ADVERSE REACTIONS SECTION.

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)] 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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 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 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 500 mcg once daily for months and year, respectively.The population had median age of 64 years (range 40 to 91), 73% were male, 92.9% were Caucasian, and had COPD with 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 roflumilast 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-treated patients and 9.9% for placebo-treated patients. The most common adverse reactions that led to discontinuation of roflumilast 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-treated patients include diarrhea, atrial fibrillation, lung cancer, prostate cancer, acute pancreatitis, and acute renal failure.Table summarizes the adverse reactions reported by >=2% of patients in the roflumilast group in controlled COPD clinical trials.Table 1: Adverse Reactions Reported by >=2% of Patients Treated with Roflumilast 500 mcg daily and Greater Than Placebo TreatmentAdverse Reactions(Preferred Term)RoflumilastPlacebo(N=4438)(N=4192)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 group at frequency of 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, depressionThe safety profile of roflumilast reported during Trial was consistent with the key pivotal studies.. 6.2 Postmarketing Experience. The following adverse reactions have been identified from spontaneous reports of roflumilast received worldwide and have not been listed elsewhere. These adverse reactions have been chosen for inclusion due to combination of seriousness, frequency of reporting or potential causal connection to roflumilast. Because these adverse reactions were reported voluntarily from population of uncertain size, it is not possible to estimate their frequency or establish causal relationship to roflumilast exposure: hypersensitivity reactions (including angioedema, urticaria, and rash), gynecomastia.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Roflumilast and its active metabolite (roflumilast N-oxide) are selective inhibitors of phosphodiesterase (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 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.. 12.2 Pharmacodynamics. In COPD patients, 4-week treatment with roflumilast 500 mcg oral once daily reduced sputum neutrophils and eosinophils by 31%, and 42%, respectively. In pharmacodynamic study in healthy volunteers, roflumilast 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.. 12.3 Pharmacokinetics. Absorption The absolute bioavailability of roflumilast following 500 mcg oral dose is approximately 80%. Maximum plasma concentrations (Cmax) of roflumilast typically occur approximately one hour after dosing (ranging from 0.5 to hours) in the fasted state while plateau-like maximum concentrations of the N-oxide metabolite are reached in approximately eight hours (ranging from to 13 hours). Food has no effect on total drug absorption, but delays time to maximum concentration (Tmax) of roflumilast by one hour and reduces Cmax by approximately 40%, however, Cmax and Tmax of roflumilast N-oxide are unaffected. An in vitro study showed that roflumilast and roflumilast N-oxide did not inhibit P-gp transporter. Distribution Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively. Volume of distribution for single-dose 500 mcg roflumilast is about 2.9 L/kg. Studies in rats with radiolabeled roflumilast indicate low penetration across the blood-brain barrier. Metabolism Roflumilast is extensively metabolized via Phase (cytochrome P450) and Phase II (conjugation) reactions. The N-oxide metabolite is the only major metabolite observed in the plasma of humans. Together, roflumilast and roflumilast N-oxide account for the majority (87.5%) of total dose administered in plasma. In urine, roflumilast was not detectable while roflumilast N-oxide was only trace metabolite (less than 1%). Other conjugated metabolites such as roflumilast N-oxide glucuronide and 4-amino-3,5-dichloropyridine N-oxide were detected in urine. While roflumilast is three times more potent than roflumilast N-oxide at inhibition of the PDE4 enzyme in vitro, the plasma AUC of roflumilast N-oxide on average is about 10-fold greater than the plasma AUC of roflumilast. In vitro studies and clinical drug-drug interaction studies suggest that the biotransformation of roflumilast to its N-oxide metabolite is mediated by CYP1A2 and 3A4. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of roflumilast and roflumilast N-oxide do not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11. Therefore, there is low probability of relevant interactions with substances metabolized by these P450 enzymes. In addition, in vitro studies demonstrated no induction of the CYP 1A2, 2A6, 2C9, 2C19, or 3A4/5 and only weak induction of CYP2B6 by roflumilast. Elimination The plasma clearance after short-term intravenous infusion of roflumilast is on average about 9.6 L/h. Following an oral dose, the median plasma effective half-life of roflumilast and its N-oxide metabolite are approximately 17 and 30 hours, respectively. Steady state plasma concentrations of roflumilast and its N-oxide metabolite are reached after approximately days for roflumilast and days for roflumilast N-oxide following once-daily dosing. Following intravenous or oral administration of radiolabeled roflumilast, about 70% of the radioactivity was recovered in the urine. 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 and (8 subjects in each group). The AUC of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively in Child-Pugh subjects and by 92% and 41%, respectively, in Child-Pugh 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 subjects and by 26% and 40%, respectively in Child-Pugh subjects, as compared to healthy subjects. Roflumilast 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering roflumilast to patients who have mild liver impairment (Child-Pugh A). Roflumilast is not recommended for use in patients with moderate or severe liver impairment (Child-Pugh or C) [see Contraindications (4) and Use in Specific Populations (8.6)]. Renal Impairment In twelve subjects with severe renal impairment administered 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 to 45 years old). No dosage adjustment is necessary for elderly patients [see Use in Specific Populations (8.5)]. Gender In Phase study evaluating the effect of age and gender on the pharmacokinetics of roflumilast and roflumilast N-oxide, 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 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 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 to 1.25) of the 90% confidence interval of the geometric mean ratio of Cmax or AUC for roflumilast or roflumilast N-oxide for Treatment (roflumilast+Coadministered Drug) vs. Reference (roflumilast). The dosing regimens of coadministered drugs was: Midazolam: 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 single oral dose of 500 mcg roflumilast resulted in 40% and 70% increase in Cmax and AUC for roflumilast, respectively, and 34% decrease and 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 strong CYP3A4 inhibitor ketoconazole (200 mg twice daily for 13 days) with single oral dose of 500 mcg roflumilast resulted in 23% and 99% increase in Cmax and AUC for roflumilast, respectively, and 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 single oral dose of 500 mcg roflumilast showed 12% and 156% increase in roflumilast Cmax and AUC along with 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 single oral dose of 500 mcg roflumilast 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 dual CYP 3A4/1A2 inhibitor cimetidine (400 mg twice daily for days) with single dose of 500 mcg oral roflumilast resulted in 46% and 85% increase in roflumilast Cmax and AUC; and 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 single oral dose of 500 mcg roflumilast with repeated doses of fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state caused 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 single oral dose of 500 mcg roflumilast 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%.. Figure1.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Chronic Obstructive Pulmonary Disease (COPD). The efficacy and safety of roflumilast in COPD was evaluated in randomized, double-blind, controlled, parallel-group clinical trials in 9394 adult patients (4425 receiving roflumilast 500 mcg) 40 years of age and older with COPD. Of the trials, two were placebo-controlled dose selection trials (Trials and 2) of months duration that evaluated the efficacy of roflumilast 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 roflumilast on COPD exacerbations, and two were 6-month efficacy trials (Trials and 8) which assessed the effect of roflumilast as add-on therapy to long-acting beta agonist or long-acting anti-muscarinic. The trials enrolled patients with nonreversible obstructive lung disease (FEV1/FVC <=70% and <=12% or 200 mL improvement in FEV1 in response to 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 to 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 to 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 and 2) explored doses of 250 mcg and 500 mcg once daily in total of 1929 patients (751 and 724 on roflumilast 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 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 roflumilast 500 mcg on COPD exacerbations when added to 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 total of 2354 patients (1178 randomized to roflumilast, 1176 to placebo). Approximately 60% of the patients enrolled had severe COPD (postbronchodilator FEV1 30% to 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.Effect on Exacerbations The effect of roflumilast 500 mcg once daily on COPD exacerbations was evaluated in five 1-year trials (Trials 3, 4, 5, and 9).Two of the trials (Trials