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<code code="34090-1" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL PHARMACOLOGY SECTION"/>
<title>12 CLINICAL PHARMACOLOGY</title>
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<code code="43679-0" codeSystem="2.16.840.1.113883.6.1" displayName="MECHANISM OF ACTION SECTION"/>
<title>12.1 Mechanism of Action</title>
<text>
<paragraph>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 DALIRESP 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.</paragraph>
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<title>12.2 Pharmacodynamics</title>
<text>
<paragraph>In COPD patients, 4‑week treatment with DALIRESP 500 mcg oral once daily reduced sputum neutrophils and eosinophils by 31%, and 42%, respectively. In a pharmacodynamic study in healthy volunteers, DALIRESP 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.</paragraph>
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<title>12.3 Pharmacokinetics</title>
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<paragraph>
<content styleCode="italics">Absorption</content>
</paragraph>
<paragraph>The absolute bioavailability of roflumilast following a 500 mcg oral dose is approximately 80%. Maximum plasma concentrations (C<sub>max</sub>) 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<sub>max</sub>) of roflumilast by one hour and reduces C<sub>max</sub> by approximately 40%, however, C<sub>max</sub> and T<sub>max</sub> of roflumilast N-oxide are unaffected. An <content styleCode="italics">in vitro</content> study showed that roflumilast and roflumilast N-oxide did not inhibit P-gp transporter.</paragraph>
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<paragraph>
<content styleCode="italics">Distribution</content>
</paragraph>
<paragraph>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.</paragraph>
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<paragraph>
<content styleCode="italics">Metabolism</content>
</paragraph>
<paragraph>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.</paragraph>
<paragraph>While roflumilast is three times more potent than roflumilast N-oxide at inhibition of the PDE4 enzyme <content styleCode="italics">in vitro</content>, the plasma AUC of roflumilast N-oxide on average is about 10-fold greater than the plasma AUC of roflumilast.</paragraph>
<paragraph>
<content styleCode="italics">In vitro</content> 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 <content styleCode="italics">in vitro</content> 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, <content styleCode="italics">in vitro</content> studies demonstrated no induction of the CYP1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak induction of CYP2B6 by roflumilast.</paragraph>
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<paragraph>
<content styleCode="italics">Elimination</content>
</paragraph>
<paragraph>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.</paragraph>
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<paragraph>
<content styleCode="italics">Special Populations</content>
</paragraph>
</text>
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<paragraph>
<content styleCode="italics">Hepatic Impairment</content>
</paragraph>
<paragraph>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<sub>max</sub> 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. DALIRESP 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering DALIRESP to patients who have mild liver impairment (Child-Pugh A). DALIRESP is not recommended for use in patients with moderate or severe liver impairment (Child-Pugh B or C) <content styleCode="italics">[see <linkHtml href="#s5">Contraindications (4)</linkHtml> and <linkHtml href="#s25">Use in Specific Populations (8.6)</linkHtml>].</content>
</paragraph>
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<paragraph>
<content styleCode="italics">Renal Impairment</content>
</paragraph>
<paragraph>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<sub>max</sub> were reduced by 16% and 12%, respectively. No dosage adjustment is necessary for patients with renal impairment <content styleCode="italics">[see <linkHtml href="#s26">Use in Specific Populations (8.7)</linkHtml>]</content>.</paragraph>
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<paragraph>
<content styleCode="italics">Age</content>
</paragraph>
<paragraph>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<sub>max</sub> for roflumilast and 19% higher in AUC and 13% higher in C<sub>max</sub> for roflumilast-N-oxide than that in young volunteers (18-45 years old). No dosage adjustment is necessary for elderly patients <content styleCode="italics">[see <linkHtml href="#s24">Use in Specific Populations (8.5)</linkHtml>]</content>.</paragraph>
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<paragraph>
<content styleCode="italics">Gender</content>
</paragraph>
<paragraph>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.</paragraph>
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<paragraph>
