Roflumilast is a phosphodiesterase-4 (PDE4) inhibitor. The PDE4 enzyme is preferentially expressed in pro-inflammatory cells; inhibition results in intracellular accumulation of cyclic-AMP, a process that appears to down-regulate inflammation. Roflumilast is used orally to reduce chronic obstructive pulmonary disease (COPD) exacerbations in adults with severe COPD associated with bronchitis and a history of exacerbations and topically for the treatment of plaque psoriasis, including intertriginous areas, in patients 6 years of age and older and seborrheic dermatitis in patients 9 years and older. In 2 clinical trials, the incidence of COPD exacerbations was reduced in patients with severe COPD with chronic bronchitis, at least 1 COPD exacerbation in the previous year, and at least a 20 pack-year smoking history; the rate ratio of COPD exacerbations of oral roflumilast- to placebo-treated patients was 0.85 (95% CI, 0.74 to 0.98) and 0.82 (95% CI, 0.71 to 0.94). Earlier trials involving patients with more heterogenous COPD disease did not demonstrate a significant reduction in COPD exacerbations; study patients included those with severe COPD associated with chronic bronchitis and/or emphysema who had a 10 pack-year smoking history. According to guidelines, addition of roflumilast should be considered in patients treated with long-acting beta-agonist (LABA)+long-acting muscarinic antagonist (LAMA)+inhaled corticosteroid (ICS) who continue to have COPD exacerbations. Oral roflumilast reduces moderate and severe exacerbations treated with systemic corticosteroids in patients with chronic bronchitis, a history of exacerbations, and severe to very severe COPD. The beneficial effects of roflumilast have been reported to be greater in patients with a prior history of hospitalization for an acute COPD exacerbation. The efficacy of roflumilast topical cream for mild to severe plaque psoriasis (n = 881; 6 to 88 years) and topical foam for seborrheic dermatitis (n = 683; 9 to 87 years) was established in 4 randomized, double-blinded clinical trials in adult and pediatric patients. A higher percentage of patients receiving roflumilast cream or foam achieved Investigators Global Assessment (IGA) treatment success (IGA score of clear or almost clear, plus a 2-grade IGA score improvement from baseline) at week 8 compared to the vehicle-controlled groups.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer with or without food.
Topical Administration
Cream/Ointment/Lotion Formulations
-For topical use only. DO NOT administer via the oral, ophthalmic, or intravaginal routes.
-Rub the cream in completely until it is no longer visible on the skin.
-Wash hands after application, unless the hands are included as an area to be treated.
Other Topical Formulations
Foam
-For topical use only. DO NOT administer via the oral, ophthalmic, or intravaginal routes.
-Shake can prior to each use.
-Apply a thin layer of cream to affected areas when they are not wet.
-Rub the foam in completely.
-Wash hands after application.
In clinical trials, psychiatric adverse reactions were reported in 6% (263/4,438) of patients treated with oral roflumilast, compared to 3% (137/4,192) of those who received placebo. Insomnia (2%), anxiety (1% to 2%), and depression (1% to 2%) occurred at a higher incidence in the active-arms of study. Insomnia was also reported in approximately 1% of patients receiving topical roflumilast in clinical trials. Screen patients for pre-existing psychiatric disorders prior to initiating oral therapy. Advise patients and families to report new onset mood or behavior changes and consider therapy discontinuation in patients who experience such changes. Suicidal ideation and attempts may also occur more frequently in roflumilast treated patients; in pre-marketing clinical trials, 2 unsuccessful suicide attempts and 1 suicide were reported among oral roflumilast treated patients as compared to 1 case of suicidal ideation among placebo treated patients. One patient completed suicide while receiving oral roflumilast in a clinical trial that assessed the effect of adding roflumilast to a fixed dose combination of inhaled corticosteroids/long-acting beta agonists on rates of COPD exacerbations over 1 year of treatment.
In clinical trials, weight loss was reported in 7% (331/4,438) of patients treated with oral roflumilast, compared to 2% (89/4,192) of those treated with placebo. Monitor weight in all patients. Consider discontinuing roflumilast in patients who experience unexplained or clinically significant weight loss. In 2 prospective studies each of 1 year duration, moderate weight loss (defined as 5% to 10% of body weight) was reported in 20% of oral roflumilast-treated patients, compared to 7% of placebo-treated patients and severe weight loss (greater than 10% body weight) was reported in 7% of roflumilast-treated versus 2% of placebo-treated patients. The majority of patients experienced a partial regain of weight after treatment discontinuation.
