Sildenafil and riociguat are formally contraindicated together because they increase cGMP-related vascular signaling through complementary mechanisms. Riociguat increases cGMP generation through soluble guanylate cyclase, while sildenafil inhibits PDE5 and reduces cGMP degradation.
The resulting interaction is primarily pharmacodynamic and can produce excessive vasodilatory effects, particularly hypotension. Current sildenafil labeling states that PDE5 inhibitors can potentiate the hypotensive effects of guanylate cyclase stimulators such as riociguat.
Human interaction data support that restriction. Studies in patients with pulmonary arterial hypertension found additive hemodynamic effects when riociguat was added to stable sildenafil, and longer combination exposure was associated with a high rate of discontinuation for hypotension. This page focuses on that specific interaction rather than duplicating the broader sildenafil contraindication or NO–cGMP pathway pages.
Current U.S. sildenafil labeling places concomitant use with a guanylate cyclase stimulator such as riociguat in the formal Contraindications section. Current riociguat labeling likewise contraindicates concomitant administration with PDE5 inhibitors including sildenafil.
The regulatory concern is hypotension. Sildenafil and riociguat act at different molecular targets but both shift the NO–sGC–cGMP system toward greater cGMP-mediated vasodilation.
This interaction therefore differs from a routine interaction that might be managed only through observation or exposure adjustment. Current labeling directs against concomitant use.
| Medicine | Primary Mechanism | Interaction Consequence |
|---|---|---|
| Sildenafil | PDE5 inhibition reduces cGMP degradation | Greater persistence of cGMP signaling |
| Riociguat | Stimulates soluble guanylate cyclase and increases cGMP generation | Greater cGMP production and vasodilatory signaling |
| Combination | Increased generation plus reduced degradation of cGMP | Additive hemodynamic effects and increased hypotension risk |
| Current U.S. label status | PDE5 inhibitor plus riociguat | Contraindicated |
The interaction occurs within the nitric oxide–soluble guanylate cyclase–cGMP signaling system. Nitric oxide normally binds soluble guanylate cyclase, which catalyzes formation of cGMP.
cGMP participates in regulation of vascular tone by promoting smooth-muscle relaxation. PDE5 counterbalances that signal by degrading cGMP.
Riociguat acts at the cGMP-generation side of this system, while sildenafil acts at the degradation side. Combining the two therefore affects both production and removal of the same second messenger.
The complete molecular sequence remains on the sildenafil NO–cGMP pathway page.
| Pathway Component | Normal Role | Drug Interaction Context |
|---|---|---|
| Nitric oxide | Activates soluble guanylate cyclase | Provides endogenous upstream signaling |
| Soluble guanylate cyclase | Catalyzes cGMP synthesis | Target of riociguat |
| cGMP | Second messenger involved in vascular smooth-muscle relaxation | Increased through riociguat and preserved through sildenafil |
| PDE5 | Hydrolyzes cGMP | Target inhibited by sildenafil |
| Combined pathway effect | Normally balanced generation and degradation | Shift toward greater cGMP-mediated vasodilatory signaling |
Sildenafil inhibits phosphodiesterase type 5, an enzyme responsible for hydrolysis of cGMP. Its immediate molecular effect is therefore reduced degradation of an existing cGMP signal.
Sildenafil does not directly stimulate soluble guanylate cyclase and does not independently generate cGMP. Its pathway position is downstream of nitric oxide and guanylate cyclase activation.
When riociguat is also present, sildenafil can preserve cGMP generated through riociguat-enhanced sGC activity. That complementary action is central to the interaction.
| Sildenafil Feature | Effect |
|---|---|
| Primary target | PDE5 |
| Direct enzymatic effect | Reduced cGMP hydrolysis |
| Direct sGC stimulation | No |
| Net pathway effect | Greater persistence of cGMP signaling |
| Interaction relevance | Preserves cGMP produced through riociguat-stimulated sGC activity |
Riociguat is a soluble guanylate cyclase stimulator with a dual mode of action. It sensitizes sGC to endogenous nitric oxide by stabilizing NO–sGC binding.
