiotics or antifungals

For more on the side effect profile of Xeljanz XR, see our guide on Xeljanz XR side effects.

If you need help locating Xeljanz XR at a pharmacy near you, medfinder can help find it for you.