Roflumilast Drug Information

The maintenance dose of roflumilast tablets is one 500 micrograms (mcg) tablet per day, with or without food. Starting treatment with a dose of Roflumilast tablets 250 mcg once daily for 4 weeks and increasing to Roflumilast tablets 500 mcg once daily thereafter may reduce the rate of treatment discontinuation in some patients. However, 250 mcg per day is not the effective (therapeutic) dose.

The maintenance dose for patients with COPD is one 500 mcg tablet per day, with or without food. Starting treatment with a dose of Roflumilast tablets 250 mcg once daily for 4 weeks and increasing to roflumilast tablets 500 mcg once daily thereafter may reduce the rate of treatment discontinuation in some patients.

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 roflumilast tablets 500 mcg once daily in four 1year placebo-controlled trials, two 6-month placebo-controlled trials, and two 6-month drug add-on trials. In these trials, 3136 and 1232 COPD patients were exposed to roflumilast tablets 500 mcg once daily for 6 months and 1 year, respectively.

The population had a median age of 64 years (range 40 to 91), 73% were male, 92.9% were Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV 1 ) of 8.9 to 89.1% predicted. In these trials, 68.5% of the patients treated with roflumilast tablets 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 roflumilast tablets -treated patients and 9.9% for placebo-treated patients.

The most common adverse reactions that led to discontinuation of roflumilast tablets 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 roflumilast tablets-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 roflumilast tablets group in 8 controlled COPD clinical trials. Table 1: Adverse Reactions Reported by ≥2% of Patients Treated with Roflumilast Tablets 500 mcg daily and Greater Than Placebo Adverse Reactions (Preferred Term) Treatment Roflumilast Tablets Placebo ( N =4438) ( N =4192) n (%) n (%) Diarrhea 420 113 Weight decreased 331 89 Nausea 209 60 Headache 195 87 Back pain 142 92 Influenza 124 112 Insomnia 105 41 Dizziness 92 45 Decreased appetite 91 15 Adverse reactions that occurred in the roflumilast tablets 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 roflumilast tablets 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 roflumilast tablets. 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 roflumilast tablets 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 roflumilast tablets. Therefore the use of strong cytochrome P450 inducers (e.g. rifampicin, phenobarbital, carbamazepine, and phenytoin) with roflumilast tablets is not recommended.

Drugs that Inhibit Cytochrome P450 (CYP) Enzymes

The co-administration of roflumilast tablets (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.

Oral Contraceptives Containing Gestodene and Ethinyl Estradiol

The co-administration of roflumilast tablets (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.

Pregnancy Risk Summary There are no randomized clinical studies of roflumilast tablets in pregnant women. In animal reproductive toxicity studies, roflumilast tablets administered to pregnant rats and rabbits during the period of organogenesis produced no fetal structural abnormalities. The highest roflumilast tablets dose in these studies was approximately 30 and 26 times, respectively, the maximum recommended human dose (MRHD). Roflumilast tablets induced post-implantation loss in rats at doses greater than or equal to approximately 10 times the MRHD. Roflumilast tablets induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, respectively, the MRHD. Roflumilast tablets 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 Roflumilast tablets should not be used during labor and delivery. There are no human studies that have investigated effects of roflumilast tablets on preterm labor or labor at term; however, animal studies showed that roflumilast tablets 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 roflumilast tablets (approximately 30 times the MRHD on an AUC basis). No evidence of structural abnormalities or effects on survival rates were observed. Roflumilast tablets did not affect embryo-fetal development at approximately 3 times the MRHD (on a mg/m 2 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 roflumilast tablets for 10 weeks and females for two weeks prior to pairing and throughout the organogenesis period. Roflumilast tablets induced pre-and post-implantation loss at doses greater than or equal to approximately 10 times the MRHD (on a mg/m 2 basis at maternal oral doses greater than or equal to 0.6 mg/kg/day). Roflumilast tablets 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 roflumilast tablets during the period of organogenesis.

Roflumilast tablets did not cause fetal structural abnormalities at exposures approximately 26 times the MRHD (on a mg/m 2 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 roflumilast tablets during the period of organogenesis and lactation. Roflumilast tablets induced stillbirth and decreased pup viability at doses corresponding to approximately 16 and 49 times, respectively, the MRHD (on a mg/m 2 basis at maternal doses greater than 2 mg/kg/day and 6 mg/kg/day, respectively). Roflumilast tablets induced delivery retardation in pregnant mice at doses greater or equal to approximately 16 times the MRHD (on a mg/m 2 basis at maternal doses greater than 2 mg/kg/day). Roflumilast tablets decreased pup rearing frequencies at approximately 49 times the MRHD (on a mg/m 2 basis at a maternal dose of 6 mg/kg/day) during pregnancy and lactation. Roflumilast tablets also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at approximately 97 times the MRHD (on a mg/m 2 basis at a maternal dose of 12 mg/kg/day).

Pediatric Use COPD does not normally occur in children. The safety and effectiveness of roflumilast tablets in pediatric patients have not been established.

The use of roflumilast tablets is contraindicated in the following condition: Moderate to severe liver impairment (Child-Pugh B or C). Moderate to severe liver impairment (Child-Pugh B or C)

Human Experience No case of overdose has been reported in clinical studies

with roflumilast tablets. During the Phase I studies of roflumilast tablets, the following symptoms were observed at an increased rate after a single oral dose of 2500 mcg and a single dose of 5000 mcg: headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess, and arterial hypotension

Management of Overdose

In case of overdose, patients should seek immediate medical help. Appropriate supportive medical care should be provided. Since roflumilast is highly protein bound, hemodialysis is not likely to be an efficient method of drug removal.

It is not known whether roflumilast is dialyzable by peritoneal dialysis.