and 4) conducted initially enrolled population of patients with severe COPD (FEV1<=50% of predicted) inclusive of those with chronic bronchitis and/or emphysema who had history of smoking of at least 10 pack years. Inhaled corticosteroids were allowed as concomitant medications and used in 61% of both roflumilast and placebo-treated patients and short-acting beta agonists were allowed as rescue therapy. The use of long-acting beta agonists, long-acting anti-muscarinics, and theophylline were prohibited. The rate of moderate or severe COPD exacerbations was co-primary endpoint in both trials. There was not symptomatic definition of exacerbation in these trials. Exacerbations were defined in terms of severity requiring treatment with moderate exacerbation defined as treatment with systemic glucocorticosteroids in Trial or systemic glucocorticosteroids and/or antibiotics in Trial and severe exacerbation defined as requiring hospitalizations and/or leading to death in Trial or requiring hospitalization in Trial 4. The trials randomized 1176 patients (567 on roflumilast) in Trial and 1514 patients (760 on roflumilast) in Trial 4. Both trials failed to demonstrate significant reduction in the rate of COPD exacerbations.Exploratory analyses of the results of Trials and identified subpopulation of patients with severe COPD associated with chronic bronchitis and COPD exacerbations within the previous year that appeared to demonstrate better response in the reduction of the rate of COPD exacerbations compared to the overall population. As result, two subsequent trials (Trial and Trial 6) were conducted that enrolled patients with severe COPD but associated with chronic bronchitis, at least one COPD exacerbation in the previous year, and at least 20 pack-year smoking history. In these trials, long-acting beta agonists and short-acting anti-muscarinics were allowed and were used by 44% and 35% of patients treated with roflumilast and 45% and 37% of patients treated with placebo, respectively. The use of inhaled corticosteroids was prohibited. As in trials and 4, the rate of moderate exacerbations (defined as requiring intervention with systemic glucocorticosteroids) or severe exacerbations (defined as leading to hospitalization and/or to death) was co-primary endpoint.Trial randomized total of 1525 patients (765 on roflumilast) and Trial randomized total of 1571 patients (772 on roflumilast). In both trials, roflumilast 500 mcg once daily demonstrated significant reduction in the rate of moderate or severe exacerbations compared to placebo (Table 2). These two trials provide the evidence to support the use of roflumilast for the reduction of COPD exacerbations. Table 2: Effect of Roflumilast on Rate of Moderate or Severe Exacerbations Study Exacerbations Per Patient-Year Roflumilast Placebo Absolute Reduction1 RR295% CI Percent Reduction3. Trial 1.1 1.3 0.2 0.85 0.74, 0.98 15 Trial 1.2 1.5 0.3 0.82 0.71, 0.94 18 Absolute reduction measured as difference between placebo and roflumilast-treated patients. RR is Rate Ratio. Percent reduction is defined as 100 (1-RR).For patients in Trials and who received concomitant long-acting beta agonists or short-acting anti-muscarinics, reduction of moderate or severe exacerbations with roflumilast was similar to that observed for the overall populations of the two trials.In Trial 9, when added to background therapy of FDC ICS/LABA, the rate ratio for COPD exacerbations among patients administered roflumilast vs. placebo was 0.92 (95% CI 0.81, 1.04).Effect on Lung Function While roflumilast is not bronchodilator, all 1-year trials (Trials 3, 4, 5, and 6) evaluated the effect of roflumilast on lung function as determined by the difference in FEV1 between roflumilast and placebo-treated patients (pre-bronchodilator FEV1 measured prior to study drug administration in three of the trials and post-bronchodilator FEV1 measured 30 minutes after administration of puffs of albuterol/salbutamol in one trial) as co-primary endpoint. In each of these trials roflumilast 500 mcg once daily demonstrated statistically significant improvement in FEV1 which averaged approximately 50 mL across the four trials. Table shows FEV1 results from Trials and which had demonstrated significant reduction in COPD exacerbations.Table 3: Effect of Roflumilast on FEV1 Study Change in FEV from Baseline, mLTrial Roflumilast Placebo Effect1 95% CI46 39 18, 60 Trial 33 -25 58 41, 75 1. Effect measured as difference between roflumilast and placebo treated patients. Lung function was also evaluated in two 6-month trials (Trials and 8) to assess the effect of roflumilast when administered as add-on therapy to treatment with long-acting beta agonist or long-acting anti-muscarinic. These trials were conducted in different population of COPD patients [moderate to severe COPD (FEV1 40 to 70% of predicted) without requirement for chronic bronchitis or frequent history of exacerbations] from that for which efficacy in reduction of exacerbations has been demonstrated and provide safety support to the