Product: Daliresp

Company: Forest

Pharmacologic class: Selective phosphodiesterase 4 (PDE4) inhibitor.

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Active ingredient: Roflumilast 500 μg; tabs.

Indication: To reduce risk of chronic obstructive pulmonary disease (COPD) exacerbations in severe COPD patients with chronic bronchitis and a history of exacerbations. Not for the relief of acute bronchospasm.

Pharmacology: Both roflumilast and its active metabolite (roflumilast N-oxide) selectively inhibit the activity of PDE4, an enzyme that mediates the breakdown of intracellular cyclic adenosine monophosphate (AMP). The resultant increased levels of intracellular cyclic AMP in lung cells may be related to the clinical effects of roflumilast, but the exact mechanism of action is not well defined.

Clinical trials: The safety and efficacy of roflumilast in the management of COPD was evaluated in several randomized, double-blind, controlled, parallel group clinical trials involving a total of 9,394 adult patients with nonreversible obstructive lung disease.

Four of these were placebo-controlled one-year trials in patients with severe COPD that were designed to evaluate the efficacy of roflumilast on COPD exacerbations. In two of these trials, inhaled corticosteroids and short-acting beta agonists were allowed. Lung function (FEV1) and the rate of moderate or severe COPD exacerbations was a co-primary endpoint. Both trials failed to show a significant reduction in the rate of COPD exacerbations.

Subsequent trials were designed based on an analysis of a subset of these patients who appeared to have a better response compared to the overall population. These two trials enrolled 3,096 patients with severe COPD associated with chronic bronchitis, at least one COPD exacerbation in the previous year, and at least a 20 pack-year smoking history.

Long-acting beta agonists and short-acting anti-muscarinics were allowed, but not inhaled corticosteroids. In both of these trials, roflumilast 500 μg once daily showed a significant reduction in the rate of moderate or severe COPD exacerbations compared to placebo. Also, in these four trials, roflumilast 500 μg daily resulted in a significant improvement in lung function.

Two additional studies were six-month efficacy trials in patients with moderate-to-severe COPD conducted to assess the effect on lung function of roflumilast as add-on therapy to a long-acting beta agonist or a long-acting anti-muscarinic. No trials have been conducted to assess the effects of roflumilast on COPD exacerbations when added to a fixed-dose combination product containing a long-acting beta agonist and inhaled corticosteroid.

Adults: 500 μg once daily.

Children: Not recommended.

Contraindications: Moderate-to-severe liver impairment.

Warnings/Precautions: Depression. Suicidal ideation. Mild liver impairment (Child-Pugh Class A). Monitor for insomnia, anxiety, depression, suicidal ideation, other mood changes; reevaluate if occurs. Monitor weight regularly; consider discontinuing if unexplained or significant weight loss occurs. Pregnancy (Cat. C). Labor & delivery, nursing mothers: not recommended.

Interactions: Concomitant strong CYP450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin): not recommended. Potentiated by CYP3A4 and CYP1A2 inhibitors (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine), and by oral contraceptives containing gestodene + ethinyl estradiol (possible increased adverse effects).

Adverse reactions: GI upset, weight decrease, headache, back pain, influenza, dizziness, decreased appetite; psychiatric effects.

How supplied: Tabs — 30

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