Gastrointestinal adverse effects, including diarrhea (10%), nausea (5%), and anorexia (2%), were reported in patients receiving oral roflumilast in clinical trials. Abdominal pain, dyspepsia, gastritis, and vomiting also occurred in 1% to 2% of patients. Diarrhea (3% or less) and nausea (1%) were also reported in patients receiving topical roflumilast in clinical trials.
Headache (4%), tremor (1% to 2%), and dizziness (2%) were reported in patients receiving oral roflumilast in clinical trials. Headache was also reported in approximately 1% to 2% of patients receiving topical roflumilast in clinical trials.
Influenza was reported in 3% of patients receiving oral roflumilast in clinical trials. Other infections reported in 1% to 2% of patients included rhinitis, sinusitis, and urinary tract infection. Upper respiratory tract infection (1%), urinary tract infection (1%), and naso-pharyngitis (2%) were also reported in patients receiving topical roflumilast in clinical trials.
Back pain (3%) and muscle cramps or spasm (1% to 2%) were reported in patients receiving oral roflumilast in clinical trials.
Hypersensitivity reactions, such as angioedema, urticaria, and rash, have been reported with postmarketing use of oral roflumilast. Application site reaction (pain and/or urticaria) was reported in less than 1% of patients receiving topical roflumilast in clinical trials.
Gynecomastia has been reported with postmarketing use of oral roflumilast.
Roflumilast is contraindicated in patients with moderate to severe hepatic disease (Child-Pugh B or C); the exposure of roflumilast is significantly increased in these patients. Consider the potential benefit:risk prior to initiating oral roflumilast therapy in patients with mild hepatic impairment (Child-Pugh A).
There are insufficient data regarding use of roflumilast during human pregnancy to inform of a drug-associated risk of major birth defects, miscarriages, or other adverse maternal or fetal outcomes. Use this medication during pregnancy only if the potential benefits to the pregnant person outweigh the potential risk to the fetus. Oral doses of roflumilast that were 3-times the maximum recommended human dose (MRHD) or more induced post-implantation loss in rats. In mice, roflumilast induced still birth and decreased pup viability at oral doses 5- and 15-times the MRHD, respectively, and adversely affected pup post-natal development when dams were treated with roflumilast at oral doses 15-times the MRHD during pregnancy and lactation periods. The manufacturer recommends that roflumilast not be used during labor and obstetric delivery. There are no human studies that have investigated effects of this drug on preterm labor or labor at term; however, disrupted labor and delivery process has been noted in animal studies. Mice administered doses at greater than or equal to approximately 16-times the MRHD exhibited slowed delivery.
There are no data available regarding the presence of roflumilast or its metabolite in human milk, the effects on the breastfed child, or the effects on milk production. The drug and/or its metabolites are excreted into the milk of lactating rats and excretion into human milk is probable; therefore, oral roflumilast should not be used during breast-feeding. To minimize potential exposure to the breastfed child, use topical roflumilast on the smallest area of skin and for the shortest duration possible while breast-feeding. Do no apply directly to the nipple and areola to avoid direct child exposure. If applied to the patient's chest, avoid exposure via direct contact with the child's skin. Consider the benefits of breast-feeding, the risk of potential drug exposure to the child, and the risk of an untreated or inadequately treated condition.
Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm. However, improved lung function may occur with oral roflumilast use over time. Statistically significant improvement in lung function, as measured by forced expiratory volume in 1 second (FEV1), has been demonstrated in oral roflumilast-treated patients as compared to placebo-treated patients in 4 clinical trials of 1-year duration. Two of these trials involved patients with severe COPD (FEV1 50% or less of predicted) inclusive of those with chronic bronchitis and/or emphysema who had a history of smoking of at least 10 pack years; the later two trials had more restrictive enrollment and involved patients with severe COPD associated with chronic bronchitis, at least one COPD exacerbation in the previous year, and at least a 20 pack-year smoking history. The average improvement in FEV1 was approximately 50 mL across the 4 trials.
