Avanafil and Riociguat: Why the Combination Is Unsafe

Most people have heard of the warning about erectile dysfunction pills and nitroglycerin. Far fewer have heard that a second, less familiar medicine carries a similar stop sign: riociguat. If you take riociguat, sold as Adempas, for a serious lung condition, the avanafil prescribing information lists the combination as contraindicated. The same applies to vericiguat (Verquvo), a related drug used in heart failure.

Because riociguat is a specialist medicine, many community pharmacists dispense it only occasionally, and many men with pulmonary hypertension are never told that sexual-health treatments can clash with it. This article is organised differently from our other interaction guides. It starts with the biology, moves on to the people who actually take riociguat, then follows the question of erectile dysfunction in this group, and ends with a set of “verification gates” that a pharmacist works through before dispensing anything in the PDE5 inhibitor family.

Important: this article is for general education. If you take riociguat or vericiguat, do not start avanafil or any other PDE5 inhibitor, and do not stop your own medicine, without direct advice from your specialist.

At a glance

Riociguat is a soluble guanylate cyclase (sGC) stimulator used for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).
Avanafil is a PDE5 inhibitor used for erectile dysfunction.
Both increase the same relaxing signal in blood vessels, cyclic GMP, from two directions.
Avanafil labelling contraindicates guanylate cyclase stimulators such as riociguat and vericiguat because of the risk of symptomatic low blood pressure.
The conflict also applies to sildenafil, tadalafil and vardenafil, so switching brands does not help.

Part one: two drugs, one signalling chain

To see why this pairing is problematic, imagine the relaxation signal in a blood vessel as a short chain of events.

Cells release nitric oxide (NO).
Nitric oxide activates an enzyme called soluble guanylate cyclase.
That enzyme produces cyclic GMP (cGMP).
cGMP tells the vessel’s smooth muscle to relax.
An enzyme called PDE5 breaks cGMP down, ending the signal.

Riociguat acts at step two. It makes soluble guanylate cyclase more sensitive to nitric oxide and can stimulate it directly, so more cGMP is made. Avanafil acts at step five. It blocks PDE5, so cGMP survives longer. Together, they raise the amount of cGMP from both sides, and the blood-vessel relaxation can go beyond what the body can handle. The label for avanafil states that PDE5 inhibitors may potentiate the hypotensive effects of guanylate cyclase stimulators, and it instructs prescribers not to use avanafil in patients taking them.

A helpful analogy

Think of filling a bath. Riociguat opens the tap wider, and avanafil partly plugs the drain. Either measure alone raises the water level in a controlled way, and clinicians can dose each accordingly. Do both at once, and the bath overflows. Here, the overflow is a fall in blood pressure that may cause fainting, reduced blood flow to vital organs, and risk of injury.

Part two: who takes riociguat, and why it matters

Riociguat is prescribed for two related forms of high blood pressure in the lungs.

Pulmonary arterial hypertension (PAH): the small arteries of the lungs narrow and stiffen, forcing the right side of the heart to work harder.
Chronic thromboembolic pulmonary hypertension (CTEPH): old blood clots in the lung arteries form scar-like obstructions, raising pressure. Riociguat is used for patients who cannot have surgery or who still have symptoms after it.

These are serious, long-term conditions, usually managed by a pulmonary hypertension centre. Because the disease is rare, patients often build close relationships with their specialist nurses and clinic pharmacists, and they may fill prescriptions through a specialty pharmacy. That can lead to a subtle problem: the local pharmacy that handles an ED prescription may never see the riociguat on file.

Why this is a high-stakes patient group

People with pulmonary hypertension already have limited cardiovascular reserve. A drop in blood pressure that a healthy person would shrug off can reduce blood flow to the heart and brain in someone whose right ventricle is under strain. Fainting during exertion, including sexual activity, is itself a recognised concern in pulmonary hypertension. This is why the contraindication is not merely theoretical and why specialist teams take it seriously.

Part three: the PDE5 twist, and why PAH patients are told to choose

Here is a detail that confuses patients. Some PDE5 inhibitors, such as sildenafil and tadalafil, are themselves approved for pulmonary arterial hypertension, though at different doses and under different brand names. Our article comparing Revatio and Viagra explains how the same molecule can be sold for lung disease and for ED.

