Is Rinvoq (upadacitinib) safe to use in an adult patient with rheumatoid arthritis, depression, and erectile dysfunction who is also taking fluoxetine and tadalafil?

Drug Interaction Safety: Rinvoq with Fluoxetine and Tadalafil

Rinvoq (upadacitinib) can be used with fluoxetine and tadalafil, as there are no direct pharmacokinetic drug interactions between these medications, but careful patient selection and monitoring for JAK inhibitor-specific cardiovascular risks is essential.

Key Safety Considerations for Rinvoq

Cardiovascular Risk Profile

• JAK inhibitors carry FDA-mandated warnings for serious cardiovascular events, thromboembolism, cancer, and death, based primarily on the ORAL Surveillance study in rheumatoid arthritis patients 1.
• The European Medicines Agency recommends JAK inhibitors should be used cautiously or avoided in patients aged ≥65 years, current or long-term smokers, those with cardiovascular disease history, or cancer history 1.
• Upadacitinib specifically showed increased rates of major adverse cardiovascular events (MACE), venous thromboembolism (particularly pulmonary embolism), and malignancies in high-risk populations 1.

Specific Drug Interaction Analysis

Fluoxetine Combination:

• No direct pharmacokinetic interaction exists between upadacitinib and fluoxetine 1, 2.
• Fluoxetine is a CYP2D6 inhibitor with a long half-life, but upadacitinib is not metabolized via this pathway 1.
• Avoid fluoxetine in elderly patients due to its long half-life and side effects; safer SSRI alternatives include venlafaxine, vortioxetine, or mirtazapine 1.
• Depression management in rheumatoid arthritis patients shows limited evidence for antidepressant efficacy specifically for pain, though SSRIs are generally well-tolerated 2.

Tadalafil Combination:

• No direct drug interaction between upadacitinib and tadalafil exists 1, 3, 4.
• Tadalafil has a 17.5-hour half-life and should not be used within 48 hours of nitrate medications due to severe hypotension risk 1.
• The combination of tadalafil with fluoxetine has been studied for premature ejaculation and showed no safety concerns beyond individual drug profiles 3.
• In rheumatoid arthritis patients with erectile dysfunction, phosphodiesterase-5 inhibitor use was associated with decreased mortality risk 4.

Monitoring Requirements

Baseline Assessment

• Check complete blood count with differential, liver enzymes, lipid panel, viral hepatitis, tuberculosis screening, and pregnancy status before initiating upadacitinib 1.
• Assess cardiovascular risk factors: age, smoking history, prior cardiovascular events, hypertension, diabetes, family history of coronary disease 1.

Ongoing Surveillance

• Monitor complete blood count and liver enzymes per routine management after baseline for upadacitinib 1.
• Recheck lipids at 12 weeks after upadacitinib initiation 1.
• Screen for signs of thromboembolism (leg swelling, chest pain, shortness of breath) and cardiovascular symptoms 1.

Clinical Decision Algorithm

Proceed with combination if:

• Patient is <65 years old without cardiovascular risk factors 1
• No history of thromboembolism, cancer, or cardiovascular disease 1
• Non-smoker or remote smoking history 1
• Patient is not on nitrate therapy (contraindication for tadalafil) 1

Use with extreme caution or avoid if:

• Age ≥65 years 1
• Active or recent smoking 1
• History of cardiovascular disease, stroke, or thromboembolism 1
• Active malignancy or history of cancer 1
• Multiple cardiovascular risk factors present 1

Common Pitfalls to Avoid

• Do not assume all JAK inhibitors have identical safety profiles—while class warnings apply, upadacitinib and tofacitinib have different selectivity and potentially different risk magnitudes 5.
• Do not overlook the tadalafil-nitrate interaction—ensure patients understand the 48-hour window and emergency implications 1.
• Do not use fluoxetine as first-line SSRI in elderly patients—its long half-life increases adverse effect risk 1.
• Do not prescribe upadacitinib as first-line therapy in high-risk cardiovascular patients—consider alternative DMARDs or biologics first 1.

Adverse Event Profile

• Minor adverse events are more common with JAK inhibitors but typically do not lead to treatment cessation 5.
• Upadacitinib-specific adverse events include elevated hepatic aminotransferases, infections (including herpes zoster), and laboratory abnormalities 1, 6.
• The combination shows no evidence of pharmacodynamic interaction that would amplify individual drug risks 3, 4.