Dalisrep

Limitations of Use

DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm.

DALIRESP 250 mcg is a starting dose, for the first 4 weeks of treatment only and is not the effective (therapeutic) dose.

Pregnancy

Lactation

Risk Summary

There is no information regarding the presence of DALIRESP in human milk, the effects on the breastfed infant, or the effects on milk production.

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. DALIRESP should not be used by women who are nursing.

Data

Animal data

Roflumilast and/or its metabolite concentrations measured 8 hours after an oral dose of 1 mg/kg given to lactating rats were 0.32 and 0.02 mcg/g in the milk and pup liver, respectively.

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 and 471 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 (12.3)].

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 gender-matched 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 (4) and Clinical Pharmacology (12.3)].

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 (12.3)].

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 (6.1)]. 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. One patient completed suicide while receiving DALIRESP in Trial 9 [see Clinical Studies (14.1)], which assessed the effect of adding roflumilast to a fixed-dose combination (FDC) of ICS/LABA on rates of exacerbations in COPD patients over 1 year of treatment. Cases of suicidal ideation and behavior, including completed suicide, have been observed in the post-marketing setting in patients with or without a history of depression.

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 (6.1)]. In addition to being reported as adverse reactions, weight was prospectively assessed in two placebo-controlled clinical trials of one year duration. In these 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 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.

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 Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Adverse Reactions in Clinical Studies

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data described below reflect exposure of 4438 patients to DALIRESP 500 mcg once daily in four 1-year placebo-controlled trials, two 6-month placebo-controlled trials, and two 6-month drug add-on trials [see Clinical Studies (14.1)]. In these trials, 3136 and 1232 COPD patients were exposed to DALIRESP 500 mcg once daily for 6 months and 1 year, respectively.

The population had a median age of 64 years (range 40-91), 73% were male, 92.9% were Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) of 8.9 to 89.1% predicted. In these trials, 68.5% of the patients treated with DALIRESP reported an adverse reaction compared with 65.3% treated with placebo.

The proportion of patients who discontinued treatment due to adverse reaction was 14.8% for DALIRESP-treated patients and 9.9% for placebo-treated patients. The most common adverse reactions that led to discontinuation of DALIRESP were diarrhea (2.4%) and nausea (1.6%).

Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in DALIRESP-treated patients include diarrhea, atrial fibrillation, lung cancer, prostate cancer, acute pancreatitis, and acute renal failure.

Table 1 summarizes the adverse reactions reported by ≥2% of patients in the DALIRESP group in 8 controlled COPD clinical trials.

Adverse reactions that occurred in the DALIRESP group at a frequency of 1 to 2% where rates exceeded that in the placebo group include:

Gastrointestinal disorders - abdominal pain, dyspepsia, gastritis, vomiting

Infections and infestations - rhinitis, sinusitis, urinary tract infection

Musculoskeletal and connective tissue disorders - muscle spasms

Nervous system disorders - tremor

Psychiatric disorders - anxiety, depression

The safety profile of roflumilast reported during Trial 9 was consistent with the key pivotal studies.

Postmarketing Experience

The following adverse reactions have been identified from spontaneous reports of DALIRESP received worldwide and have not been listed elsewhere. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to DALIRESP. Because these adverse reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to DALIRESP exposure:  hypersensitivity reactions (including angioedema, urticaria, and rash), gynecomastia.

Drugs that Induce Cytochrome P450 (CYP) Enzymes

Strong cytochrome P450 enzyme inducers decrease systemic exposure to roflumilast and may reduce the therapeutic effectiveness of DALIRESP. Therefore the use of strong cytochrome P450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, and phenytoin) with DALIRESP is not recommended [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

Drugs that Inhibit Cytochrome P450 (CYP) Enzymes

The co-administration of DALIRESP (500 mcg) with CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) may increase roflumilast systemic exposure and may result in increased adverse reactions. The risk of such concurrent use should be weighed carefully against benefit [see Clinical Pharmacology (12.3)].

Oral Contraceptives Containing Gestodene and Ethinyl Estradiol

The co-administration of DALIRESP (500 mcg) with oral contraceptives containing gestodene and ethinyl estradiol may increase roflumilast systemic exposure and may result in increased side effects. The risk of such concurrent use should be weighed carefully against benefit [see Clinical Pharmacology (12.3)].

