Sildenafil and nitrate medicines are formally contraindicated together because sildenafil can potentiate the blood-pressure-lowering effects of nitric oxide donors. Current U.S. labeling applies the restriction to organic nitrates or organic nitrites in any form, whether they are used regularly or intermittently.
The interaction is pharmacodynamic rather than a CYP-mediated metabolism interaction. Nitrates increase nitric oxide–cGMP signaling, while sildenafil inhibits PDE5 and slows cGMP breakdown. Combining those actions can amplify vascular smooth-muscle relaxation and produce excessive hypotension.
Current labeling also states that the safe time for administering nitrates after sildenafil has not been established. Even though sildenafil concentrations are much lower 24 hours after a dose than around peak exposure, the label does not establish nitrate coadministration at 24 hours as safe.
Current U.S. sildenafil labeling places nitric oxide donors such as organic nitrates and organic nitrites in the formal Contraindications section. The restriction applies to use in any form and to both regular and intermittent nitrate exposure.
The reason is not simply that both drugs can lower blood pressure independently. Sildenafil was shown experimentally to potentiate the hypotensive effects of nitrates, creating a stronger interaction than the ordinary additive blood-pressure considerations seen with many antihypertensive medicines.
The same core nitrate contraindication appears across major sildenafil product contexts, including ED-oriented sildenafil tablets and the REVATIO PAH framework.
| Interaction Element | Current Sildenafil Label Context |
|---|---|
| Organic nitrates | Contraindicated |
| Organic nitrites | Contraindicated in applicable sildenafil tablet labeling |
| Regular nitrate use | Included in the contraindication |
| Intermittent nitrate use | Included in the contraindication |
| Any nitrate dosage form | The restriction is not limited to one route or presentation |
| Primary risk | Potentiation of hypotensive effects |
The interaction is explained by convergence on the nitric oxide–cGMP signaling pathway. Organic nitrates act as nitric oxide donors or generate nitric-oxide-related signaling that activates soluble guanylate cyclase.
Guanylate cyclase increases intracellular cyclic guanosine monophosphate, or cGMP. In vascular smooth muscle, increased cGMP contributes to relaxation and vasodilation.
PDE5 normally breaks down cGMP. Sildenafil inhibits PDE5, slowing that breakdown. When nitrate-driven cGMP production and sildenafil-driven reduction in cGMP degradation occur together, the vascular signal can become substantially amplified.
| Pathway Step | Role in the Sildenafil–Nitrate Interaction |
|---|---|
| Organic nitrate / nitrite | Increases nitric oxide-related signaling |
| Nitric oxide | Activates soluble guanylate cyclase |
| Guanylate cyclase | Increases cGMP formation |
| cGMP | Promotes vascular smooth-muscle relaxation |
| PDE5 | Normally degrades cGMP |
| Sildenafil | Inhibits PDE5 and slows cGMP breakdown |
| Combined effect | Amplified cGMP-mediated vasodilation |
Nitrates and sildenafil do not interact because one substantially raises the plasma concentration of the other. Instead, they act at different points within the same physiological signaling system.
Nitrate medicines increase the upstream nitric oxide signal and promote formation of cGMP. Sildenafil acts farther downstream by limiting PDE5-mediated cGMP degradation.
This explains why the interaction is pharmacodynamic. The critical issue is enhanced physiological response to overlapping signaling rather than altered sildenafil absorption, CYP metabolism or AUC.
| Feature | Nitrates | Sildenafil |
|---|---|---|
| Primary interaction domain | Nitric oxide signaling | PDE5 inhibition |
| Effect on cGMP system | Increases cGMP-generating signal | Reduces cGMP breakdown |
| Main combined consequence | Greater vasodilatory signaling | Greater vasodilatory signaling |
| CYP interaction? | Not the primary mechanism | Not the primary mechanism |
Sildenafil alone has systemic vasodilatory effects and can produce transient decreases in blood pressure. Nitrates also produce vasodilation, but through increased nitric oxide–cGMP signaling.
