Meta Information
ID:pde5-inhibitors
Name:
Schema Version:2.4_uniform_evidence_2026_06_18
Created
2026-05-21T22:30:00Z
Model
phase-a-upgrade-claude-sonnet-4.6
Interactions
Target id:
/class/nitrates
Target name:
Nitrate Medications
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
PDE5 inhibitors potentiate the hypotensive effects of nitrates by increasing cGMP levels, leading to excessive vasodilation and a potentially life-threatening drop in blood pressure.
Actionable advice:
Absolutely avoid taking PDE5 inhibitors if you are using any form of nitrate medication (e.g., nitroglycerin).
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
12.2 Pharmacodynamics Effects on Blood Pressure When Administered with Nitrates In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates.
Label source:
Action type:
avoid
Target id:
/intervention/riociguat
Target name:
Riociguat
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Both PDE5 inhibitors and riociguat (a soluble guanylate cyclase stimulator) increase cGMP levels, and their combined use can cause severe, symptomatic hypotension.
Actionable advice:
PDE5 inhibitors and riociguat should not be taken together under any circumstances.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
4 CONTRAINDICATIONS Use with organic nitrates or riociguat. ( 4 ) History of hypersensitivity reaction to sildenafil or any component of the tablet. ( 4 ) Sildenafil citrate is contraindicated in patients with: Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [see Warnings and Precautions ( 5.1 )] .
Label source:
Action type:
avoid
Target id:
/class/cyp3a4-strong-inhibitors
Target name:
Strong CYP3A4 Inhibitors
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Strong inhibitors of the CYP3A4 enzyme block the metabolism of PDE5 inhibitors, leading to dangerously high drug levels and an increased risk of severe side effects like hypotension and priapism.
Actionable advice:
Co-administration should be avoided, or a significantly reduced starting dose of the PDE5 inhibitor used as directed by a physician.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
For patients taking concomitant strong CYP3A4 inhibitors (including ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir and telithromycin), do not use avanafil [see Drug Interactions ( 7.2 )].
Label source:
Action type:
avoid
Target id:
/condition/hepatic-impairment
Target name:
Severe Liver Impairment
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
PDE5 inhibitors are primarily metabolized by the liver. Severe liver disease significantly impairs this process, leading to much higher drug levels and an increased risk of toxicity.
Actionable advice:
Use is not recommended or requires significant dose reduction under strict medical supervision in severe liver disease.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
7 Hepatic Impairment In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (47% for C max and 85% for AUC).
Label source:
FDA label: Sildenafil
Action type:
avoid
Target id:
/condition/renal-impairment
Target name:
Severe Kidney Impairment
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
The clearance of PDE5 inhibitors and their metabolites can be significantly reduced in severe kidney disease, leading to drug accumulation and increased risk of side effects.
Actionable advice:
In severe kidney impairment, start a PDE5 inhibitor at the lowest dose (e.g., sildenafil 25 mg) and have your prescriber set the dose; avoid combining with nitrates.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Consider a starting dose of 25 mg in patients > 65 years, patients with hepatic impairment (e.g., cirrhosis), and patients with severe renal impairment (creatinine clearance <30 mL/minute) because administration of VIAGRA in these patients resulted in higher plasma levels of sildenafil
Label source:
FDA label: Sildenafil (VIAGRA)
Action type:
avoid
Target id:
/class/alpha-blockers
Target name:
Alpha-Blockers
Severity:
moderate
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
4
Hours after target:
4
Description:
Both alpha-blockers (often used for BPH or hypertension) and PDE5 inhibitors cause vasodilation, and their combined use can lead to an additive drop in blood pressure, causing dizziness or fainting.
Actionable advice:
Doses should be separated by at least 4 hours, and the lowest effective dose of each medication is best used to start.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
7.5 Alpha-Blockers PDE5 inhibitors, including tadalafil, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects.
Label source:
Action type:
separate
Target id:
/class/antihypertensives
Target name:
Antihypertensive Medications
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
PDE5 inhibitors have a mild systemic vasodilatory effect that can add to the blood pressure-lowering effects of other antihypertensive drugs, increasing the risk of hypotension.
Actionable advice:
Blood pressure should be monitored when starting or adjusting doses, and potential dizziness is worth being aware of.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
As with other PDE5 inhibitors, tadalafil has mild systemic vasodilatory properties that may result in transient decreases in blood pressure.
Label source:
Action type:
monitor
Target id:
/dietary/alcohol-acute
Target name:
Alcohol (Acute Consumption)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Both alcohol and PDE5 inhibitors can lower blood pressure. Consuming them together, especially in large amounts, increases the risk of orthostatic hypotension (dizziness upon standing), headache, and increased heart rate.
Actionable advice:
Alcohol intake is best limited when using PDE5 inhibitors to minimize the risk of side effects.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Substantial consumption of alcohol (e.g., 5 units or greater) in combination with tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache.
Label source:
Action type:
informational_none
Target id:
/dietary/grapefruit-pomelo
Target name:
Grapefruit or Grapefruit Juice
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Grapefruit contains compounds that inhibit the CYP3A4 enzyme in the gut wall, which can significantly increase the absorption and blood levels of PDE5 inhibitors, raising the risk of side effects.
Actionable advice:
Grapefruit or grapefruit juice is best avoided while using PDE5 inhibitors.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Other CYP3A4 inhibitors: Although specific interactions have not been studied, other CYP3A4 inhibitors, including grapefruit juice would likely increase vardenafil exposure.