Mechanism of Action

Roflumilast and its active metabolite (roflumilast N-oxide) are selective inhibitors of phosphodiesterase 4 (PDE4). Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic-3′,5′-adenosine monophosphate (cyclic AMP)-metabolizing enzyme in lung tissue) activity leads to accumulation of intracellular cyclic AMP. While the specific mechanism(s) by which DALIRESP exerts its therapeutic action in COPD patients is not well defined, it is thought to be related to the effects of increased intracellular cyclic AMP in lung cells.

Pharmacodynamics

In COPD patients, 4‑week treatment with DALIRESP 500 mcg oral once daily reduced sputum neutrophils and eosinophils by 31%, and 42%, respectively. In a pharmacodynamic study in healthy volunteers, DALIRESP 500 mcg once daily reduced the number of total cells, neutrophils and eosinophils found in bronchoalveolar lavage fluid following segmental pulmonary lipopolysaccharide (LPS) challenge by 35%, 38% and 73%, respectively. The clinical significance of these findings is unknown.

Pharmacokinetics

Special Populations

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 AUC 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 gender-matched 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 (4) and Use in Specific Populations (8.6)].

Renal Impairment

In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, roflumilast and roflumilast N-oxide AUCs 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 Use in Specific Populations (8.7)].

Age

Roflumilast 500 mcg once daily for 15 days was studied in young, middle aged, and elderly healthy subjects. The exposure in elderly (>65 years of age) were 27% higher in AUC and 16% higher in Cmax for roflumilast and 19% higher in AUC and 13% higher in Cmax for roflumilast-N-oxide than that in young volunteers (18-45 years old). No dosage adjustment is necessary for elderly patients [see Use in Specific Populations (8.5)].

Gender

In a Phase I study evaluating the effect of age and gender on the pharmacokinetics of roflumilast and roflumilast N-oxide, a 39% and 33% increase in roflumilast and roflumilast N-oxide AUC were noted in healthy female subjects as compared to healthy male subjects. No dosage adjustment is necessary based on gender.

Smoking

The pharmacokinetics of roflumilast and roflumilast N-oxide were comparable in smokers as compared to non-smokers. There was no difference in Cmax between smokers and non-smokers when roflumilast 500 mcg was administered as a single dose to 12 smokers and 12 non-smokers. The AUC of roflumilast in smokers was 13% less than that in non-smokers while the AUC of roflumilast N-oxide in smokers was 17% more than that in non-smokers.

Race

As compared to Caucasians, African Americans, Hispanics, and Japanese showed 16%, 41%, and 15% higher AUC, respectively, for roflumilast and 43%, 27%, and 16% higher AUC, respectively, for roflumilast N-oxide. As compared to Caucasians, African Americans, Hispanics, and Japanese showed 8%, 21%, and 5% higher Cmax, respectively, for roflumilast and 43%, 27%, and 17% higher Cmax, respectively, for roflumilast N-oxide. No dosage adjustment is necessary for race.

Drug Interactions

Drug interaction studies were performed with roflumilast and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction [see Drug Interactions (7)]. No significant drug interactions were observed when 500 mcg oral roflumilast was administered with inhaled salbutamol, formoterol, budesonide and oral montelukast, digoxin, theophylline, warfarin, sildenafil, midazolam, or antacids.

The effect of concomitant drugs on the exposure of roflumilast and roflumilast N-oxide is shown in the Figure 1 below.

Figure 1. Effect of concomitant drugs on the exposure of roflumilast and roflumilast N-oxide. Note that the dashed lines indicate the lower and higher bounds (0.8-1.25) of the 90% confidence interval of the geometric mean ratio of Cmax or AUC for roflumilast or roflumilast N-oxide for Treatment (DALIRESP+Coadministered Drug) vs. Reference (DALIRESP). The dosing regimens of coadministered drugs was: Midazolam: 2 mg po SD; Erythromycin: 500 mg po TID; Ketoconazole: 200 mg po BID; Rifampicin: 600 mg po QD; Fluvoxamine: 50 mg po QD; Digoxin: 250 mcg po SD; Maalox: 30 mL po SD; Salbutamol: 0.2 mg po TID; Cimetidine: 400 mg po BID; Formoterol: 40 mcg po BID; Budesonide: 400 mcg po BID; Theophylline: 375 mg po BID; Warfarin: 250 mg po SD; Enoxacin: 400 mg po BID; Sildenafil: 100 mg SD; Minulet (combination oral contraceptive): 0.075 mg gestodene/0.03 mg ethinylestradiol po QD; Montelukast: 10 mg po QD

Drug interactions considered to be significant are described in more detail below [see Warnings and Precautions (5.4) and Drug Interactions (7)].