<content styleCode="italics">Smoking</content>
</paragraph>
<paragraph>The pharmacokinetics of roflumilast and roflumilast N-oxide were comparable in smokers as compared to non-smokers. There was no difference in C<sub>max</sub> 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.</paragraph>
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<paragraph>
<content styleCode="italics">Race</content>
</paragraph>
<paragraph>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<sub>max</sub>, respectively, for roflumilast and 43%, 27%, and 17% higher C<sub>max</sub>, respectively, for roflumilast N-oxide. No dosage adjustment is necessary for race.</paragraph>
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<paragraph>
<content styleCode="italics">Drug Interactions</content>
</paragraph>
<paragraph>Drug interaction studies were performed with roflumilast and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction <content styleCode="italics">[see <linkHtml href="#s13">Drug Interactions (7)</linkHtml>].</content> 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.</paragraph>
<paragraph>The effect of concomitant drugs on the exposure of roflumilast and roflumilast N-oxide is shown in the Figure 1 below.</paragraph>
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<paragraph>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 (0.8-1.25) of the 90% confidence interval of the geometric mean ratio of C<sub>max</sub> or AUC for roflumilast or roflumilast N-oxide for Treatment (DALIRESP+Coadministered Drug) vs. Reference (DALIRESP). The dosing regimens of coadministered drugs was: Midazolam: 2 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</paragraph>
<paragraph>Drug interactions considered to be significant are described in more detail below <content styleCode="italics">[see <linkHtml href="#s10">Warnings and Precautions (5.4)</linkHtml> and <linkHtml href="#s13">Drug Interactions (7)</linkHtml>].</content>
</paragraph>
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<paragraph>Inhibitors of CYP3A4 and CYP1A2:</paragraph>
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<paragraph>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 a single oral dose of 500 mcg DALIRESP resulted in 40% and 70% increase in C<sub>max</sub> and AUC for roflumilast, respectively, and a 34% decrease and a 4% increase in C<sub>max</sub> and AUC for roflumilast N-oxide, respectively.</paragraph>
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<paragraph>Ketoconazole: In an open-label crossover study in 16 healthy volunteers, the coadministration of a strong CYP3A4 inhibitor ketoconazole (200 mg twice daily for 13 days) with a single oral dose of 500 mcg DALIRESP resulted in 23% and 99% increase in C<sub>max</sub> and AUC for roflumilast, respectively, and a 38% reduction and 3% increase in C<sub>max</sub> and AUC for roflumilast N-oxide, respectively.</paragraph>
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<paragraph>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 a single oral dose of 500 mcg DALIRESP showed a 12% and 156% increase in roflumilast C<sub>max</sub> and AUC along with a 210% decrease and 52% increase in roflumilast N-oxide C<sub>max</sub> and AUC, respectively.</paragraph>
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<paragraph>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 a single oral dose of 500 mcg DALIRESP resulted in an increased C<sub>max</sub> and AUC of roflumilast by 20% and 56%, respectively. Roflumilast N-oxide C<sub>max</sub> was decreased by 14% while roflumilast N-oxide AUC was increased by 23%.</paragraph>
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<paragraph>Cimetidine: In an open-label crossover study in 16 healthy volunteers, the coadministration of a dual CYP 3A4/1A2 inhibitor cimetidine (400 mg twice daily for 7 days) with a single dose of 500 mcg oral DALIRESP resulted in a 46% and 85% increase in roflumilast C<sub>max</sub> and AUC; and a 4% decrease in C<sub>max</sub> and 27% increase in AUC for roflumilast N-oxide, respectively.</paragraph>
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<paragraph>Oral Contraceptives containing Gestodene and Ethinyl Estradiol:</paragraph>
<paragraph>In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single oral dose of 500 mcg DALIRESP with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state caused a 38% increase and 12% decrease in C<sub>max</sub> of roflumilast and roflumilast N-oxide, respectively. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively.</paragraph>
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<paragraph>Inducers of CYP enzymes:</paragraph>
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<paragraph>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 a single oral dose of 500 mcg DALIRESP resulted in reduction of roflumilast C<sub>max</sub> and AUC by 68% and 79%, respectively; and an increase of roflumilast N-oxide C<sub>max</sub> by 30% and reduced roflumilast N-oxide AUC by 56%.</paragraph>
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