Controlled clinical pharmacology studies demonstrated that sildenafil can increase the blood-pressure response to glyceryl trinitrate, also called nitroglycerin. In one crossover study, subjects were less tolerant of intravenous glyceryl trinitrate after sildenafil, and a sublingual glyceryl trinitrate challenge produced a substantially greater systolic blood-pressure decrease during sildenafil treatment than during placebo.
A later time-course study also found a greater blood-pressure response to sublingual glyceryl trinitrate after sildenafil in men with stable angina for several hours after sildenafil administration. These experimental findings support the formal contraindication but do not define a universally safe waiting interval.
| Evidence Element | Finding |
|---|---|
| Interaction type | Pharmacodynamic hypotensive interaction |
| Glyceryl trinitrate / nitroglycerin | Blood-pressure-lowering effects were potentiated by sildenafil in controlled studies |
| Stable-angina time-course study | Greater BP reduction was detected for several hours after sildenafil |
| Regulatory conclusion | Concomitant nitrate use is contraindicated |
| Universal safe post-sildenafil interval established? | No |
The contraindication is broader than a single drug called nitroglycerin. Current sildenafil labeling refers to nitric oxide donors such as organic nitrates or organic nitrites in any form.
Current U.S. patient information gives common examples including nitroglycerin, isosorbide mononitrate and isosorbide dinitrate. Nitroglycerin itself can appear in multiple dosage forms, including tablets, sprays, patches and ointments.
Sildenafil patient information also warns about recreational products commonly called 'poppers' that contain organic nitrate or nitrite compounds. The important point is the pharmacological category rather than whether the product is prescription, intermittent or recreational.
| Nitrate / Nitrite Example | Label Context |
|---|---|
| Nitroglycerin | Nitrate medicine; contraindicated with sildenafil |
| Nitroglycerin tablets | Included regardless of dosage form |
| Nitroglycerin spray | Included regardless of dosage form |
| Nitroglycerin patch | Included regardless of dosage form |
| Nitroglycerin ointment | Included regardless of dosage form |
| Isosorbide mononitrate | Nitrate medicine listed in sildenafil patient information |
| Isosorbide dinitrate | Nitrate medicine listed in sildenafil patient information |
| Recreational organic nitrate / nitrite 'poppers' | Also included in sildenafil patient-information warnings |
Nitroglycerin, also called glyceryl trinitrate, is the most extensively studied example of the sildenafil–nitrate interaction. It is used in cardiovascular care and can be administered through several different formulations.
Controlled interaction studies demonstrate that sildenafil increases sensitivity to nitroglycerin's hypotensive effects. This evidence is one reason the nitrate contraindication is stronger than the caution used for many other blood-pressure-lowering medicines.
Route does not remove the interaction. Sildenafil patient information specifically includes nitroglycerin tablets, patches, sprays and ointments among nitrate examples.
| Nitroglycerin Feature | Sildenafil Interaction Context |
|---|---|
| Alternative name | Glyceryl trinitrate / GTN |
| Drug category | Organic nitrate / nitric oxide donor |
| Interaction mechanism | Amplified NO–cGMP-mediated vasodilation |
| Evidence | Human controlled interaction studies demonstrate potentiated hypotensive effects |
| Sildenafil label status | Contraindicated |
| Different nitroglycerin formulations | Do not remove the nitrate contraindication |
Viagra contains sildenafil citrate and delivers sildenafil as the active moiety, so its nitrate restriction is a sildenafil pharmacology issue rather than a brand-specific phenomenon.
The same basic concern extends beyond the Viagra brand. Generic ED sildenafil products and PAH-oriented sildenafil products also contain sildenafil and carry nitrate contraindication language in their applicable U.S. prescribing information.
Brand, indication and dosage form can change other parts of product labeling, but they do not create an exception to the underlying sildenafil–nitrate interaction.
| Product Context | Nitrate Interaction |
|---|---|
| Viagra | Contraindicated with nitrate medicines |
| Generic ED sildenafil | Contraindicated with nitric oxide donors such as organic nitrates or nitrites |
| REVATIO sildenafil | Contraindicated with organic nitrates in any form, regularly or intermittently |
| Underlying reason | Shared sildenafil PDE5 pharmacology |
Not every medicine that lowers blood pressure with sildenafil is formally contraindicated. Alpha-blockers and antihypertensive medicines, for example, are generally handled through warnings, precautions and product-specific management.