That raises an obvious question: if PDE5 inhibitors treat PAH, why can they not be added to riociguat? Studies examined exactly that. A small clinical trial that added riociguat to sildenafil in PAH patients did not show a favourable clinical benefit, and it reported more low blood pressure along with safety concerns in the follow-up phase. As a result, regulators made the combination a contraindication on the riociguat label, and avanafil labelling mirrors it. In practice, specialists choose either a PDE5 inhibitor or a guanylate cyclase stimulator for the same patient, and they manage any switch carefully with a defined gap between the drugs.

So if you are a man with PAH on riociguat who also has ED, the options are not to add a PDE5 inhibitor for ED. The better route is to ask your specialist whether your PAH regimen could ever change and whether non-PDE5 ED therapies are suitable.

Part four: what about vericiguat?

Vericiguat belongs to the same sGC stimulator family and is used for certain adults with symptomatic chronic heart failure and reduced ejection fraction after a recent decompensation. The avanafil label names it alongside riociguat as a contraindicated partner. The logic is identical: two routes to higher cGMP and a risk of symptomatic hypotension.

If you take vericiguat, the pharmacist check proceeds along the same lines as for riociguat. Heart-failure patients also often take nitrates or diuretics, which creates additional layers of risk. If any of these apply to you, read our companion article on avanafil and isosorbide dinitrate, since BiDil and other heart-failure regimens contain a nitrate.

Part five: the verification gates

Think of the pharmacist’s review as a series of gates. A prescription passes through them one at a time, and if a gate fails, the dispensing stops until the problem is resolved.

Gate 1: identity of every active drug

The pharmacist checks whether the profile includes riociguat (Adempas), vericiguat (Verquvo) or any other guanylate cyclase stimulator. Because specialty pharmacies may fill these, the pharmacist also asks you directly.

Gate 2: other nitric-oxide pathway drugs

Riociguat is itself contraindicated with nitrates, and with PDE5 inhibitors in general. The pharmacist therefore also checks for nitroglycerin, isosorbide products and any other PDE5 inhibitor. See avanafil and nitroglycerin for more.

Gate 3: the reason for the prescription

Is the avanafil being prescribed for ED, or has someone confused it with a pulmonary hypertension drug? Avanafil is approved only for erectile dysfunction, and there is no pulmonary hypertension indication. A pharmacist will clarify if the prescriber or the patient has mixed up PDE5 inhibitors.

Gate 4: recent changes

Have you recently switched from a PDE5 inhibitor to riociguat, or the reverse? The guidance for switching sets minimum intervals, and the specialist, not the pharmacist, must define them. A pharmacist will check the date of the last dose of each drug and will contact the prescriber if the timeline is unclear.

Gate 5: other interacting medicines

The pharmacist reviews medicines that change riociguat levels or blood pressure, including strong azole antifungals, certain HIV protease inhibitors, antacids that affect absorption, and other antihypertensives. Smoking also matters, because it reduces riociguat exposure; any change in smoking status should be shared with your specialist.

Gate 6: the person’s overall cardiovascular picture

Labels for PDE5 inhibitors advise against use where sexual activity is inadvisable for cardiovascular reasons. For someone with pulmonary hypertension, the pharmacist will encourage a conversation with the specialist about exertion, safe activity levels, and warning signs.

Gate 7: documentation

If any gate fails, the pharmacist records the issue, notifies the prescriber, and explains the reason to you. Many pharmacies add a permanent alert to the profile so that the next pharmacist is warned.

Part six: erectile dysfunction in pulmonary hypertension

Erectile dysfunction is common in men with chronic cardiopulmonary disease. Several factors contribute: reduced oxygen delivery, fatigue, medicines, anxiety, low testosterone and the emotional toll of living with a serious illness. In pulmonary hypertension, specialists increasingly recognise sexual health as part of quality of life, even if the topic is rarely raised unprompted.

