Included as part of the PRECAUTIONS section.

Treatment of Acute Bronchospasm

DALIRESP is not a bronchodilator and should not be used for the relief of acute bronchospasm.

Psychiatric Events including Suicidality

Treatment with DALIRESP is associated with an increase in psychiatric adverse reactions. In 8 controlled clinical trials 5.9% (263) of patients treated with DALIRESP 500 mcg daily reported psychiatric adverse reactions compared to 3.3% (137) treated with placebo. The most commonly reported psychiatric adverse reactions were insomnia, anxiety, and depression which were reported at higher rates in those treated with DALIRESP 500 mcg daily (2.4%, 1.4%, and 1.2% for DALIRESP versus 1.0%, 0.9%, and 0.9% for placebo, respectively) [see ADVERSE REACTIONS]. Instances of suicidal ideation and behavior, including completed suicide, have been observed in clinical trials. Three patients experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) while receiving DALIRESP compared to one patient (suicidal ideation) who received placebo.

Before using DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with DALIRESP in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with DALIRESP if such events occur.

Weight Decrease

Weight loss was a common adverse reaction in DALIRESP clinical trials and was reported in 7.5% (331) of patients treated with DALIRESP 500 mcg once daily compared to 2.1% (89) treated with placebo [see ADVERSE REACTIONS]. In addition to being reported as adverse reactions, weight was prospectively assessed in two placebo-controlled clinical trials of one year duration. Inthese studies, 20% of patients receiving roflumilast experienced moderate weight loss (defined as between 5-10% of body weight) compared to 7% of patients who received placebo. In addition, 7% of patients who received roflumilast compared to 2% of patients receiving placebo experienced severe ( > 10% body weight) weight loss. During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving DALIRESP. Patients treated with DALIRESPshould have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of DALIRESP should be considered.

Drug Interactions

A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. The administration of the cytochrome P450 enzyme inducer rifampicin resulted in a reduction in exposure, which may result in a decrease in the therapeutic effectiveness of DALIRESP. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) with DALIRESP is not recommended. [see Drugs That Induce Cytochrome P450 (CYP) Enzymes and CLINICAL PHARMACOLOGY].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies were conducted in hamsters and mice with roflumilast to evaluate its carcinogenic potential. In 2-year oral gavage carcinogenicity studies, roflumilast treatment resulted in dose-related, statistically significant increases in the incidence of undifferentiated carcinomas of nasal epithelium in hamsters at ≥ 8 mg/kg/day (approximately 11 times the MRHD based on summed AUCs of roflumilast and its metabolites). The tumorigenicity of roflumilast appears to be attributed to a reactive metabolite of 4-amino­3,5-dichloro-pyridine N-oxide (ADCP N-oxide). No evidence of tumorigenicity was observed in mice at roflumilast oral doses up to 12and 18 mg/kg/day in females and males, respectively (approximately 10 and 15 times the MRHD, respectively, based on summed AUCs of roflumilast and its metabolites).

Roflumilast tested positive in an in vivo mouse micronucleus test, but negative in the following assays: Ames test for bacterial gene mutation, in vitro chromosome aberration assay in human lymphocytes, in vitro HPRT test with V79 cells, an in vitro micronucleus test with V79 cells, DNA adduct formation assay in rat nasal mucosa, liver and testes, and in vivo mouse bone marrow chromosome aberration assay. Roflumilast N-oxide was negative in the Ames test and in vitro micronucleus test with V79 cells.

In a human spermatogenesis study, roflumilast 500 mcg had no effects on semen parameters or reproductive hormones during the 3­month treatment period and the following 3-month off-treatment period. In a fertility study, roflumilast decreased fertility rates in male rats at 1.8-mg/kg/day (approximately 29 times the MRHD on a mg/m² basis). These rats also showed increases in the incidence of tubular atrophy, degeneration in the testis and spermiogenic granuloma in the epididymides. No effect on male rat fertility rate orreproductive organ morphology was observed at 0.8 mg/kg/day (approximately 13 times the MRHD on a mg/m²basis). No effect on female fertility was observed up to the highest roflumilast dose of 1.5 mg/kg/day in rats (approximately 24 times the MRHD on a mg/m²basis).