Nitrates are different because sildenafil has been shown to potentiate their hypotensive effects and the combination appears explicitly in the Contraindications section of current prescribing information.
That regulatory distinction is important. Calling the nitrate interaction merely a general blood-pressure caution would understate the label classification, while calling every sildenafil blood-pressure interaction a contraindication would overstate other interactions.
| Interaction | Typical Sildenafil Label Classification |
|---|---|
| Organic nitrates / nitric oxide donors | Contraindicated |
| Riociguat / guanylate cyclase stimulators | Contraindicated |
| Alpha-blockers | Caution / hypotension precautions |
| Antihypertensive medicines | Potential additive blood-pressure effects |
| CYP3A inhibitors | Exposure interaction with product-specific guidance |
The nitrate interaction is not unique to sildenafil as a drug-class concept. Other PDE5 inhibitors also interfere with cGMP degradation and have their own nitrate contraindications in product labeling.
However, timing and pharmacokinetic characteristics differ among individual PDE5 inhibitors, so restrictions from another drug should not be copied onto sildenafil or vice versa.
This page therefore remains sildenafil-specific. Comparisons among PDE5 inhibitors belong on the sildenafil vs other PDE5 inhibitors page.
| Concept | Interpretation |
|---|---|
| PDE5 inhibition | Shared class mechanism relevant to nitrate interaction |
| Nitrate contraindication | Appears across PDE5 inhibitor labeling |
| Pharmacokinetics | Differ among individual PDE5 inhibitors |
| Timing rules | Must be read from the specific product label |
| Class comparison | Sildenafil vs Other PDE5 Inhibitors |
The nitrate interaction is one of two major sildenafil medication combinations classified as formal contraindications in current U.S. labeling; guanylate cyclase stimulators such as riociguat form the other major interaction-based category.
Other sildenafil interactions operate through different mechanisms. CYP3A4 inhibitors can raise sildenafil exposure, alpha-blockers and antihypertensives can add to blood-pressure lowering, and CYP inducers can reduce exposure.
Keeping these mechanisms separate prevents the nitrate contraindication from being treated as though it were an ordinary CYP or antihypertensive interaction.
| Topic | Dedicated Page |
|---|---|
| General interactions | Sildenafil Drug Interactions |
| CYP3A4 interactions | Sildenafil and CYP3A4 |
| Riociguat interaction | Sildenafil and Riociguat Interaction |
| Contraindications | Sildenafil Contraindications |
Nitrates increase nitric oxide–cGMP signaling while sildenafil inhibits PDE5-mediated cGMP breakdown. Sildenafil has been shown to potentiate nitrate-related hypotensive effects, so current U.S. labeling classifies concomitant use as contraindicated.
Current sildenafil labeling applies the contraindication broadly to organic nitrates or organic nitrites in any form. Patient information gives examples including nitroglycerin, isosorbide mononitrate, isosorbide dinitrate and recreational organic nitrate or nitrite products commonly called poppers.
Yes. Sildenafil patient information specifically includes nitroglycerin tablets, sprays, patches and ointments among nitrate examples. The contraindication is based on the nitrate pharmacology rather than one specific dosage form.
Current U.S. sildenafil labeling states that it is unknown when nitrates can be safely administered after sildenafil. Although sildenafil plasma concentrations are much lower 24 hours after a dose than near peak exposure, the label does not establish coadministration at 24 hours as safe.
No. It is primarily a pharmacodynamic interaction involving amplified nitric oxide–cGMP-mediated vasodilation rather than a CYP-mediated change in sildenafil exposure.
No. Nitrate use is a formal contraindication in current U.S. sildenafil labeling, which is a stronger regulatory category than a general warning or precaution.