Ways to open the conversation

“I take riociguat. I have noticed changes in my sexual function. Could we talk about it?”
“Is it safe for me to be sexually active given my condition?”
“Which treatments for erectile dysfunction would not interfere with my PAH medicines?”

Options a specialist might discuss

The exact list depends on your health, but common categories include:

Vacuum erection devices that use suction rather than medicines.
Intracavernosal or urethral alprostadil, which acts locally in the penis. Your specialist will weigh any effect on blood pressure.
Testosterone evaluation and treatment where low levels are confirmed.
Counselling and sex therapy, which help with anxiety, body image and communication with a partner. Our guide on overcoming psychological erectile dysfunction may offer a starting point.
Pacing and positioning strategies to reduce breathlessness during intimacy, taught by pulmonary rehabilitation teams.
Medication review to see whether any other prescription may be contributing.

Be cautious about supplements marketed for circulation. Some contain stimulants or undeclared drugs, and others lower blood pressure. Our summary of supplements marketed to boost penile blood flow describes why evidence is mixed and why anything you take should be shared with your care team.

Part seven: living with a carefully titrated drug

Riociguat is not started at a full dose. Specialists begin low and increase gradually, checking blood pressure at each step, because the drug itself can lower it. A patient who feels settled at one dose may be on the path to a higher one. That detail matters for two reasons.

Your blood pressure may be less predictable than it looks. During titration, the margin between a comfortable blood pressure and a symptomatic one is narrow. Adding a PDE5 inhibitor at this stage would be particularly unwise.
Dose changes alter the interaction landscape. A medicine list that was reviewed six months ago may no longer describe your current regimen. Ask your pharmacist to refresh the profile whenever the dose changes.

Riociguat is also supplied through restricted distribution programmes in some countries, mainly because of its risk to unborn babies. That is unrelated to the PDE5 interaction, but it explains why the medicine often comes from a specialty pharmacy that your local pharmacist cannot see. Never assume the two systems share information automatically.

Rules for switching between drug families

Patients sometimes ask how long they must wait after stopping a PDE5 inhibitor before starting riociguat, or the other way around. The details are set out in the riociguat labelling and managed by specialists, and they can differ by drug and by dose. For the purposes of this article, three general principles are worth knowing.

A switch is a planned event. It is arranged by the specialist, with a clear last-dose date for the outgoing drug.
Self-directed overlap is not acceptable. Taking “one last ED pill” before a switch, or “one dose of the old drug” after, undermines the plan.
Different PDE5 inhibitors clear at different speeds. Sildenafil and tadalafil, for instance, do not leave the body at the same rate. Our guides to how long sildenafil lasts and how long Cialis stays in your system explain why generic waiting rules are unreliable.

If your specialist has told you the exact interval that applies to you, ask them to write it down and give a copy to your pharmacist.

Everyday life with pulmonary hypertension and intimacy

Medicines are one piece of the puzzle. Many people with pulmonary hypertension find that practical adjustments make intimacy easier and safer.

Plan for energy. Choose times of day when you feel strongest, and avoid sex immediately after a heavy meal or on a day when symptoms are worse.
Use positions that reduce effort. Positions in which you are supported, such as lying on your side or sitting, may reduce breathlessness.
Keep supplemental oxygen available if you use it, and discuss with your team whether to use it during activity.
Stop if you feel unwell. Chest pain, dizziness, severe breathlessness or fainting are reasons to stop and seek help.
Talk with your partner. Open communication reduces pressure and fear. A shared understanding of warning signs helps both of you.

Pulmonary rehabilitation programmes can build fitness safely and may improve confidence. Many teams include a nurse or psychologist who is comfortable discussing sexual health, even if you have to ask for it.

What good telehealth and online screening should ask

Online ED services are convenient, but a screening form is only as good as its questions. A responsible service should ask about:

Any use of nitrates or nitrate-like products, including poppers
Any lung or heart condition, including pulmonary hypertension and heart failure
Any use of riociguat, vericiguat, or other guanylate cyclase stimulators
Other blood-pressure medicines, alpha-blockers and recent cardiac events
Liver and kidney disease
Other ED medicines already in your possession

If the form lists only nitrates and skips guanylate cyclase stimulators, answer anyway in a free-text box or contact a clinician. Rare drugs are exactly the ones that automated checklists tend to omit. Our overview of the best ED drug choices also explains why a personal medical history should drive the choice, not the other way round.

