Merck Singulair Churg-Strauss Cases Reported In "Dear Doctor" Letter

Merck Singulair labeling has been changed to include precautions regarding "rare cases" of Churg-Strauss syndrome-like symptoms in patients receiving the leukotriene receptor antagonist for asthma.

"In rare cases, patients on therapy with Singulair [montelukast] may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy," revised labeling states.

Merck is informing physicians of changes to the "precautions" and "adverse reactions" sections of labeling through a "Dear Doctor" letter, which the company sent to 120,000 physicians and 45,000 pharmacists Dec. 3.

Revised labeling states that "these events usually, but not always, have been associated with the reduction of oral corticosteroid therapy." Merck estimates the incidence of the event in the approximately 600,000 patients who have received Singulair worldwide to be about .003%, or 18 reports.

"Patients presenting with these conditions had significant asthma histories and were receiving multiple asthma medications, often including systemic corticosteroids," the Dear Doctor letter explains. "On review, some of these cases had features consistent with these conditions present prior to initiation of therapy with Singulair." Labeling adds that "a causal association between Singulair and these underlying conditions has not been established."

Singulair's original labeling noted that Churg-Strauss syndrome has not been seen in montelukast clinical trials but had been observed in patients receiving another leukotriene antagonist, Zeneca's Accolate.

Original labeling had stated that while "reduction in systemic corticosteroid dose in patients receiving another leukotriene antagonist has been followed in rare cases by the occurrence of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complication, and/or neuropathy sometimes presenting as Churg-Strauss syndrome...a causal relationship with leukotriene receptor antagonism has not been established and the phenomenon was not observed in clinical trials of montelukast."

Upon its approval on Feb. 20 in the U.S., Singulair received an indication for the prevention and chronic treatment of asthma in adults and children more than six years old. However, in Europe, where it was approved on Feb. 4, the indication was limited to "add-on therapy in those patients with mild to moderate asthma who are inadequately controlled on inhaled corticosteroids and in whom 'as needed' short acting agonists provide inadequate control of asthma" ("The Pink Sheet" Feb. 16, T&G-4).

European labeling for the drug noted that "the possibility that receptor antagonists may be associated with the emergence of Churg-Strauss syndrome cannot be excluded." The EU labeling also stressed that Singulair be used only as an add-on therapy, and recommended against withdrawing corticosteroids.

In September, the U.K. Medicines Control Agency released a report citing 173 postmarketing reports of 317 adverse drug reactions associated with Singulair, including some cases of CSS ("The Pink Sheet" Sept. 7, p. 17).

The precautions concerning cases of CSS-like symptoms in Singulair patients could reduce the drug's edge over its competitor Accolate (zafirlukast). Since its launch in March, Singulair has made significant inroads into Accolate's market share for leukotriene agents.

Singulair accounted for 35.1% of new prescriptions for leukotriene agents in its first three months on the market, while Accolate dominated the market with a 62.8% share. Abbott's leukotriene inhibitor Zyflo (zileuton), which has not been associated with Churg-Strauss but carries liver warnings, held a 2.1% share of leukotriene scripts ("The Pink Sheet" July 27, p. 21).

A Feb. 11 Journal of the American Medical Association article analyzed eight cases of CSS following withdrawal of corticosteroid therapy in patients taking Accolate. The article suggested that the patients "may have had a primary eosinophilic infiltrative disorder that had been clinically recognized as asthma, was quelled by steroid treatment, and was unmasked following corticosteroid withdrawal facilitated by zafirlukast."

Merck reported $41 mil. in U.S. sales of Singulair for third quarter 1998, and $55 mil. in sales worldwide for the quarter ("The Pink Sheet" Oct. 19, p. 25).