Tadalafil and Vardenafil Should Not Be Given Together
The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) explicitly states that the suitable delay before nitrate administration after the use of vardenafil has not been determined, though blood pressure generally returns to baseline by 24 hours. 1 However, no major medical academy or guideline society has issued a recommendation stating that tadalafil and vardenafil should not be given together.
Key Safety Guidance on PDE5 Inhibitor Combinations
Contraindicated Combinations
The only absolute contraindication for all PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) is concurrent use with nitrates in any form. 1, 2
- Nitrates must be avoided for at least 24 hours after sildenafil or vardenafil, and 48 hours after tadalafil due to the risk of profound, potentially fatal hypotension. 1, 2
- The ACCF/AHA guidelines emphasize that nitrate use within 24 hours after sildenafil has been associated with profound hypotension, MI, and even death. 1
Riociguat and PDE5 Inhibitor Combination
The European Society of Cardiology/European Respiratory Society (ESC/ERS) explicitly states that the combination of riociguat (a soluble guanylate cyclase stimulator) and any PDE5 inhibitor is contraindicated due to hypotension and other relevant side effects detected in clinical trials. 1
Combining Two PDE5 Inhibitors Together
There is no guideline recommendation or evidence supporting the use of two different PDE5 inhibitors simultaneously (such as tadalafil plus vardenafil). 2
- The American College of Physicians recommends optimizing the dose of a single PDE5 inhibitor rather than adding a second one, due to increased risk of severe hypotension and other adverse effects. 2
- An adequate trial consists of at least 5 separate attempts at maximum dose before declaring treatment failure. 2
- If one PDE5 inhibitor fails, switching to a different PDE5 inhibitor is appropriate, not combining them. 2
Clinical Implications
The question appears to conflate two separate safety issues: the contraindication of PDE5 inhibitors with nitrates, and the lack of evidence for combining two PDE5 inhibitors together. 1, 2
- All three PDE5 inhibitors (sildenafil, vardenafil, tadalafil) have similar efficacy and safety profiles. 1
- The primary differences are pharmacokinetic: tadalafil has a half-life of 17.5 hours, while sildenafil and vardenafil have half-lives of approximately 4 hours. 1
- There is no therapeutic rationale or safety data supporting concurrent use of multiple PDE5 inhibitors. 2
Common Pitfalls to Avoid
- Do not prescribe any PDE5 inhibitor to patients on nitrate therapy, regardless of the specific agent. 1
- Do not combine two different PDE5 inhibitors in an attempt to improve efficacy—instead, optimize dosing of a single agent or address modifiable factors affecting treatment response. 2
- Do not combine riociguat with any PDE5 inhibitor in pulmonary hypertension patients. 1