Roflumilast

Dosage and Administration ( 2 ) 1/2018 Warnings and Precautions, Psychiatric Events including Suicidality ( 5.2 ) 8/2017

1 INDICATIONS AND USAGE Roflumilast Tablets are 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 are 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 are 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 are 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 )

3 DOSAGE FORMS AND STRENGTHS Roflumilast tablets 250 mcg are supplied as white to off white colored, round shaped, flat face, beveled edge, uncoated tablets, debossed with ‘0.25’ on one face and plain on other face. Each tablet contains 250 mcg of roflumilast. Roflumilast tablets 500 mcg are supplied as white to off white colored, circular shaped, flat face, beveled edge, uncoated tablets, debossed with ‘0.5’ on one face and plain on other face. Each tablet contains 500 mcg of roflumilast. Tablets: 250 mcg, 500 mcg ( 3 )

4 CONTRAINDICATIONS The use of roflumilast tablets are 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) ] . Moderate to severe liver impairment (Child-Pugh B or C) ( 4 )

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 Novadoz Pharmaceuticals LLC at 1-855-668-2369 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 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 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 adversereactions 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 ofuncertain 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), …

5.4 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 roflumilast. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin) with roflumilast is not recommended [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )].

7 DRUG INTERACTIONS 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 ) 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 )]. 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. Therefore the use of strong cytochrome P450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, and phenytoin) with roflumilast 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 (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 (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 )].

8 USE IN SPECIFIC POPULATIONS Nursing Mothers: Roflumilast tablets should not be used by women who are nursing as excretion of roflumilast and/or its metabolites into human milk is probable and there are no human studies that have investigated effects of roflumilast tablets on breast-fed infants. ( 8.2 ) 8.1 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 …

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.

11 DESCRIPTION The active ingredient in roflumilast tablets is roflumilast. Roflumilast and its active metabolite (roflumilast N-oxide) are selective phosphodiesterase 4 (PDE4) inhibitors. The chemical name of roflumilast is N-(3,5-dichloropyridine-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide or. Its molecular formula is C 17 H 14 Cl 2 F 2 N 2 O 3 and the molecular weight is 403.22. The chemical structure is: The drug substance is a white to off-white non-hygroscopic granular powder with a melting point of 160°C. It is practically insoluble in water and hexane; sparingly soluble in ethanol and methanol; and soluble in N,N-Dimethyl formamide. Roflumilast 250 mcg are supplied as white to off-white, round tablets, debossed with "4" on one side, "C" on the other side. Roflumilast 500 mcg tablets are supplied as white to off-white, round tablets, debossed with "0.5" on one side, "R" on the other side. Each tablet contains 250 mcg or 500 mcg of roflumilast. Each roflumilast tablet for oral administration contains the following inactive ingredients: lactose monohydrate, corn starch, hydroxypropyl cellulose and magnesium stearate. Structure

10 OVERDOSAGE 10.1 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. 10.2 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Roflumilast tablets 250 mcg are supplied as white to off-white, round tablets, debossed with "4" on one side, "C" on the other side. Roflumilast 250 mcg tablets are available: 2 Blisters of 14's tablets in a Carton: NDC 73190-086-28 Roflumilast 500 mcg tablets are supplied as white to off-white, round tablets, debossed with "0.5" on one side, "R" on the other side. Roflumilast 500 mcg tablets are available in: Bottles of 30: NDC 73190-087-30 Bottles of 90: NDC 73190-087-90 16.2 Storage and Handling Store roflumilast tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature].

16.1 How Supplied Roflumilast tablets 250 mcg are supplied as white to off-white, round tablets, debossed with "4" on one side, "C" on the other side. Roflumilast 250 mcg tablets are available: 2 Blisters of 14's tablets in a Carton: NDC 73190-086-28 Roflumilast 500 mcg tablets are supplied as white to off-white, round tablets, debossed with "0.5" on one side, "R" on the other side. Roflumilast 500 mcg tablets are available in: Bottles of 30: NDC 73190-087-30 Bottles of 90: NDC 73190-087-90