Roflumilast

12.1 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 roflumilast tablets 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.

1 INDICATIONS AND USAGE Roflumilast tablets 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 Roflumilast tablets is not a bronchodilator and is not indicated for the relief of acute bronchospasm. Roflumilast tablets 250 mcg is a starting dose, for the first 4 weeks of treatment only and is not the effective (therapeutic) dose. Roflumilast tablets is a selective phosphodiesterase 4 inhibitor 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. ( 1 , 14 ) Limitations of Use: Roflumilast tablets is not a bronchodilator and is not indicated for the relief of acute bronchospasm. ( 1 , 14 ) Roflumilast tablets 250 mcg is a starting dose, for the first 4 weeks of treatment only and is not the effective (therapeutic) dose. ( 2 , 14 )

2 DOSAGE AND ADMINISTRATION 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 [ see Clinical Studies ( 14.1 ) ]. 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.( 2 )

6 ADVERSE REACTIONS The following adverse reactions are described in greater detail in other sections: Psychiatric Events Including Suicidality [see Warnings and Precautions (5.2) ] Weight Decrease [see Warnings and Precautions (5.3) ] Most common adverse reactions (≥2%) are diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness and decreased appetite. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 [see Clinical Studies (14.1) ]. 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 (9.5) 113 (2.7) Weight decreased 331 (7.5) 89 (2.1) Nausea 209 (4.7) 60 (1.4) Headache 195 (4.4) 87 (2.1) Back pain 142 (3.2) 92 (2.2) Influenza 124 (2.8) 112 (2.7) Insomnia 105 (2.4) 41 (1.0) Dizziness 92 (2.1) 45 (1.1) Decreased appetite 91 (2.1) 15 (0.4) 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 6.2 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.

7 DRUG INTERACTIONS A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2 [see Clinical Pharmacology (12.3) ]. Use with inhibitors of CYP3A4 or dual inhibitors of CYP3A4 and CYP1A2 (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) will increase roflumilast systemic exposure and may result in increased adverse reactions. The risk of such concurrent use should be weighed carefully against benefit.( 7.2 ) 7.1 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 [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3) ]. 7.2 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 [see Clinical Pharmacology (12.3) ]. 7.3 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 [see Clinical Pharmacology (12.3) ].