Riociguat also directly stimulates soluble guanylate cyclase through a separate binding interaction independently of nitric oxide.
Both actions increase generation of cGMP. This differs fundamentally from sildenafil, which acts after cGMP has already been formed by reducing its PDE5-mediated degradation.
| Riociguat Mechanism | Pathway Effect |
|---|---|
| Sensitizes sGC to endogenous NO | Enhances NO-dependent sGC signaling |
| Direct sGC stimulation | Stimulates sGC independently of NO |
| cGMP generation | Increases |
| Primary molecular target | Soluble guanylate cyclase |
| Difference from sildenafil | Increases cGMP production rather than inhibiting its breakdown |
The central safety concern is excessive vasodilatory signaling and hypotension. Riociguat increases cGMP generation while sildenafil decreases cGMP degradation, so their actions can be additive even though the drugs bind different molecular targets.
Current riociguat labeling specifically states that coadministration with PDE5 inhibitors is contraindicated because of hypotension. Current sildenafil labeling similarly states that PDE5 inhibitors may potentiate the hypotensive effects of guanylate cyclase stimulators.
The concern is therefore supported by both mechanism and observed clinical pharmacology rather than being based only on a theoretical pathway overlap.
| Interaction Level | Combined Effect |
|---|---|
| cGMP production | Increased through riociguat |
| cGMP degradation | Reduced through sildenafil |
| Vascular smooth-muscle signaling | Greater relaxation / vasodilatory drive |
| Hemodynamic consequence | Additive blood-pressure-lowering effects |
| Primary labeled safety concern | Hypotension |
| Regulatory classification | Contraindicated combination |
Riociguat is the active drug, while ADEMPAS is the original U.S. brand product containing riociguat. Generic riociguat products can also carry the same active-drug interaction because the contraindication is based on riociguat pharmacology rather than brand naming.
Riociguat is used in specific pulmonary hypertension settings, including pulmonary arterial hypertension and selected chronic thromboembolic pulmonary hypertension contexts.
The sildenafil interaction therefore applies to riociguat as the active medicine, whether the product is identified by the ADEMPAS brand or by the generic drug name.
| Term | Meaning |
|---|---|
| Riociguat | Soluble guanylate cyclase stimulator active drug |
| ADEMPAS | Branded riociguat product |
| Generic riociguat | Product containing the same active drug |
| Sildenafil | PDE5 inhibitor active drug |
| Interaction basis | Active-drug pharmacology rather than brand name |
Drug interactions range from modest exposure changes to combinations that product labeling directs against using together. Sildenafil with riociguat belongs to the latter category.
Both sildenafil and riociguat U.S. prescribing information classify the combination as contraindicated rather than describing it merely as a precaution requiring routine monitoring.
This classification is supported by pharmacodynamic evidence showing additive hemodynamic effects and clinically important hypotension during combination treatment.
| Regulatory Category | Meaning in This Context |
|---|---|
| Contraindication | Current labeling directs against concomitant sildenafil and riociguat use |
| Warning / precaution | Lower regulatory category used for other risks that do not automatically prohibit concomitant use |
| Pharmacokinetic interaction | Would primarily involve altered drug exposure |
| Sildenafil–riociguat interaction | Primarily pharmacodynamic and formally contraindicated |
Both nitrates and riociguat can produce dangerous pharmacodynamic overlap with sildenafil through the broader NO–cGMP system, but the upstream mechanisms differ.
Organic nitrates act as nitric oxide donors and increase NO-related signaling. Riociguat instead acts directly on soluble guanylate cyclase: it sensitizes sGC to endogenous nitric oxide and can stimulate the enzyme independently of nitric oxide.
Sildenafil acts farther downstream by inhibiting PDE5-mediated cGMP degradation. Both combinations are contraindicated, but their mechanistic explanations and label-specific timing language should remain separate.