roflumilast COPD program.Starting dose titration trialThe tolerability of roflumilast was evaluated in 12-week randomized, double-blind, parallel group trial in patients with severe COPD associated with chronic bronchitis (Trial 10). At screening, patients were required to have had at least one exacerbation in the previous year. total of 1323 patients were randomized to receive roflumilast 500 mcg once day for 12 weeks (n=443), roflumilast 500 mcg every other day for weeks followed by roflumilast 500 mcg once day for weeks (n=439), or roflumilast 250 mcg once day for weeks followed by roflumilast 500 mcg once day for weeks (n=441).Over the 12 week study period, the percentage of patients discontinuing treatment was 6.2% lower in patients initially receiving roflumilast 250 mcg daily for weeks followed by roflumilast 500 mcg daily for weeks (18.4%) compared to those receiving roflumilast 500 mcg daily for 12 weeks (24.6%) (Odds Ratio 0.66; 95% CI: 0.47 to 0.93; p=0.017). Because this trial was limited to 12 weeks in duration, whether initiation of dosing with roflumilast 250 mcg improves the long term tolerability of roflumilast 500 mcg has not been determined.. Absolute reduction measured as difference between placebo and roflumilast-treated patients.. RR is Rate Ratio.. Percent reduction is defined as 100 (1-RR).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide). Bronchospasm Roflumilast is not bronchodilator and should not be used for immediate relief of breathing problems (i.e., as rescue medication). Psychiatric Events including Suicidality Treatment with roflumilast is associated with an increase in psychiatric adverse reactions. Cases of suicidal ideation and behavior, including completed suicide, have been observed in the post-marketing setting in patients with or without history of depression. The risks and benefits of treatment with roflumilast in patients with history of depression and/or suicidal thoughts or behavior should be carefully considered. Advise patients, caregivers, and families 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 so that the risks and benefits of continuing treatment with roflumilast may be considered [see Warnings and Precautions (5.2)]. Weight Decrease Weight loss was common adverse reaction in roflumilast clinical trials. During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving roflumilast. Advise patients treated with roflumilast to have their weight monitored regularly. If unexplained weight loss occurs, patients should inform their healthcare provider so that the weight loss can be evaluated, as discontinuation of roflumilast may need to be considered [see Warnings and Precautions (5.3)].Drug Interactions The use of cytochrome P450 enzyme inducers resulted in reduction in exposure which may result in decreased therapeutic effectiveness of roflumilast. The use of strong cytochrome P450 enzyme inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin) with roflumilast is not recommended [see Drugs that Induce Cytochrome P450 (CYP) Enzymes (7.1) and Clinical Pharmacology (12.3)]. Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown RoadEast Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, IndiaRevised: 05/2023. Bronchospasm Psychiatric Events including Suicidality Weight Decrease Drug Interactions.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption The absolute bioavailability of roflumilast following 500 mcg oral dose is approximately 80%. Maximum plasma concentrations (Cmax) of roflumilast typically occur approximately one hour after dosing (ranging from 0.5 to hours) in the fasted state while plateau-like maximum concentrations of the N-oxide metabolite are reached in approximately eight hours (ranging from to 13 hours). Food has no effect on total drug absorption, but delays time to maximum concentration (Tmax) of roflumilast by one hour and reduces Cmax by approximately 40%, however, Cmax and Tmax of roflumilast N-oxide are unaffected. An in vitro study showed that roflumilast and roflumilast N-oxide did not inhibit P-gp transporter. Distribution Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively. Volume of distribution for single-dose 500 mcg roflumilast is about 2.9 L/kg. Studies in rats with radiolabeled roflumilast indicate low penetration across the blood-brain barrier. Metabolism Roflumilast is extensively metabolized via Phase (cytochrome P450) and Phase II (conjugation) reactions. The N-oxide metabolite is the only major metabolite observed in the plasma of humans. Together, roflumilast and roflumilast N-oxide account for the majority (87.5%) of total dose administered in plasma. In urine, roflumilast was not detectable while roflumilast N-oxide was only trace metabolite (less than 1%). Other conjugated metabolites such as roflumilast N-oxide glucuronide and 4-amino-3,5-dichloropyridine N-oxide were detected in urine. While roflumilast is three times more potent than roflumilast N-oxide at inhibition of the PDE4 enzyme in vitro, the plasma AUC of roflumilast N-oxide on average is about 10-fold greater than the plasma AUC of roflumilast. In vitro studies and clinical drug-drug interaction studies suggest that the biotransformation of roflumilast to its N-oxide metabolite is mediated by CYP1A2 and 3A4. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of roflumilast and roflumilast N-oxide do not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11. Therefore, there is low probability of relevant interactions with substances metabolized by these P450 enzymes. In addition, in vitro studies demonstrated no induction of the CYP 1A2, 2A6, 2C9, 2C19, or 3A4/5 and only weak induction of CYP2B6 by roflumilast. Elimination The plasma clearance after short-term intravenous infusion of roflumilast is on average about 9.6 L/h. Following an oral dose, the median plasma effective half-life of roflumilast and its N-oxide metabolite are approximately 17 and 30 hours, respectively. Steady state plasma concentrations of roflumilast and its N-oxide metabolite are reached after approximately days for roflumilast and days for roflumilast N-oxide following once-daily dosing. Following intravenous or oral administration of radiolabeled roflumilast, about 70% of the radioactivity was recovered in the urine. 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 and (8 subjects in each group). The AUC of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively in Child-Pugh subjects and by 92% and 41%, respectively, in Child-Pugh 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 subjects and by 26% and 40%, respectively in Child-Pugh subjects, as compared to healthy subjects. Roflumilast 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering roflumilast to patients who have mild liver impairment (Child-Pugh A). Roflumilast is not recommended for use in patients with moderate or severe liver impairment (Child-Pugh or C) [see Contraindications (4) and Use in Specific Populations (8.6)]. Renal Impairment In twelve subjects with severe renal impairment administered 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 to 45 years old). No dosage adjustment is necessary for elderly patients [see Use in Specific Populations (8.5)]. Gender In Phase study evaluating the effect of age and gender on the pharmacokinetics of roflumilast and roflumilast N-oxide, 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 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 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 to 1.25) of the 90% confidence interval of the geometric mean ratio of Cmax or AUC for roflumilast or roflumilast N-oxide for Treatment (roflumilast+Coadministered Drug) vs. Reference (roflumilast). The dosing regimens of coadministered drugs was: Midazolam: 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 single oral dose of 500 mcg roflumilast resulted in 40% and 70% increase in Cmax and AUC for roflumilast, respectively, and 34% decrease and 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 strong CYP3A4 inhibitor ketoconazole (200 mg twice daily for 13 days) with single oral dose of 500 mcg roflumilast resulted in 23% and 99% increase in Cmax and AUC for roflumilast, respectively, and 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 single oral dose of 500 mcg roflumilast showed 12% and 156% increase in roflumilast Cmax and AUC along with 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 single oral dose of 500 mcg roflumilast 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 dual CYP 3A4/1A2 inhibitor cimetidine (400 mg twice daily for days) with single dose of 500 mcg oral roflumilast resulted in 46% and 85% increase in roflumilast Cmax and AUC; and 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 single oral dose of 500 mcg roflumilast with repeated doses of fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state caused 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 single oral dose of 500 mcg roflumilast 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%.. Figure1.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary There are no randomized clinical studies of roflumilast in pregnant women. In animal reproductive toxicity studies, roflumilast administered to pregnant rats and rabbits during the period of organogenesis produced no fetal structural abnormalities. The highest roflumilast dose in these studies was approximately 30 and 26 times, respectively, the maximum recommended human dose (MRHD). Roflumilast induced post-implantation loss in rats at doses greater than or equal to approximately 10 times the MRHD. Roflumilast induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, respectively, the MRHD. Roflumilast 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 to 4% and 15 to 20%, respectively.Clinical Considerations Labor and delivery Roflumilast should not be used during labor and delivery. There are no human studies that have investigated effects of roflumilast on preterm labor or labor at term; however, animal studies showed that roflumilast 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 (approximately 30 times the MRHD on an AUC basis). No evidence of structural abnormalities or effects on survival rates were observed. Roflumilast did not affect embryo-fetal development at approximately times the MRHD (on mg/m2 basis at maternal oral dose of 0.2 mg/kg/day). In fertility and embryo-fetal development study, male rats were dosed orally with up to 1.8 mg/kg/day roflumilast for 10 weeks and females for two weeks prior to pairing and throughout the organogenesis period. Roflumilast induced pre- and post-implantation loss at doses greater than or equal to approximately 10 times the MRHD (on mg/m2 basis at maternal oral doses greater than or equal to 0.6 mg/kg/day). Roflumilast 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 during the period of organogenesis. Roflumilast did not cause fetal structural abnormalities at exposures approximately 26 times the MRHD (on 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 roflumilast during the period of organogenesis and lactation. Roflumilast induced stillbirth and decreased pup viability at doses corresponding to approximately 16 and 49 times, respectively, the MRHD (on mg/m2 basis at maternal doses >2 mg/kg/day and mg/kg/day, respectively). Roflumilast induced delivery retardation in pregnant mice at doses greater or equal to approximately 16 times the MRHD (on mg/m2 basis at maternal doses >2 mg/kg/day). Roflumilast decreased pup rearing frequencies at approximately 49 times the MRHD (on mg/m2 basis at maternal dose of mg/kg/day) during pregnancy and lactation. Roflumilast also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at approximately 97 times the MRHD (on mg/m2 basis at maternal dose of 12 mg/kg/day).

SPL MEDGUIDE SECTION.

MEDICATION GUIDE. Roflumilast Tablets(roe FLOO mi last)Read this Medication Guide before you start taking roflumilast tablets and each time you get refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.What is the most important information should know about roflumilast tablets Roflumilast tablets can cause serious side effects. Tell your healthcare provider right away if you have any of the symptoms listed below while taking roflumilast tablets. 1. Roflumilast tablets may cause mental health problems including suicidal thoughts and behavior. Some people taking roflumilast tablets may develop mood or behavior problems including: thoughts of suicide or dyingattempt to commit suicide trouble sleeping (insomnia) new or worse anxiety new or worse depression acting on dangerous impulses other unusual changes in your behavior or mood 2. Weight loss. Roflumilast tablets can cause weight loss. You should check your weight on regular basis. You will also need to see your healthcare provider regularly to have your weight checked. If you notice that you are losing weight, call your healthcare provider. Your healthcare provider may ask you to stop taking roflumilast tablets if you lose too much weight. Roflumilast tablets may affect the way other medicines work, and other medicines may affect how roflumilast tablets work. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. What are roflumilast tablets Roflumilast tablets are prescription medicine used in adults with severe Chronic Obstructive Pulmonary Disease (COPD) to decrease the number of flare-ups or the worsening of COPD symptoms (exacerbations). Roflumilast tablets are not bronchodilator and should not be used for treating sudden breathing problems. Your healthcare provider may give you other medicine to use for sudden breathing problems. It is not known if roflumilast tablets are safe and effective in children. Who should not take roflumilast tabletsDo not take roflumilast tablets if you:have certain liver problems. Talk with your healthcare provider before you take roflumilast tablets if you have liver problems. What should tell my healthcare provider before taking roflumilast tablets Before you take roflumilast tablets, tell your healthcare provider if you: have or have had history of mental health problems including depression and suicidal behavior. have liver problems have any other medical conditions are pregnant or plan to become pregnant. It is not known if roflumilast tablets will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. are breastfeeding or plan to breastfeed. It is not known if roflumilast passes into your breast milk. You and your healthcare provider should decide if you will take roflumilast tablets or breastfeed. You should not do both. How should take roflumilast tablets Take roflumilast tablets exactly as your healthcare provider tells you to take it. Roflumilast tablets can be taken with or without food. If you take more than your prescribed dose of roflumilast tablets, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of roflumilast tablets Roflumilast tablets can cause serious side effects, including: See What is the most important information should know about roflumilast tablets The most common side effects of roflumilast tablets include: diarrhea weight loss nausea headache back pain flu like