Inhibitors of CYP3A4 and CYP1A2:

Erythromycin: In an open-label crossover study in 16 healthy volunteers, the coadministration of CYP3A4 inhibitor erythromycin (500 mg three times daily for 13 days) with a single oral dose of 500 mcg DALIRESP resulted in 40% and 70% increase in Cmax and AUC for roflumilast, respectively, and a 34% decrease and a 4% increase in Cmax and AUC for roflumilast N-oxide, respectively.

Ketoconazole: In an open-label crossover study in 16 healthy volunteers, the coadministration of a strong CYP3A4 inhibitor ketoconazole (200 mg twice daily for 13 days) with a single oral dose of 500 mcg DALIRESP resulted in 23% and 99% increase in Cmax and AUC for roflumilast, respectively, and a 38% reduction and 3% increase in Cmax and AUC for roflumilast N-oxide, respectively.

Fluvoxamine: In an open-label crossover study in 16 healthy volunteers, the coadministration of dual CYP 3A4/1A2 inhibitor fluvoxamine (50 mg daily for 14 days) with a single oral dose of 500 mcg DALIRESP showed a 12% and 156% increase in roflumilast Cmax and AUC along with a 210% decrease and 52% increase in roflumilast N-oxide Cmax and AUC, respectively.

Enoxacin: In an open-label crossover study in 16 healthy volunteers, the coadministration of dual CYP 3A4/1A2 inhibitor enoxacin (400 mg twice daily for 12 days) with a single oral dose of 500 mcg DALIRESP resulted in an increased Cmax and AUC of roflumilast by 20% and 56%, respectively. Roflumilast N-oxide Cmax was decreased by 14% while roflumilast N-oxide AUC was increased by 23%.

Cimetidine: In an open-label crossover study in 16 healthy volunteers, the coadministration of a dual CYP 3A4/1A2 inhibitor cimetidine (400 mg twice daily for 7 days) with a single dose of 500 mcg oral DALIRESP resulted in a 46% and 85% increase in roflumilast Cmax and AUC; and a 4% decrease in Cmax and 27% increase in AUC for roflumilast N-oxide, respectively.

Oral Contraceptives containing Gestodene and Ethinyl Estradiol:

In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single oral dose of 500 mcg DALIRESP with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state caused a 38% increase and 12% decrease in Cmax of roflumilast and roflumilast N-oxide, respectively. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively.

Inducers of CYP enzymes:

Rifampicin: In an open-label, three-period, fixed-sequence study in 15 healthy volunteers, coadministration of the strong CYP3A4 inducer rifampicin (600 mg once daily for 11 days) with a single oral dose of 500 mcg DALIRESP resulted in reduction of roflumilast Cmax and AUC by 68% and 79%, respectively; and an increase of roflumilast N-oxide Cmax by 30% and reduced roflumilast N-oxide AUC by 56%.

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-amino-3,5-dichloro-pyridine N-oxide (ADCP N-oxide). No evidence of tumorigenicity was observed in mice at roflumilast oral doses up to 12 and 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 3-month 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). The male rats also showed increases in the incidence of tubular atrophy, degeneration in the testis and spermiogenic granuloma in the epididymides. No effect on rat fertility rate or male reproductive organ morphology was observed at 0.6 mg/kg/day (approximately 10 times the MRHD on a mg/m2 basis). In a female fertility study, no effect on 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/m2 basis).

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 (FEV1) were co-primary efficacy outcome measures in the four 1-year 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 (12.3)].

An additional placebo-controlled 1-year trial (Trial 9) evaluated the effect of DALIRESP 500 mcg on COPD exacerbations when added to a fixed-dose combination (FDC) product containing an inhaled corticosteroid and long-acting beta agonist (ICS/LABA). At screening, patients were required to have two or more exacerbations in the previous year. This trial randomized a total of 2354 patients (1178 randomized to DALIRESP, 1176 to placebo). Approximately 60% of the patients enrolled had severe COPD (postbronchodilator FEV1 30%-50% of predicted) associated with chronic bronchitis and 39% had very severe COPD (postbronchodilator FEV1 ≤ 30% of predicted) associated with chronic bronchitis; mean age of 64 years, 69% male, and 80% Caucasian. The use of long-acting muscarinic antagonists was allowed.