The nitrate-specific restriction is covered on the sildenafil and nitrates interaction page.
| Interaction Partner | Primary Mechanism | Relationship to Sildenafil |
|---|---|---|
| Organic nitrates / nitrites | Increase nitric oxide-related signaling | Sildenafil preserves downstream cGMP |
| Riociguat | Sensitizes and directly stimulates soluble guanylate cyclase | Sildenafil preserves the additional cGMP generated |
| Sildenafil | Inhibits PDE5-mediated cGMP degradation | Common downstream contributor |
| Current label status | Different upstream mechanisms | Both nitrate and riociguat combinations are contraindicated |
The sildenafil–riociguat interaction is primarily pharmacodynamic. The central problem is amplification of physiological signaling rather than one medicine substantially increasing the plasma concentration of the other.
Current riociguat labeling describes an exploratory interaction study in seven patients with PAH receiving stable sildenafil 20 mg three times daily. Sequential single riociguat doses of 0.5 mg and 1 mg produced additive hemodynamic effects.
With continued combination treatment using sildenafil 20 mg three times daily and riociguat 1 to 2.5 mg three times daily, current labeling reports one death possibly related to the combination and a high rate of discontinuation for hypotension.
These data explain why the combination is not treated like a routine CYP-mediated exposure interaction. Broader sildenafil pharmacodynamics is covered on the sildenafil pharmacodynamics page.
| Evidence | Observed Finding |
|---|---|
| Exploratory interaction study | 7 PAH patients on stable sildenafil |
| Background sildenafil | 20 mg three times daily |
| Single riociguat doses | 0.5 mg and 1 mg sequentially |
| Acute finding | Additive hemodynamic effects |
| Longer combination exposure | Riociguat 1–2.5 mg three times daily with sildenafil |
| Safety finding | High rate of discontinuation for hypotension |
| Serious outcome reported in label | One death possibly related to the combination |
| Primary interaction type | Pharmacodynamic |
Riociguat is one of the major interaction-based contraindications in current sildenafil labeling. It should be separated from nitrates, CYP-mediated exposure interactions and general hypotension precautions.
Current riociguat labeling also contains specific transition instructions between riociguat and PDE5 inhibitors. For sildenafil, the label states that sildenafil should be discontinued at least 24 hours before riociguat is administered, and riociguat should be discontinued at least 24 hours before a PDE5 inhibitor is administered.
Those intervals belong to riociguat's product-label transition framework. They should not be reframed as evidence that unsupervised switching or concomitant treatment is otherwise appropriate.
| Topic | Dedicated Page |
|---|---|
| General contraindications | Sildenafil Contraindications |
| Nitrate interaction | Sildenafil and Nitrates Interaction |
| Drug interactions | Sildenafil Drug Interactions |
| CYP3A4 interactions | Sildenafil and CYP3A4 |
They affect complementary parts of the cGMP pathway. Riociguat increases cGMP generation through soluble guanylate cyclase, while sildenafil inhibits PDE5-mediated cGMP degradation. The resulting additive vasodilatory effect can increase the risk of hypotension, and current U.S. labeling contraindicates concomitant use.
Riociguat sensitizes soluble guanylate cyclase to endogenous nitric oxide and also directly stimulates the enzyme independently of nitric oxide, increasing cGMP generation. Sildenafil acts downstream by inhibiting PDE5 and reducing cGMP breakdown.
Yes. Current riociguat labeling describes an exploratory study in seven PAH patients on stable sildenafil in which single riociguat doses produced additive hemodynamic effects. With longer combination exposure, the label reports a high rate of discontinuation for hypotension and one death possibly related to the combination.
It is primarily pharmacodynamic. The main concern is overlapping cGMP-mediated vasodilatory and hemodynamic effects rather than a CYP-mediated change in sildenafil concentration.
Current riociguat labeling states that sildenafil should be discontinued at least 24 hours before riociguat is administered. It also states that riociguat should be discontinued at least 24 hours before a PDE5 inhibitor is administered. These are product-label transition instructions rather than a general authorization for unsupervised switching.
No. Nitrates increase nitric oxide-related signaling, while riociguat acts directly on soluble guanylate cyclase and also sensitizes it to endogenous nitric oxide. Sildenafil acts downstream of both mechanisms by reducing cGMP degradation.