What NSAID (Non-Steroidal Anti-Inflammatory Drug) is safe to take with fluoxetine (Prozac) and Abilify (Aripiprazole)?

NSAID Selection with Fluoxetine and Aripiprazole

Acetaminophen is the safest first-line analgesic for patients taking fluoxetine and aripiprazole, as it avoids both the bleeding risk from NSAID-SSRI interactions and has no significant drug interactions with either medication. 1

Primary Recommendation: Acetaminophen First

• Acetaminophen (650-1000 mg every 6 hours, maximum 4000 mg/day) should be the initial choice because it does not affect serotonin reuptake or platelet function and has no clinically significant interactions with fluoxetine or aripiprazole 1
• This avoids the well-documented increased bleeding risk when SSRIs like fluoxetine are combined with NSAIDs 2

If NSAIDs Are Necessary: Specific Recommendations

When acetaminophen provides insufficient pain relief, the following hierarchy applies:

Best NSAID Option: Celecoxib (COX-2 Inhibitor)

• Celecoxib is the preferred NSAID choice because it does not inhibit platelet aggregation and has lower gastrointestinal bleeding risk compared to non-selective NSAIDs 2
• COX-2 inhibitors are associated with lower incidence of GI side effects and do not inhibit platelet aggregation, which is particularly important given fluoxetine's effect on platelet function 2

Alternative: Low-Dose Ibuprofen (Short-Term Only)

• If celecoxib is unavailable, use ibuprofen 400 mg (maximum 1200 mg/day) for the shortest duration possible (ideally <5 days) 1
• Ibuprofen at low doses has relatively lower ulcerogenic potential compared to other non-selective NSAIDs 2
• Use the lowest effective dose for the shortest duration 2

Other Acceptable Options

• Naproxen is preferred over other non-selective NSAIDs for patients with cardiovascular concerns 2
• Non-acetylated salicylates (salsalate 2-3 g/day in divided doses, or choline magnesium salicylate) do not inhibit platelet aggregation and may be safer alternatives 2

Critical Safety Considerations

Bleeding Risk Management

• The combination of SSRIs (fluoxetine) and NSAIDs increases GI bleeding risk 3-6 fold 2
• Emerging data suggest SSRIs independently increase GI bleeding risk, which is potentiated by concomitant NSAID use 2
• If NSAIDs must be used with fluoxetine, add a proton pump inhibitor (PPI) for gastroprotection 2

Drug Interaction Concerns

• Fluoxetine is a potent inhibitor of CYP2D6, CYP2C, and CYP3A4 enzymes, which can affect metabolism of other medications 3, 4
• However, NSAIDs do not have clinically significant interactions through these pathways 5
• The primary concern is the pharmacodynamic interaction affecting bleeding risk, not pharmacokinetic interactions 2

NSAIDs to Avoid

• Avoid ketorolac except for very short-term use (maximum 5 days), as it has high bleeding risk 2
• Avoid high-dose or prolonged NSAID therapy in this population 2
• Avoid combining multiple NSAIDs (including over-the-counter products) 2

Monitoring Requirements

If NSAIDs are prescribed with fluoxetine:

• Monitor for signs of GI bleeding (black stools, hematemesis, unexplained anemia) 2
• Check baseline CBC and consider fecal occult blood testing 2
• Assess for bruising or other bleeding manifestations 2