Clinical Studies

Chronic Obstructive Pulmonary Disease (COPD)

The efficacy and safety of DALIRESP (roflumilast) in COPD was evaluated in 8 randomized double-blind, controlled, parallel group clinical trials in 9394 adult patients (4425 receiving DALIRESP 500 mcg) 40 years of age and older with COPD. Of the 8 trials, two were placebo-controlled dose selection trials (Trials 1 and 2) of 6 months duration that evaluated the efficacy of DALIRESP 250 mcg and 500 mcg once daily, four were placebo-controlled 1-year trials (Trials 3, 4, 5, and 6) primarily designed to evaluate the efficacy of DALIRESP on COPD exacerbations, and two were 6-month efficacy trials (Trials 7 and 8) which assessed the effect of DALIRESP as add-on therapy to a long-acting beta agonist or long-acting anti-muscarinic. The 8 trials enrolled patients with nonreversible obstructive lung disease (FEV₁/FVC ≤ 70% and ≤ 12% or 200 mL improvement in FEV₁ in response to 4 puffs of albuterol/salbutamol) but the severity of airflow obstruction at baseline was different among the trials. Patients enrolled in the dose selection trials had the full range of COPD severity (FEV₁ 30-80% predicted); median age of 63 years, 73% male, and 99% Caucasian. Patients enrolled in the four exacerbation trials had severe COPD (FEV₁ ≤ 50% predicted); median age of 64 years, 74% male, and 90% Caucasian. Patients enrolled in the two 6-month efficacy trials had moderate to severe COPD (FEV₁ 40-70% predicted); median age of 65 years, 68% male, and 97% Caucasian. COPD exacerbations and lung function (FEV 1) were co-primary efficacy outcome measures in the four 1­year trials. In the two 6-month supportive efficacy trials, lung function (FEV₁) alone was the primary efficacy outcome measure.

The two 6-month dose-selection efficacy trials (Trials 1 and 2) explored doses of 250 mcg and 500 mcg once daily in a total of 1929 patients (751 and 724 on DALIRESP 250 and 500 mcg, respectively. The selection of the 500 mcg dose was primarily based on nominal improvements in lung function (FEV₁) over the 250 mcg dose. The once daily dosing regimen was primarily based on the determination of a plasma half-life of 17 hours for roflumilast and 30 hours for its active metabolite roflumilast N-oxide [see CLINICAL PHARMACOLOGY].

Effect on Exacerbations

The effect of DALIRESP 500 mcg once daily on COPD exacerbations was evaluated in four 1-year trials (Trials 3, 4, 5, and 6).

Two of the trials (Trials 3 and 4) conducted initially enrolled a population of patients with severe COPD (FEV₁ ≤ 50% of predicted) inclusive of those with chronic bronchitis and/or emphysema who had a history of smoking of at least 10 pack years. Inhaled corticosteroids were allowed as concomitant medications and used in 61% of both DALIRESP and placebo-treated patients and short­acting beta agonists were allowed as rescue therapy. The use of long-acting beta agonists, long-acting anti-muscarinics, and theophylline were prohibited. The rate of moderate or severe COPD exacerbations was a co-primary endpoint in both trials. There was not a symptomatic definition of exacerbation in these 2 trials. Exacerbations were defined in terms of severity requiring treatment with a moderate exacerbation defined as treatment with systemic glucococorticosteroids in Trial 3 or systemic glucocorticosteroids and/or antibiotics in Trial 4 and a severe exacerbation defined as requiring hospitalizations and/or leading to death in Trial 3 or requiring hospitalization in Trial 4. The trials randomized 1176 patients (567 on DALIRESP) in Trial 3 and 1514 patients (760 on DALIRESP) in Trial 4. Both trials failed to demonstrate a significant reduction in the rate of COPD exacerbations.

