Food, slow titration recommended to tame Uptravi side effects

Therapy works like prostacyclin, a substance that causes blood vessels to relax

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Experts recommend taking Uptravi (selexipag) with food and slowly titrating it up, at a frequency of less than weekly or by raising one of the two daily doses, as tolerated, while caring for any side effects adults with pulmonary arterial hypertension (PAH) may be having.

The recommendation came from a panel of doctors and nurses who met as part of a consensus study aimed at minimizing side effects and helping patients live better. It was funded by Janssen, now Johnson & Johnson Innovative Medicine, which markets Uptravi. Sheryl Wu, a pharmacist at the University of California San Diego Health, presented the study’s highlights in a poster session at the 2024 American Thoracic Society (ATS) conference, held last month in San Diego.

“The main takeaways … included taking selexipag with food, slowing down the titration frequency to less than weekly, stair-stepping the titration with the initial increase in the evening and proactive side effect management,” Wu said in a written Q&A with Pulmonary Hypertension News.

An abstract to Wu’s poster, “Expert Consensus on Best Practices for Oral Selexipag Titration and Management of Expected Prostacyclin Side Effects in Patients with Pulmonary Arterial Hypertension (PAH),” appeared in the American Journal of Respiratory and Critical Care Medicine.

Uptravi works similarly to prostacyclin, a substance in the body that causes blood vessels to relax. In PAH, where blood pressure in the arteries of the lungs is abnormally high, Uptravi relaxes blood vessels, lowering blood pressure and easing symptoms.

“Like all medications, selexipag comes with great benefits, but also [comes] with side effects,” Wu said. “If we can manage the side effects of the medication, have the good effects outweigh the bad, patients will be willing and able to persist and continue therapy.”

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Making Uptravi more tolerable to PH patients

To reach a consensus about improving its tolerability, 17 experts in the U.S. (11 doctors, five nurse practitioners, and one registered nurse) participated in a Delphi panel, which combines expert opinions over repeated rounds of rating.

While all of them had their own methods for dosing, they agreed on starting and titrating Uptravi according to U.S. package insert guidelines. To improve its tolerability, they recommended taking Uptravi with food, slowing the titration, or increasing the evening dose first.

Nearly two-thirds (64%) of their patients ended up on doses of 1200-1600 micrograms twice daily, and experts took into account factors like age and coexisting conditions (for example, scleroderma or long-lasting pain) when titrating up.

Common and bothersome side effects, such as headaches and diarrhea, usually went away in six to eight weeks, whereas flushing, muscle pain, nausea, and vomiting resolved within two to four weeks.

Before starting treatment, patients should be informed about possible side effects and how to manage them. “Side effect management should start with shared decision-making with the patient along with education and expectations of the medication effects,” said Wu, who noted researchers continue to “explore ways to support clinicians and patients with respect to improving selexipag patient adherence and clinical outcomes.”

Patients on Uptravi are often on background medication with an endothelin receptor antagonist (ERA), a phosphodiesterase type 5 inhibitor (PDE5i), or both. While guidelines recommend the dual combination for most PAH patients of low or intermediate risk, many still take only one medication.

Choosing the right treatment

In another study presented at the 2024 ATS conference, 195 healthcare providers in the U.S. were asked about what makes them decide on the dual combination and whether a single tablet like Opsynvi (macitentan and tadalafil) would be a solution.

The most important factors were current treatment, the cause of PAH, coexisting conditions, and side effect history. A single tablet could help start treatment sooner and improve compliance, but concerns about cost and side effects could hinder its use.

“I was most surprised that current treatment, cause of PAH, and comorbidities were more motivating in deciding to use upfront combination therapy than in markers of disease progression such as hospitalization, symptom progression, or functional class,” Nicholas Kolaitis, MD, of University of California San Francisco, said in a separate written Q&A. “I also found it interesting that providers were likely to use upfront combination therapy in the presence of cardiopulmonary comorbidiites. I think this reflects a difference in practice amongst PAH experts between the U.S. approach to treatment and the current 2022 ESC/ERS guidelines.”

Kolaitis said Opsynvi “has the potential to reduce the number of prior authorization requests a team has to obtain to get patients to combination therapy, so it may reduce burden.”

“I do think it will help with patient adherence. Any time you are able to reduce pill burden, it helps patients,” he said.

Kolaitis’ presentation was titled “Provider Preferences Regarding the Use of Combination ERA+PDE5i for the Treatment of Pulmonary Arterial Hypertension: Results From a Discrete Choice Experiment.” The study was funded by Actelion, which transitioned to Johnson & Johnson Innovative Medicine.

More than two-thirds (76.9%) of healthcare providers said they were willing to switch to a dual combination like Opsynvi, which in clinical testing has shown improved blood flow with PAH. Many doctors “may not be familiar” with the option yet, Kolaitis said. “I believe that the factors limiting use of upfront combination therapy in patients with PAH vary by practice location. There are many times where the initial diagnosis of PAH occurs at a non-expert center. As such, the burden of initial treatment falls on non-expert providers. These providers are often familiar with the PDE5i, but may not be familiar with upfront combination therapy.”

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