Summary Safety Review - Nitric Oxide and Treprostinil - Assessing the Potential Risk of Pulmonary Edema in Patients with Pulmonary Veno-occlusive Disease

Nitric oxide-containing products and treprostinil-containing products

Pulmonary edema (build up of fluid in the lungs) in patients with pulmonary veno-occlusive disease (condition characterized by the blockage of the blood vessels that carry blood from the lungs to the heart) (PVOD)

• Health Canada’s review found a possible link between the use of either nitric oxide or treprostinil, and the risk of pulmonary edema in patients with PVOD.

• Health Canada will work with the manufacturers to update the product safety information in the Canadian product monograph (CPM) for all nitric oxide-containing products and treprostinil-containing products to include the risk of pulmonary edema in patients with PVOD.

Health Canada reviewed the potential risk of pulmonary edema with the use of either nitric oxide or treprostinil in patients with PVOD. The safety review was triggered by a case reported to the Canada Vigilance database.

Nitric oxide and treprostinil belong to a larger class of prescription drugs called pulmonary vasodilators (drugs that widen blood vessels in the lungs to allow blood to flow more easily). The safety review focused on nitric oxide and treprostinil since the CPM for all other pulmonary vasodilators already include the risk of pulmonary edema in patients with PVOD.

• Nitric oxide is a prescription drug authorized for sale in Canada for the treatment of hypoxic respiratory failure (when there is not enough oxygen in the blood) in babies who have been born at 34 weeks or later, with evidence of pulmonary hypertension (high blood pressure in the lung).

• Treprostinil is a prescription drug authorized for sale in Canada for the treatment of persistent pulmonary hypertension (long term high blood pressure in the arteries of the lungs) in certain patients, who do not respond adequately to standard therapy.

• Nitric oxide has been marketed in Canada since 2005. It is currently available as a gas for inhalation in either 100 or 800 ppm per cylinder under the brand names INOmax and Kinox.

• Treprostinil has been marketed in Canada since 2004. It is currently available as a solution for injection in 4 different strengths (1.0, 2.5, 5.0 and 10.0 mg/mL) under the brand name Remodulin. A generic version is also available.

• The exact amount of usage of nitric oxide in Canada could not be determined based on the limitations of the data available.

• Approximately 6,000 treprostinil prescriptions were filled in Canadian pharmacies between 2019 and 2023.

• Health Canada reviewed the available information from searches of the Canada Vigilance database^a, international databases and the scientific literature.

• At the time of the review, Health Canada had received 15 Canadian reports of pulmonary edema, of which 2 were related to the use of nitric oxide (including the case that triggered this safety review) and 13 were related to the use of treprostinil. However, none of these cases were assessed further since they did not meet the definition of PVOD.

• Health Canada reviewed 12 international cases of pulmonary edema in patients with PVOD taking either nitric oxide (9) or treprostinil (3). Of those 12 cases, 7 nitric oxide cases and all treprostinil cases were found to be possibly linked, 1 nitric oxide case was unlikely to be linked, and 1 nitric oxide case was unassessable due to missing information. Eight deaths were reported among the 12 cases reviewed (7 for nitric oxide and 1 for treprostinil), of which 5 were unlikely to be linked with the use of either nitric oxide or treprostinil, and 3 were unassessable due to missing information.

• Health Canada also reviewed 5 articles published in the scientific literature. Despite some evidence suggesting that cautious use of either nitric oxide or treprostinil in the short-term may improve or stabilize some patients with PVOD, these results may not predict the development of pulmonary edema with long-term therapy in these patients.

• Health Canada’s review of the available information found a possible link between the use of either nitric oxide or treprostinil, and the risk of pulmonary edema in patients with PVOD.

• Health Canada will work with the manufacturers to update the CPM for all nitric oxide-containing products and treprostinil-containing products to include the risk of pulmonary edema in patients with PVOD.

• Health Canada encourages consumers and healthcare professionals to report any side effects related to nitric oxide or treprostinil, and other health products, to the Canada Vigilance Program.

• Health Canada will continue to monitor safety information involving nitric oxide and treprostinil, as it does for all health products on the Canadian market, to identify and assess potential harms. Health Canada will take appropriate and timely action should new health risks be identified.

The analysis that contributed to this safety review included scientific literature, Canadian and international information, and what is known about the use of nitric oxide and treprostinil both in Canada and internationally.

For additional information, contact the Marketed Health Products Directorate.

1. Canadian reports can be accessed through the Canada Vigilance Online Database.