Ambrisentan (Letairis) Drug Interactions: What to Avoid and What to Tell Your Doctor

Ambrisentan (Letairis) is processed in the body through multiple enzyme and transport pathways, which means it can interact with a significant number of other medications. Some interactions are minor, some require dose adjustments, and a few are serious enough to prohibit the combination altogether. This guide covers the most important ambrisentan drug interactions to be aware of in 2026.

Always bring a complete list of your medications — including over-the-counter drugs, vitamins, and supplements — to every appointment with your PAH specialist and pharmacist.

Contraindicated Combination: Sparsentan

Sparsentan (Filspari), used for IgA nephropathy, is an endothelin antagonist combined with an angiotensin receptor blocker. Combining sparsentan with ambrisentan is contraindicated — meaning the combination must never be used. Coadministration of two endothelin antagonists is associated with increased risks of:

Hypotension (dangerously low blood pressure)

Syncope (fainting)

Hyperkalemia (dangerously high potassium levels)

Acute renal failure

Major Interaction: Cyclosporine (Dose Adjustment Required)

Cyclosporine is an immunosuppressant used after organ transplants and for autoimmune conditions. When taken together with ambrisentan, cyclosporine inhibits OATP1B1/1B3 transporters and significantly increases ambrisentan blood levels — roughly doubling exposure.

If you must take cyclosporine and ambrisentan together, your doctor will limit your ambrisentan dose to 5 mg once daily maximum. Never increase your ambrisentan dose without discussing your cyclosporine use with your doctor first.

Medications That Increase Ambrisentan Levels

These drugs inhibit the enzymes or transporters that clear ambrisentan from the body, potentially causing ambrisentan levels to rise — increasing both the medication's effects and the risk of side effects:

CYP3A4 inhibitors: Idelalisib (a strong CYP3A4 inhibitor — avoid), cobicistat/elvitegravir (typically contraindicated for CYP3A4 substrates), certain antifungals and antibiotics

OATP1B1/1B3 inhibitors: Cyclosporine (dose-limit to 5 mg), enasidenib (avoid — may cause serious toxicity), sofosbuvir/velpatasvir (use caution), ceftobiprole (avoid or use alternative), leniolisib (avoid or monitor)

CYP2C19 inhibitors: Cannabidiol (CBD) and cenobamate can increase ambrisentan levels through CYP2C19 inhibition; consider dose reduction if clinically indicated

Medications That Decrease Ambrisentan Levels

These drugs speed up the metabolism or clearance of ambrisentan, potentially reducing its effectiveness:

CYP3A4 inducers: Apalutamide (a strong CYP3A4 inducer) significantly reduces ambrisentan exposure — avoid this combination or substitute another drug; evaluate for loss of therapeutic effect

Rifampin (rifampicin): A strong inducer of multiple CYP and P-gp pathways that may significantly reduce ambrisentan levels — discuss this with your PAH specialist if you need treatment for tuberculosis or other infections

Medications Affected by Ambrisentan

Ambrisentan is not just a target of drug interactions — it can also affect the levels of other medications you take:

Ambrisentan inhibits CYP3A4 and can increase levels of CYP3A4 substrates including combined hormonal contraceptives (birth control pills, patches, rings, injections) and conjugated estrogens

This interaction is clinically important: while birth control is required with ambrisentan, hormonal contraceptives alone are not considered reliable enough — you must also use a barrier method or other non-hormonal backup

Supplements and Herbal Products

Some herbal products and supplements may also interact with ambrisentan:

St. John's Wort: A strong CYP3A4 inducer that could significantly reduce ambrisentan levels — avoid while taking ambrisentan

Shepherd's purse: May theoretically interfere with blood pressure control — use caution

Grapefruit juice: May inhibit CYP3A4 and increase ambrisentan levels — talk to your doctor about whether to limit intake

What to Tell Your Doctor and Pharmacist

Before starting ambrisentan, provide your full medication list to your PAH specialist and pharmacist — including:

All prescription medications (including immunosuppressants, antivirals, antifungals, antibiotics, cancer drugs)

Over-the-counter medications

All vitamins, minerals, and herbal supplements

CBD products or cannabinoids

If you are struggling to find ambrisentan at your pharmacy, medfinder can help locate it near you. For more safety information, see our guide on ambrisentan side effects and when to call your doctor.