Exploratory analyses of the results of Trials 3 and 4 identified a subpopulation of patients with severe COPD associated with chronic bronchitis and COPD exacerbations within the previous year that appeared to demonstrate a better response in the reduction of the rate of COPD exacerbations compared to the overall population. As a result, two subsequent trials (Trial 5 and Trial 6) were conducted that enrolled patients with severe COPD but associated with chronic bronchitis, at least one COPD exacerbation in the previous year, and at least a 20 pack-year smoking history. In these trials, long-acting beta agonists and short-acting anti-muscarinics were allowed and were used by 44% and 35% of patients treated with DALIRESP and 45% and 37% of patients treated with placebo, respectively. The use of inhaled corticosteroids was prohibited. As in trials 3 and 4, the rate of moderate exacerbations (defined as requiring intervention with systemic glucocorticosteroids) or severe exacerbations (defined as leading to hospitalization and/or to death) was a co-primary endpoint.

Trial 5 randomized a total of 1525 patients (765 on DALIRESP) and Trial 6 randomized a total of 1571 patients (772 on DALIRESP). In both trials, DALIRESP 500 mcg once daily demonstrated a significant reduction in the rate of moderate or severe exacerbations compared to placebo (Table 2). These two trials provide the evidence to support the use of DALIRESP for the reduction of COPD exacerbations.

Table 2: Effect of DALIRESP on Rate of Moderate or Severe Exacerbations

For patients in Trials 5 and 6 who received concomitant long-acting beta agonists or short-acting anti-muscarinics, reduction of moderate or severe exacerbations with DALIRESP was similar to that observed for the overall populations of the two trials.

Effect on Lung Function

While DALIRESP is not a bronchodilator, all 1-year trials (Trials 3, 4, 5, and 6) evaluated the effect of DALIRESP on lung function as determined by the difference in FEV₁ between DALIRESP and placebo-treated patients (pre-bronchodilator FEV₁ measured prior to study drug administration in three of the trials and post-bronchodilator FEV₁ measured 30 minutes after administration of 4 puffs of albuterol/salbutamol in one trial) as a co-primary endpoint. In each of these trials DALIRESP 500 mcg once daily demonstrated a statistically significant improvement in FEV₁ which averaged approximately 50 mL across the four trials. Table 3 shows FEV₁ results from Trials 5 and 6 which had demonstrated a significant reduction in COPD exacerbations.

Table 3: Effect of DALIRESP on FEV₁

Lung function was also evaluated in two 6-month trials (Trials 7 and 8) to assess the effect of DALIRESP when administered as add­on therapy to treatment with a long-acting beta agonist or a long-acting anti-muscarinic. These trials were conducted in a different population of COPD patients [moderate to severe COPD (FEV₁ 40 to 70% of predicted) without a requirement for chronic bronchitis or frequent history of exacerbations] from that for which efficacy in reduction of exacerbations has been demonstrated and provide safetysupport to the DALIRESP COPD program.

No trials have been conducted to assess the effects of DALIRESP on COPD exacerbations when added to a fixed-dose combination product containing a long-acting beta agonist and inhaled corticosteroid.

Patient Counseling Information

See FDA-approved Medication Guide.

Bronchospasm

DALIRESP is not a bronchodilator and should not be used for the relief of acute bronchospasm. [see WARNINGS AND PRECAUTIONS].

Psychiatric Events including Suicidality

Treatment with DALIRESP is associated with an increase in psychiatric adverse reactions. In clinical trials, 5.9% (263) of patients treated with DALIRESP 500 mcg daily reported psychiatric adverse reactions compared to 3.3% (137) treated with placebo. The most commonly reported psychiatric adverse events were insomnia, anxiety, and depression which were reported at higher rates in those treated with DALIRESP 500 mcg (2.4%, 1.4%, and 1.2% for DALIRESP versus 1.0%, 0.9%, and 0.9% for placebo, respectively). Instances of suicidal ideation and behavior, including completed suicide, have been observed in clinical trials. Three patients experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) while receiving DALIRESP compared to one patient (suicidal ideation) who received placebo.

Before using DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with DALIRESP in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with DALIRESP if such events occur [see WARNINGS AND PRECAUTIONS].

Weight Decrease

Weight loss was a common adverse reaction in DALIRESP clinical trials and was reported in 7.5% (331) of patients treated with DALIRESP 500 mcg once daily compared to 2.1% (89) treated with placebo. In two placebo-controlled clinical trials of one year duration in which weight was prospectively assessed, 20% of patients receiving roflumilast experienced moderate weight loss (defined as between 5-10% of body weight) compared to 7% of patients who received placebo and 7% of patients who received roflumilast compared to 2% of patients receiving placebo experienced severe ( > 10% body weight) weight loss. During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving DALIRESP. Patients treated with DALIRESP should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of DALIRESP should be considered [see WARNINGS AND PRECAUTIONS].