For partners and caregivers

If you care for someone with pulmonary hypertension or heart failure, you may be the person who notices a change first. A few practical suggestions:

Learn the names of the person’s key medicines and keep a copy of the list on your phone.
Encourage them to mention sexual health at appointments, and offer to attend if they would like support.
If you find ED pills in the house, ask whether a clinician knows about them.
Know what to do in an emergency: where the list is, who to call, and which hospital holds the medical records.

Part eight: scenarios

The following scenarios are fictional composites used to illustrate how decisions unfold.

Scenario one: the new prescription

A man in his fifties with CTEPH takes riociguat three times a day. He visits a telehealth service and requests avanafil for ED. The service asks only about nitrates. At the pharmacy, the pharmacist sees riociguat on the profile from the specialty pharmacy and declines to dispense, then calls the telehealth prescriber. The result is a referral to the pulmonary hypertension clinic for a joint discussion.

Scenario two: the switch

A man has taken sildenafil for PAH and his specialist is moving him to riociguat. He mentions he sometimes uses an ED pill at the weekend. The specialist explains that he must not use any PDE5 inhibitor, including leftover pills, while on riociguat and must follow the exact washout schedule. The pharmacist notes this on his file.

Scenario three: the borrowed pill

A man on vericiguat after a heart-failure admission takes a friend’s avanafil tablet. Twenty minutes later he feels faint and sits down. His partner calls emergency services and gives the names of both medicines. He recovers after monitoring in the emergency department. His care team reviews safer options and records the incident.

Common questions people have about the label

Is it the dose of avanafil that matters?

No. The contraindication does not depend on using a lower strength. The risk is the pharmacological overlap, so even 50 mg would not be an acceptable workaround.

Does timing help, for example taking riociguat in the morning and avanafil at night?

Riociguat is usually taken three times daily, and its effects continue across the day. No label sets out a safe timing pattern for combining it with a PDE5 inhibitor. Specialists handle transitions between the drugs using defined intervals that apply to switching, not to taking both.

What about herbal blood-flow boosters?

These products are not standardised, and some contain hidden prescription drugs. Treat them as medicines and discuss them with your clinician. Our guide to nitric oxide supplements for erectile dysfunction explains why this deserves caution.

If I choose a different PDE5 inhibitor, will that avoid the problem?

No. Sildenafil, tadalafil and vardenafil also carry contraindications with riociguat. For help understanding how they differ in the general ED population, see avanafil versus Viagra and avanafil versus vardenafil, but remember that those comparisons assume you are not on a guanylate cyclase stimulator.

What if my symptoms of low blood pressure appear hours later?

Symptoms can be delayed, especially with long-acting medicines. Seek urgent care for fainting, chest pain, breathlessness or confusion, and report the exact timing of each drug.

Safety net: what to do if you took both

Sit or lie down at once, with legs elevated if possible.
Call your local emergency number if you feel faint, short of breath, or have chest pain or palpitations.
Tell responders that you take riociguat (or vericiguat) and that you took avanafil, with times and doses.
Inform your pulmonary hypertension or heart-failure team the same day.
Do not take any further doses until a clinician reviews your situation.

Tips for staying organised

Carry a wallet card that lists riociguat or vericiguat and the line “No PDE5 inhibitors or nitrates.”
Use a single community pharmacy for everything except specialty drugs, and make sure that pharmacy knows what the specialty pharmacy supplies.
Tell every new prescriber, including telehealth clinicians, that you take a guanylate cyclase stimulator.
Review your medicine list at every clinic visit.
Keep old ED pills out of your cabinet to prevent accidental use.

Where to read next

To see how avanafil behaves in other medicine pairings, read avanafil and tamsulosin. For a general guide to choosing ED therapies in people with other conditions, see the safest drug for erectile dysfunction. More topics are collected on the PinkViva blog.

References

This article is intended for general education and is not a substitute for professional medical advice. Always confirm details with your specialist and pharmacist.