Is it safe to take Wellbutrin (bupropion), Cardizem (diltiazem), fluoxetine, Xarelto (rivaroxaban), Ropinirole (ropinirole), and Valsartan-Hydrochlorothiazide (valsartan and hydrochlorothiazide) together for a 59-year-old patient with a history of atrial fibrillation?

Drug Interaction Safety Assessment

This medication combination requires careful monitoring due to significant drug interactions, particularly between diltiazem (Cardizem) and rivaroxaban (Xarelto), which substantially increases bleeding risk in atrial fibrillation patients. 1

Critical Drug Interaction: Diltiazem and Rivaroxaban

Concomitant use of diltiazem with rivaroxaban increases major bleeding risk by 84% (adjusted HR 1.84) and any bleeding-related hospitalization by 56% (adjusted HR 1.56) in atrial fibrillation patients. 1 This interaction occurs because diltiazem is a moderate CYP3A4 and P-glycoprotein inhibitor, which increases rivaroxaban plasma concentrations through pharmacokinetic interactions. 2, 1

• The increased bleeding risk with diltiazem-rivaroxaban combination occurs consistently regardless of kidney function status (both with and without CKD). 1
• Real-world data from 4,544 atrial fibrillation patients showed an additional 2.4 bleeding events per 100 person-years when diltiazem was used with DOACs compared to DOACs alone. 1
• This interaction was specific to DOACs; no increased bleeding was observed when diltiazem was combined with warfarin. 1

Antidepressant Considerations

Both bupropion (Wellbutrin) and fluoxetine are being used concurrently, which is unusual and potentially problematic. While guidelines for atrial fibrillation management recommend beta-blockers as first-line agents that can also help manage depression symptoms 3, using two antidepressants simultaneously requires psychiatric justification.

• Fluoxetine is a potent CYP2D6 inhibitor that can interact with multiple medications in this regimen.
• The combination of two antidepressants increases risk of serotonin syndrome and other adverse effects, though this specific combination is sometimes used clinically.

Rate Control Strategy for Atrial Fibrillation

For this 59-year-old with atrial fibrillation, the current rate control approach using diltiazem is guideline-concordant, but the specific combination with rivaroxaban creates unacceptable bleeding risk. 4

• Diltiazem (a nondihydropyridine calcium channel antagonist) is Class I recommended for rate control in atrial fibrillation. 4
• Beta-blockers are equally effective and recommended as first-line agents for rate control. 4
• Digoxin is only effective for rate control at rest and should be second-line. 4

Anticoagulation Management

Rivaroxaban is appropriate for stroke prevention in this atrial fibrillation patient, but the dose may need adjustment or alternative anticoagulation should be considered given the diltiazem interaction. 4

• Chronic anticoagulation is Class I recommended for atrial fibrillation patients regardless of CHA₂DS₂-VASc score in most guidelines. 4
• The bleeding risk from the diltiazem-rivaroxaban interaction may outweigh benefits in this specific combination. 1

Other Medication Considerations

Ropinirole (for restless legs syndrome or Parkinson's disease) and valsartan-hydrochlorothiazide (for hypertension) have no significant interactions with the atrial fibrillation management regimen. 4

• Valsartan-hydrochlorothiazide is appropriate for hypertension management in atrial fibrillation patients. 4
• No specific contraindications exist for ropinirole use in atrial fibrillation. 4

Recommended Action Plan

Replace diltiazem with a beta-blocker (metoprolol or atenolol) for rate control to eliminate the dangerous drug interaction with rivaroxaban. 4

• Beta-blockers are equally effective as diltiazem for rate control and carry Class I recommendation. 4
• Metoprolol 25-200 mg twice daily or metoprolol succinate 50-400 mg daily are appropriate starting regimens. 4
• Target resting heart rate should be <100 beats per minute. 5
• If beta-blockers are contraindicated, consider switching from rivaroxaban to warfarin, as the diltiazem-warfarin combination does not increase bleeding risk. 1

Monitor closely for bleeding signs if diltiazem must be continued with rivaroxaban: gastrointestinal bleeding, hematuria, and unexplained bruising are the most common manifestations. 2, 1

Reassess the need for dual antidepressant therapy (bupropion plus fluoxetine) with the prescribing psychiatrist to ensure clinical justification exists for this combination.