symptoms problems sleeping (insomnia) dizziness decreased appetite Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of roflumilast tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How do store roflumilast tablets Store roflumilast tablets at 68 to 77F (20 to 25C) Keep roflumilast tablets and all medicines out of the reach of children. General information about roflumilast tabletsMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use roflumilast tablets for condition for which it was not prescribed. Do not give roflumilast tablets to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about roflumilast tablets. For more information about roflumilast tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about roflumilast tablets that is written for health professionals. For more information about roflumilast tablets, call Aurobindo Pharma USA, Inc. at 1-866-850-2876.What are the ingredients in roflumilast tablets Active ingredient: roflumilast Inactive ingredients: corn starch, hypromellose, lactose monohydrate, magnesium stearate and poloxamer.This Medication Guide has been approved by the U.S. Food and Drug Administration. Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown RoadEast Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, IndiaRevised: 05/2023. thoughts of suicide or dying. attempt to commit suicide trouble sleeping (insomnia) new or worse anxiety new or worse depression acting on dangerous impulses other unusual changes in your behavior or mood have certain liver problems. Talk with your healthcare provider before you take roflumilast tablets if you have liver problems. have or have had history of mental health problems including depression and suicidal behavior. have liver problems have any other medical conditions are pregnant or plan to become pregnant. It is not known if roflumilast tablets will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. are breastfeeding or plan to breastfeed. It is not known if roflumilast passes into your breast milk. You and your healthcare provider should decide if you will take roflumilast tablets or breastfeed. You should not do both. Take roflumilast tablets exactly as your healthcare provider tells you to take it. Roflumilast tablets can be taken with or without food. If you take more than your prescribed dose of roflumilast tablets, call your healthcare provider or go to the nearest hospital emergency room right away. diarrhea weight loss nausea headache back pain flu like symptoms problems sleeping (insomnia) dizziness decreased appetite Store roflumilast tablets at 68 to 77F (20 to 25C).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Nursing Mothers: Roflumilast 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 on breast-fed infants. (8.2). 8.1 Pregnancy. Risk Summary There are no randomized clinical studies of roflumilast in pregnant women. In animal reproductive toxicity studies, roflumilast administered to pregnant rats and rabbits during the period of organogenesis produced no fetal structural abnormalities. The highest roflumilast dose in these studies was approximately 30 and 26 times, respectively, the maximum recommended human dose (MRHD). Roflumilast induced post-implantation loss in rats at doses greater than or equal to approximately 10 times the MRHD. Roflumilast induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, respectively, the MRHD. Roflumilast 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 to 4% and 15 to 20%, respectively.Clinical Considerations Labor and delivery Roflumilast should not be used during labor and delivery. There are no human studies that have investigated effects of roflumilast on preterm labor or labor at term; however, animal studies showed that roflumilast 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 (approximately 30 times the MRHD on an AUC basis). No evidence of structural abnormalities or effects on survival rates were observed. Roflumilast did not affect embryo-fetal development at approximately times the MRHD (on mg/m2 basis at maternal oral dose of 0.2 mg/kg/day). In fertility and embryo-fetal development study, male rats were dosed orally with up to 1.8 mg/kg/day roflumilast for 10 weeks and females for two weeks prior to pairing and throughout the organogenesis period. Roflumilast induced pre- and post-implantation loss at doses greater than or equal to approximately 10 times the MRHD (on mg/m2 basis at maternal oral doses greater than or equal to 0.6 mg/kg/day). Roflumilast 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 during the period of organogenesis. Roflumilast did not cause fetal structural abnormalities at exposures approximately 26 times the MRHD (on 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 roflumilast during the period of organogenesis and lactation. Roflumilast induced stillbirth and decreased pup viability at doses corresponding to approximately 16 and 49 times, respectively, the MRHD (on mg/m2 basis at maternal doses >2 mg/kg/day and mg/kg/day, respectively). Roflumilast induced delivery retardation in pregnant mice at doses greater or equal to approximately 16 times the MRHD (on mg/m2 basis at maternal doses >2 mg/kg/day). Roflumilast decreased pup rearing frequencies at approximately 49 times the MRHD (on mg/m2 basis at maternal dose of mg/kg/day) during pregnancy and lactation. Roflumilast also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at approximately 97 times the MRHD (on mg/m2 basis at maternal dose of 12 mg/kg/day).. 