Drug Interactions

The administration of the cytochrome P450 enzyme inducer rifampicin resulted in a reduction in exposure which may result in a decrease in the therapeutic effectiveness of DALIRESP. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) with DALIRESP is not recommended [see Drugs That Induce Cytochrome P450 (CYP) Enzymes and CLINICAL PHARMACOLOGY].

Use In Specific Populations

Pregnancy

Teratogenic effects

Pregnancy Category C: There are no adequate and well controlled studies of DALIRESP in pregnant women. DALIRESP was not teratogenic in mice, rats, or rabbits. DALIRESP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

DALIRESP induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, respectively, the maximum recommended human dose (MRHD) (on a mg/m² basis at maternal doses > 2 mg/kg/day and 6 mg/kg/day, respectively). DALIRESP induced post-implantation loss in rats at doses greater than or equal to approximately 10 times the MRHD (on a mg/m² basis at maternal doses ≥ 0.6 mg/kg/day). No treatment-related effects on embryo-fetal development were observed in mice, rats, and rabbits at approximately 12, 3, and 26 times the MRHD, respectively (on a mg/m²basis at maternal doses of 1.5, 0.2, and 0.8 mg/kg/day, respectively).

Nonteratogenic effects

DALIRESP has been shown to adversely affect pup post-natal development when dams were treated with the drug during pregnancy and lactation periods in mice. These studies found that DALIRESP decreased pup rearing frequencies at approximately 49 times the MRHD (on a mg/mg²basis at a maternal dose of 6 mg/kg/day) during pregnancy and lactation. DALIRESP also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at approximately 97 times the MRHD (on a mg/m² basis at a maternal dose of 12 mg/kg/day) during pregnancy and lactation.

Labor and Delivery

DALIRESP should not be used during labor and delivery. There are no human studies that have investigated effects of DALIRESP on preterm labor or labor at term; however, animal studies showed that DALIRESP disrupted the labor and delivery process in mice. DALIRESP induced delivery retardation in pregnant mice at doses greater than or equal to approximately 16 times the MRHD (on a mg/m² basis at a maternal dose of > 2 mg/kg/day).

Nursing Mothers

Roflumilast and/or its metabolites are excreted into the milk of lactating rats. Excretion of roflumilast and/or its metabolites into human milk is probable. There are no human studies that have investigated effects of DALIRESP on breast-fed infants. DALIRESP should not be used by women who are nursing.

Pediatric Use

COPD does not normally occur in children. The safety and effectiveness of DALIRESP in pediatric patients have not been established.

Geriatric Use

Of the 4438 COPD subjects exposed to DALIRESP for up to 12 months in 8 controlled clinical trials, 2022 were > 65 years of age and471 were > 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients,but greater sensitivity of some older individuals cannot be ruled out. Based on available data for roflumilast, no adjustment of dosage in geriatric patients is warranted [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

Roflumilast 250 mcg once daily for 14 days was studied in subjects with mild-to-moderate hepatic impairment classified as Child-Pugh A and B (8 subjects in each group). The AUCs of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively in Child-Pugh A subjects and by 92% and 41%, respectively in Child-Pugh B subjects, as compared to age-, weight- and gender­matched healthy subjects. The Cmax of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively in Child-Pugh A subjects and by 26% and 40%, respectively in Child-Pugh B subjects, as compared to healthy subjects. DALIRESP 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering DALIRESP to patients who have mild liver impairment (Child-Pugh A). DALIRESP is not recommended for use in patients with moderate or severe liver impairment (Child-Pugh B or C) [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY].

Renal Impairment

In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, the AUCs of roflumilast and roflumilast N-oxide were decreased by 21% and 7%, respectively and Cmax were reduced by 16% and 12%, respectively. No dosage adjustment is necessary for patients with renal impairment [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 4/27/2012
This monograph has been modified to include the generic and brand name in many instances.