roflumilast 0.5 MG/ML Topical Cream

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 are 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 are 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. ( 1 , 14 )

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 )

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 tablets in patients with a 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 tablets. ( 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 tablets is not a bronchodilator and should not be used for the relief of acute bronchospasm. 5.2 Psychiatric Events including Suicidality Treatment with roflumilast tablets is associated with an increase in psychiatric adverse reactions. In 8 controlled clinical trials 5.9% (263) of patients treated with roflumilast tablets 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 tablets 500 mcg daily (2.4%, 1.4%, and 1.2% for roflumilast tablets 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 tablets compared to one patient (suicidal ideation) who received placebo. One patient completed suicide while receiving roflumilast tablets in Trial 9 [see Clinical Studies (14.1) ] , which assessed the effect of adding roflumilast to a fixed-dose combination (FDC) of ICS/LABA on rates of exacerbations in COPD patients over 1 year of treatment. Cases of suicidal ideation and behavior, including completed suicide, have been observed in the post-marketing setting in patients with or without a history of depression. Before using roflumilast tablets in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with roflumilast tablets 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 tablets if such events occur. 5.3 Weight Decrease Weight loss was a common adverse reaction in roflumilast tablets clinical trials and was reported in 7.5% (331) of patients treated with roflumilast tablets 500 mcg once daily compared to 2.1% (89) treated with placebo [see Adverse Reactions (6.1) ] . In addition to being reported as adverse reactions, weight was prospectively assessed in two placebo-controlled clinical trials of one year duration. In these studies, 20% of patients receiving roflumilast experienced moderate weight loss (defined as between 5 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 (greater than 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 tablets. Patients treated with roflumilast tablets should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of roflumilast tablets should be considered. 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 tablets. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin) with roflumilast tablets is not recommended [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ].

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 )

CLINICAL PHARMACOLOGY 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 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 a 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 a 500 mcg oral dose is approximately 80%. Maximum plasma concentrations (C max ) of roflumilast typically occur approximately one hour after dosing (ranging from 0.5 to 2 hours) in the fasted state while plateau-like maximum concentrations of the N-oxide metabolite are reached in approximately eight hours (ranging from 4 to 13 hours). Food has no effect on total drug absorption, but delays time to maximum concentration (T max ) of roflumilast by one hour and reduces C max by approximately 40%, however, C max and T max 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 I (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 a 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 a 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 a 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 4 days for roflumilast and 6 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 A and B (8 subjects in each group). The AUC of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively in Child-Pugh A subjects and by 92% and 41%, respectively, in Child-Pugh B subjects, as compared to age-, weight-, and gender-matched healthy subjects. The C max of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively, in Child-Pugh A subjects and by 26% and 40%, respectively in Child-Pugh B subjects, as compared to healthy subjects. 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 B or C) [see Contraindications ( 4 ) and Use in Specific Populations ( 8.6 ) ]. Renal Impairment In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, roflumilast and roflumilast N-oxide AUCs were decreased by 21% and 7%, respectively and C max were reduced by 16% and 12%, respectively. No dosage adjustment is necessary for patients with renal impairment [see Use inSpecific 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 C max for roflumilast and 19% higher in AUC and 13% higher in C max for roflumilast-N-oxide than that in young volunteers (18-45 years old). No dosage adjustment is necessary for elderly patients [ see Use in Specific Populations ( 8.5 )] . Gender In a Phase I study evaluating the effect of age and gender on the pharmacokinetics of roflumilast and roflumilast N-oxide, a 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 C max between smokers and non-smokers when roflumilast 500 mcg was administered as a 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 C max , respectively, for roflumilast and 43%, 27%, and 17% higher C max , 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 1 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-