Dalisrep
(roflumilast)Dosage & Administration
The maintenance dose for patients with COPD is one 500 mcg tablet per day, with or without food. Starting treatment with a dose of DALIRESP 250 mcg once daily for 4 weeks and increasing to DALIRESP 500 mcg once daily thereafter may reduce the rate of treatment discontinuation in some patients.
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Dalisrep Prescribing Information
DALIRESP® is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.
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.
The maintenance dose of DALIRESP is one 500 micrograms (mcg) tablet per day, with or without food.
Starting treatment with a dose of DALIRESP 250 mcg once daily for 4 weeks and increasing to DALIRESP 500 mcg once daily thereafter may reduce the rate of treatment discontinuation in some patients [see Clinical Studies (14.1)]. However, 250 mcg per day is not the effective (therapeutic) dose.
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- DALIRESP 250 mcg tablets are white to off-white, round, embossed with “D” on one side and “250” on the other side
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- DALIRESP 500 mcg tablets are white to off-white, round, embossed with “D” on one side and “500” on the other side
Pregnancy
Risk Summary
There are no randomized clinical studies of DALIRESP in pregnant women. In animal reproductive toxicity studies, DALIRESP administered to pregnant rats and rabbits during the period of organogenesis produced no fetal structural abnormalities. The highest DALIRESP dose in these studies was approximately 30 and 26 times, respectively, the maximum recommended human dose (MRHD). DALIRESP induced post-implantation loss in rats at doses greater than or equal to approximately 10 times the MRHD. DALIRESP induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, respectively, the MRHD. 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 at doses corresponding to 49 times the MRHD (see Data).
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
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.
Data
Animal data
In an embryo-fetal development study, pregnant rats were dosed orally during the period of organogenesis with up to 1.8 mg/kg/day DALIRESP (approximately 30 times the MRHD on an AUC basis). No evidence of structural abnormalities or effects on survival rates were observed. DALIRESP did not affect embryo-fetal development at approximately 3 times the MRHD (on a mg/m2 basis at a maternal oral dose of 0.2 mg/kg/day).
In a fertility and embryo-fetal development study, male rats were dosed orally with up to 1.8 mg/kg/day DALIRESP for 10 weeks and females for two weeks prior to pairing and throughout the organogenesis period. DALIRESP induced pre- and post-implantation loss at doses greater than or equal to approximately 10 times the MRHD (on a mg/m2 basis at maternal oral doses greater than or equal to 0.6 mg/kg/day). DALIRESP did not cause fetal structural abnormalities at exposures up to approximately 29 times the MRHD (on an AUC basis at maternal oral doses up to 1.8 mg/kg/day).
In an embryo-fetal development study in rabbits, pregnant does were dosed orally with 0.8 mg/kg/day DALIRESP during the period of organogenesis. DALIRESP did not cause fetal structural abnormalities at exposures approximately 26 times the MRHD (on a mg/m2 basis at maternal oral doses of 0.8 mg/kg/day).
In pre- and post-natal developmental studies in mice, dams were dosed orally with up to 12 mg/kg/day
DALIRESP during the period of organogenesis and lactation. DALIRESP induced stillbirth and decreased pup
viability at doses corresponding to approximately 16 and 49 times, respectively, the MRHD (on a mg/m2
basis at maternal doses >2 mg/kg/day and 6 mg/kg/day, respectively). DALIRESP induced delivery retardation in pregnant mice at doses greater or equal to approximately 16 times the MRHD (on a mg/m2 basis at maternal doses >2 mg/kg/day). DALIRESP decreased pup rearing frequencies at approximately 49 times the MRHD (on a mg/m2 basis 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).
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)].
The use of DALIRESP is contraindicated in the following condition:
Moderate to severe liver impairment (Child-Pugh B or C) [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6)].
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)].