A six-year NDA review for Fisons' anti-inflammatory agent Tilade (nedocromil) ended Dec. 30 with FDA clearance of the product for "maintenance therapy in the management of patients with mild to moderate bronchial asthma." Launch will take place in the second quarter, Fisons said. "Manufacture of Tilade begins immediately; shipments should start in the second quarter with availability to patients shortly thereafter," Fisons advised. While the company is building stockpiles for the U.S. launch, it must also be cleared for the use of chlorofluorocarbons in the inhaler, a standard process for new inhalers. Tilade will be copromoted in the U.S. by Rhone-Poulenc Rorer under an agreement in principle announced Dec. 31. In exchange for rights to Tilade, RPR has granted Fisons copromotion rights to its inhaled steroid Azmacort (triamcinolone). Azmacort sales more than doubled in 1991 to $86 mil. The two companies will have a total of 800 sales reps detailing the products. The firms' emphasized the "complementary" nature of the two therapies. "Tilade and Azmacort each have a unique and important pharmacologic action, and the two drugs play a complementary role in contributing to the successful treatment of asthma," Rhone-Poulenc Rorer said. The copromotion agreement will also help Fisons differentiate Tilade from its older asthma inhaler, Intal (cromolyn), first approved in the U.S. in 1973. Both products are indicated for similar conditions and call for similar dosing schedules. While nedocromil is a chemical analogue of cromolyn, the two products are differentiated by therapeutic class: Tilade is an anti- inflammatory; Intal is a mast cell stabilizer/anti-allergic. Fisons called Tilade "the first new generation chemical entity in asthma therapy in nearly a decade" and said it represents "a new class of anti-inflammatory drug." The company expects "an enthusiastic reception from physicians to generate significant numbers of patient prescriptions" for Tilade. Tilade is indicated for four-times-daily dosing to provide a total of 14 mg of nedocromil per day. "In patients under good control on four times daily dosing...a lower dose can be tried," labeling states. "If use of lower doses is attempted, Tilade should first be reduced to a three times daily regimen (10.5 mg of Tilade per day) then, after several weeks on continued good control, to twice a day (7 mg of Tilade per day)." The "Clinical Studies" section of labeling includes results from a 120-patient 14-week comparison of Tilade to placebo and a 206-patient comparison of Tilade, Intal and placebo. Tilade was "significantly superior to placebo for all measurements" in the first trial, labeling states. In the latter trial, Tilade outperformed placebo in all categories, but Intal outperformed Tilade for nighttime asthma and forced emitted volume. The approved labeling may make switching patients from Intal to Tilade difficult for Fisons. "In allergic asthmatics who are well controlled on cromolyn sodium, there is no evidence that the substitution of Tilade for cromolyn sodium would confer additional benefit to the patient," labeling states. "Efficacy with one agent is not known to be predictive of efficacy with the other." Tilade "is not indicated for the reversal of acute bronchospasm," labeling states. Intal's labeling does allow for prophylactic use in acute bronchospasm: "In patients who develop acute bronchoconstriction in response to exposure to exercise, toluene diisocyanate, environmental pollutants, known antigens, etc., Intal inhaler should be used shortly before exposure to the precipitating factor." Tilade labeling notes that "laboratory studies" have suggested similar benefit from pretreatment with Tilade, but that "controlled studies have not been carried out to assess the clinical significance of these findings." "Tilade is generally well tolerated," labeling states. Fisons' adverse event database includes 5,352 patients who received Tilade in clinical trials. A total of 2,042 patients were in placebo controlled trials of which 7% withdrew due to adverse events, compared to 6% of the 1,875 placebo patients. The only statistically more frequent reason for withdrawal in the Tilade group was bad taste (2.1% versus .4% for placebo). Like Intal, Tilade carries a label warning that it is "not a bronchodilator" and therefore should not be used in status asthmaticus. Tilade labeling also includes general precautionary statments about the possibility of coughing and bronchospasm in some patients and about the need for careful monitoring if steroid therapy is reduced for patients on Tilade. Fisons filed an NDA (19-660) for Tilade on Feb. 27, 1987, and FDA's Pulmonary-Allergy Drugs Advisory Committee recommended it for approval on June 11, 1990 ("The Pink Sheet" June 18, 1990, p. 10). The approval of Tilade may have been delayed in the past year by the ongoing manufacturing compliance problems at Fisons' Holmes Chapel, U.K. facility. Fisons has withdrawn injectable iron dextran and Opticrom brand chromolyn eye drops from the U.S. market following recalls in 1990 and 1991 ("The Pink Sheet" Dec. 23, 1991, p. 7). FDA also documented problems with leaking air valves on the Intal inhaler; the agency apparently did not request a recall because of the therapeutic importance of the product. The Tilade approval may mark a significant step forward by Fisons in the protracted process of reestablishing FDA's confidence in the U.K. manufacturing facilities. According to final labeling, Tilade for the U.S. market will be manufactured by Fisons in the U.K.
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