8.2 Lactation. Risk Summary There is no information regarding the presence of roflumilast 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. Roflumilast should not be used by women who are nursing. Data Animal data Roflumilast and/or its metabolite concentrations measured hours after an oral dose of mg/kg given to lactating rats were 0.32 and 0.02 mcg/g in the milk and pup liver, respectively.. 8.4 Pediatric Use. COPD does not normally occur in children. The safety and effectiveness of roflumilast in pediatric patients have not been established.. 8.5 Geriatric Use. Of the 4438 COPD subjects exposed to roflumilast for up to 12 months in 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)]. 8.6 Hepatic Impairment. Roflumilast 250 mcg once daily for 14 days was studied in subjects with mild-to-moderate hepatic impairment classified as Child-Pugh and (8 subjects in each group). The AUCs of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively, in Child-Pugh subjects and by 92% and 41%, respectively, in Child-Pugh 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 subjects and by 26% and 40%, respectively in Child-Pugh subjects, as compared to healthy subjects. Roflumilast 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering roflumilast to patients who have mild liver impairment (Child-Pugh A). Roflumilast is not recommended for use in patients with moderate or severe liver impairment (Child-Pugh or C) [see Contraindications (4) and Clinical Pharmacology (12.3) ].. 8.7 Renal Impairment. In twelve subjects with severe renal impairment administered 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Acute Bronchospasm: Do not use for the relief of acute bronchospasm. (5.1)Psychiatric Events including Suicidality: Advise patients, their caregivers, and families 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. Carefully weigh the risks and benefits of treatment with roflumilast in patients with history of depression and/or suicidal thoughts or behavior. (5.2)Weight Decrease: Monitor weight regularly. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of roflumilast. (5.3) Drug Interactions: Use with strong cytochrome P450 enzyme inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin) is not recommended. (5.4). Acute Bronchospasm: Do not use for the relief of acute bronchospasm. (5.1). Psychiatric Events including Suicidality: Advise patients, their caregivers, and families 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. Carefully weigh the risks and benefits of treatment with roflumilast in patients with history of depression and/or suicidal thoughts or behavior. (5.2). Weight Decrease: Monitor weight regularly. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of roflumilast. (5.3). Drug Interactions: Use with strong cytochrome P450 enzyme inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin) is not recommended. (5.4). 5.1 Treatment of Acute Bronchospasm. Roflumilast is not bronchodilator and should not be used for the relief of acute bronchospasm.. 5.2 Psychiatric Events including Suicidality. Treatment with roflumilast is associated with an increase in psychiatric adverse reactions. In controlled clinical trials 5.9% (263) of patients treated with roflumilast 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 roflumilast 500 mcg daily (2.4%, 1.4%, and 1.2% for roflumilast 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 roflumilast compared to one patient (suicidal ideation) who received placebo. One patient completed suicide while receiving roflumilast in Trial [see Clinical Studies (14.1)], which assessed the effect of adding roflumilast to fixed-dose combination (FDC) of ICS/LABA on rates of exacerbations in COPD patients over 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 history of depression. Before using roflumilast in patients with history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with roflumilast 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 roflumilast if such events occur.. 5.3 Weight Decrease. Weight loss was common adverse reaction in roflumilast clinical trials and was reported in 7.5% (331) of patients treated with roflumilast 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 to 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 roflumilast. Patients treated with roflumilast should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of roflumilast should be considered.. 5.4 Drug Interactions. 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 reduction in exposure, which may result in 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)].