Celgene Corporation's German subsidiary last week issued a “Dear Health Care Professional” letter warning that thalidomide increases the risk of blood clots in arteries, which can lead to heart attacks and strokes. According to Celgene’s letter, the prescribing information for thalidomide in Europe has been updated to include a warning about this risk.

In Europe, thalidomide (Thalomid) is approved for use in combination with melphalan (Alkeran) and prednisone in newly diagnosed multiple myeloma patients over the age of 65 and newly diagnosed patients who are not candidates for stem cell transplantation. 

In the United States, thalidomide's officially approved use is in combination with dexamethasone (Decadron) in any newly diagnosed multiple myeloma patient, regardless of age or transplant status.

The European and U.S. prescribing information for thalidomide already contain a warning that the drug increases the risk of venous thromboembolic events (blood clots in a vein or clots that break off and block an artery to the lungs).

The letter from Celgene Germany, however, states that “patients treated with thalidomide are at an increased risk for the development of arterial thromboembolic events. This includes myocardial infarcts [heart attacks] and cerebrovascular events [strokes], in addition to the already known risk of venous thromboembolic events.”

The letter explains that this risk was determined after “a recent analysis of data collected after thalidomide’s launch showed that approximately a third of all thromboembolic events reported in relation to thalidomide use were of arterial origin, with the majority being [heart attacks] and [strokes] (52.4 percent and 19.8 percent, respectively).”  The letter goes on to state, “The pathological mechanism of arterial thrombosis in patients treated with thalidomide is not yet known.”

The letter advises that measures should be taken to reduce a patient’s risk of these events, including the cessation of smoking and addressing any high blood pressure, triglyceride, or cholesterol issues a patient may have.

The greatest risk of blood clots or associated events appears to occur within the first five months of thalidomide treatment.  Therefore, patients should also take an anti-clotting agent during this time in an attempt to prevent blood clots, heart attack, and stroke.  This is particularly recommended for patients who are already at risk for blood clots and related events, such as those with a history of thromboembolic events.

Additionally, hormone replacement therapy in women and erythropoietin, a red blood cell stimulating agent, can increase a person’s risk of thromboembolic events, so these medications should be used with caution in myeloma patients being treated with thalidomide.

The letter from Celgene Germany states that the European prescribing information for thalidomide has been updated to reflect the newly recognized risk of heart attack and stroke.  However, the updated version is not yet available on the European Medicines Agency’s website.

It seems unlikely that this new safety warning will noticeably change how thalidomide is used in clinical practice, since it already is typically given in combination with anti-clotting agents. The new warning highlights, however, the importance of these anti-clotting agents and that physicians should educate and carefully monitor patients on thalidomide who have other risk factors for heart attack and stroke.

It was also announced this morning that the Korean Food and Drug Administration posted a similar warning about thalidomide’s risk and plans to conduct further studies into thalidomide’s safety.

A spokesperson for the U.S. Food and Drug Administration has informed The Beacon that the FDA also is investigating this matter, but the agency cannot provide any further details at this time.

Revlimid (lenalidomide), which is chemically similar to thalidomide, also contains a warning about an increased risk of venous thromboembolic events.  However, according to a study that the Beacon covered yesterday, the risk is several times greater with thalidomide than Revlimid (see related Beacon news). 

For more information, see Celgene’s letter (pdf in German) or The Korea Herald.