Is isosorbide (isosorbide mononitrate) safe to use with tadalafil (phosphodiesterase inhibitor)?

Isosorbide is Absolutely Contraindicated with Tadalafil

Isosorbide (isosorbide mononitrate) should never be used concomitantly with tadalafil due to the risk of severe, potentially life-threatening hypotension. 1, 2, 3 This combination is classified as a Class III: Harm recommendation with Level B-NR evidence in the 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients with Chronic Coronary Disease.

Mechanism of Dangerous Interaction

The dangerous interaction occurs because:

1. Complementary vasodilatory pathways:

   • Isosorbide mononitrate releases nitric oxide, which activates guanylate cyclase to increase cyclic guanosine monophosphate (cGMP)
   • Tadalafil inhibits phosphodiesterase type 5 (PDE5), which normally breaks down cGMP
   • When combined, this leads to excessive cGMP accumulation and profound vasodilation 1, 4

2. Magnitude of effect: The combination can cause blood pressure drops that are significantly greater than either medication alone, with mean maximal decreases in standing systolic blood pressure of 26-36 mmHg 4

3. Duration of risk: Tadalafil has a particularly long half-life (17.5 hours) compared to other PDE5 inhibitors, creating an extended period of risk 1

Timing Considerations

Due to tadalafil's long half-life, the contraindication extends for a significant period:

• Patients on tadalafil should avoid nitrates for at least 48 hours after their last dose 1, 5
• Conversely, patients on isosorbide mononitrate should not take tadalafil while on nitrate therapy 2, 3

Clinical Consequences of Combined Use

The potential consequences of this interaction include:

• Severe hypotension
• Syncope (fainting)
• Myocardial ischemia
• Stroke
• Death 3, 4, 6

Alternative Management Options

For patients with erectile dysfunction who require nitrate therapy:

1. Prioritize cardiovascular health: In patients with chronic coronary disease requiring nitrate therapy, the decision to use PDE5 inhibitors should be guided by the need for continued nitrate therapy versus other available treatment options 1

2. Consider discontinuation of nitrates: In stable patients with minimal angina symptoms, the clinician may consider whether nitrate therapy can be safely discontinued to allow for PDE5 inhibitor use

3. Explore alternative ED treatments: Non-PDE5 inhibitor options for erectile dysfunction may be considered for patients who must remain on nitrate therapy

Monitoring and Precautions

If a patient has taken tadalafil and requires emergency nitrate administration for a life-threatening situation:

1. At least 48 hours should have elapsed since the last tadalafil dose
2. Nitrates should only be administered under close medical supervision
3. Continuous hemodynamic monitoring is essential 3

This contraindication is absolute and applies to all forms of isosorbide (mononitrate and dinitrate) and all PDE5 inhibitors, though tadalafil presents the longest duration of risk due to its extended half-life.