Label source:
FDA label: Vardenafil (LEVITRA)
Action type:
avoid
Target id:
/class/cyp3a4-moderate-inhibitors
Target name:
Moderate CYP3A4 Inhibitors
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Moderate inhibitors of the CYP3A4 enzyme can slow the metabolism of PDE5 inhibitors, leading to increased drug levels and a higher risk of side effects. Dose adjustment is often necessary.
Actionable advice:
It is important to consult a physician, as a lower dose of the PDE5 inhibitor may be required.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Co-administration of erythromycin, a moderate CYP3A4 inhibitor, resulted in 160% and 182% increases in sildenafil Cmax and AUC, respectively.
Label source:
FDA label: Sildenafil (VIAGRA)
Action type:
informational_none
Target id:
/class/broad-spectrum-inducers
Target name:
Metabolic Enzyme Inducers (e.g., St. John's Wort, Rifampin)
Severity:
moderate
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
These substances speed up the activity of the CYP3A4 enzyme, causing the body to break down and clear PDE5 inhibitors more quickly, which can significantly reduce their effectiveness.
Actionable advice:
Strong enzyme inducers are best avoided with PDE5 inhibitors, as they may not work effectively.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
CYP3A4 inducers can increase the rate of Tegretol metabolism. Drugs that have been shown, or that would be
expected, to decrease plasma carbamazepine levels include cisplatin, doxorubicin HCl, felbamate, fosphenytoin,
rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline.
Label source:
FDA label: Carbamazepine [class-derived from: Carbamazepine]
Action type:
avoid
Target id:
/condition/priapism-risk
Target name:
Conditions Predisposing to Priapism
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Individuals with conditions such as sickle cell anemia, multiple myeloma, or leukemia are at a higher risk of developing priapism (a prolonged, painful erection), a rare but serious side effect of PDE5 inhibitors.
Actionable advice:
This is best used with caution and under medical guidance in those with a condition that increases the risk of priapism.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Treatment for erectile dysfunction should generally be used with caution by patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease) or by patients who have conditions that may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).
Label source:
FDA label: Vardenafil (LEVITRA)
Action type:
informational_none
Target id:
/condition/retinitis-pigmentosa
Target name:
Retinitis Pigmentosa
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
PDE5 inhibitors have a minor inhibitory effect on PDE6, an enzyme found in the retina. In patients with certain hereditary retinal disorders like retinitis pigmentosa, this can pose a risk to vision.
Actionable advice:
Use of PDE5 inhibitors is generally not recommended for individuals with retinitis pigmentosa.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
There are no controlled clinical data on the safety or efficacy of sildenafil tablets in patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases); if prescribed, this should be done with caution.
Label source:
Action type:
avoid
Target id:
/dietary/high-fat-meal
Target name:
High-Fat Meal
Severity:
minor
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
2
Hours after target:
2
Description:
A high-fat meal can delay the absorption of certain PDE5 inhibitors (especially sildenafil and vardenafil), resulting in a slower onset of action and potentially a less potent effect.
Actionable advice:
For fastest onset, it is best taken on an empty stomach or at least 2 hours away from a high-fat meal.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
When sildenafil tablet is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%.
Label source:
Action type:
separate
Target id:
/intervention/l-citrulline
Target name:
L-Citrulline or L-Arginine
Severity:
minor
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
1
Hours after target:
0
Description:
These amino acids are precursors to nitric oxide (NO). Since PDE5 inhibitors work by prolonging the action of NO, combining them may enhance vasodilatory effects, though this could also slightly increase the risk of low blood pressure.
Actionable advice:
If combining, be mindful of potential additive effects like lightheadedness; consider taking the supplement about an hour before the medication.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Citrulline and nitrite treatments partially normalized adipose lipid-redox signatures. Citrulline restored phospholipid remodeling and nitro-oleic acid signaling, whereas nitrite preferentially enhanced stress-associated signaling lipids.
Label source:
PubMed: Integrated Lipidomics and Nitro-Fatty Acid Profiling Link Adipose Redox Imbalance to Alzheimer's Disease-Related Neurovascular Injury. (PMID 42239044)
Action type:
separate
Target id:
/intervention/dietary-nitrate
Target name:
Dietary Nitrates (e.g., Beetroot Juice, Leafy Greens)
Severity:
minor
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Foods rich in nitrates can increase the body's production of nitric oxide, which may synergize with the mechanism of PDE5 inhibitors to improve vasodilation. This is distinct and much safer than pharmaceutical nitrates.
Actionable advice:
Consuming nitrate-rich foods as part of a healthy diet is generally safe and may be beneficial.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
This potentiation is thought to result from the combined effects of nitrates and tadalafil tablets on the nitric oxide/cGMP pathway [see Clinical Pharmacology (12.2) ] .
Label source:
Action type:
informational_none
Target id:
/class/qt-prolonging-agents
Target name:
QT-Prolonging Medications
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Some PDE5 inhibitors (e.g., vardenafil) can cause a small, dose-dependent prolongation of the QT interval. Combining with other drugs that have this effect could theoretically increase the risk of cardiac arrhythmias.
Actionable advice:
This is best used with caution when taking other medications known to prolong the QT interval, and it is worth talking to a doctor.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
A postmarketing study evaluating the effect of combining LEVITRA with another drug of comparable QT effect showed an additive QT effect when compared with either drug alone. These observations should be considered in clinical decisions when prescribing LEVITRA to patients with known history of QT prolongation or patients who are taking medications known to prolong the QT interval.
Label source:
FDA label: Vardenafil (LEVITRA)
Action type:
informational_none