Use systemic roflumilast with caution, if at all, in patients with a history of anxiety, insomnia, depression, and/or suicidal ideation or behavior. Treatment has been associated with an increase in psychiatric adverse reactions. Advise all patients receiving roflumilast, and their caregivers and families, 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. In 8 controlled clinical trials, 5.9% of patients treated with oral roflumilast 500 mcg daily reported psychiatric adverse reactions as compared to 3.3% of those treated with placebo. Three study patients receiving roflumilast demonstrated suicidal behaviors, 1 suicide and 2 suicide attempts, while 1 case of suicidal ideation was reported in patients receiving placebo. One patient completed suicide while receiving oral roflumilast in a clinical trial that assessed the effect of adding roflumilast to a fixed dose combination of inhaled corticosteroids/long-acting beta agonists (LABAs) on rates of COPD exacerbations over 1 year of treatment.
The propellants in roflumilast topical foam are flammable. Instruct patients to avoid fire, flame, and tobacco smoking during and immediately following application.
For the prevention of severe chronic obstructive pulmonary disease (COPD) exacerbations in chronic bronchitis patients with severe COPD associated with a history of COPD exacerbations:
Oral dosage:
Adults: 250 mcg PO once daily for 4 weeks, then increase to the therapeutic/effective dose of 500 mcg PO once daily. Titration reduces the rate of treatment discontinuation by 6.2% in patients compared to those receiving 500 mcg/day initially; however, 250 mcg/day is not the effective (therapeutic) dose. Always use roflumilast in combination with at least 1 long-acting bronchodilator. According to guidelines, addition of roflumilast should be considered in patients treated with long-acting beta-agonist (LABA)+long-acting muscarinic antagonist (LAMA)+inhaled corticosteroid (ICS) who continue to have exacerbations. Roflumilast reduces moderate and severe exacerbations treated with systemic corticosteroids in patients with chronic bronchitis, a history of exacerbations, and severe to very severe COPD. The beneficial effects of roflumilast have been reported to be greater in patients with a prior history of hospitalization for an acute COPD exacerbation. Roflumilast is not a bronchodilator and is not intended for the treatment of acute bronchospasm.
For the treatment of plaque psoriasis, including intertriginous areas:
Topical dosage (cream):
Adults: Apply topically to the affected area(s) once daily.
Children and Adolescents 6 to 17 years: Apply topically to the affected area(s) once daily.
For the treatment of seborrheic dermatitis:
Topical dosage (foam):
Adults: Apply a thin layer topically to the affected area(s) on skin or scalp once daily.
Children and Adolescents 9 to 17 years: Apply a thin layer topically to the affected area(s) on skin or scalp once daily.
Maximum Dosage Limits:
-Adults
500 mcg/day PO; 1 application/day topically for cream or foam.
-Geriatric
500 mcg/day PO; 1 application/day topically for cream or foam.
-Adolescents
1 application/day topically for cream or foam; safety and efficacy of the oral tablet have not been established.
-Children
9 to 12 years: 1 application/day topically for cream or foam; safety and efficacy of the oral tablet have not been established.
6 to 8 years: 1 application/day topically for cream; safety and efficacy of the topical foam or oral tablet have not been established.
1 to 5 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild hepatic impairment (Child-Pugh class A): Caution is recommended for oral use, but specific recommendations are not available. No dosage adjustment is needed for topical use.
Moderate to severe hepatic impairment (Child-Pugh class B or C): Use is contraindicated.
Patients with Renal Impairment Dosing
No dosage adjustment is needed.
*non-FDA-approved indication
Adagrasib: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with adagrasib is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the exposure of roflumilast by 99%.
Amiodarone: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with amiodarone is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A and CYP1A2 substrate and amiodarone is a CYP3A/CYP1A2 inhibitor. Coadministration with other dual CYP3A/CYP1A2 inhibitors increased the exposure of roflumilast by 85% to 156%.
Amobarbital: (Major) Coadminister barbiturates and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Barbiturates induce CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Apalutamide: (Major) Coadministration of roflumilast with apalutamide is not recommended due to decreased plasma concentrations of roflumilast. Roflumilast is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased roflumilast exposure by 80%; exposure to roflumilast N-oxide was decreased by 56%.
Aprepitant, Fosaprepitant: (Moderate) Use caution if roflumilast and aprepitant, fosaprepitant are used concurrently and monitor for an increase in roflumilast-related adverse effects for several days after administration of a multi-day aprepitant regimen. Roflumilast is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of roflumilast. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aspirin, ASA; Butalbital; Caffeine: (Major) Coadminister barbiturates and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Barbiturates induce CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Atazanavir; Cobicistat: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with cobicistat is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of roflumilast by 99%.
Barbiturates: (Major) Coadminister barbiturates and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Barbiturates induce CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Berotralstat: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with berotralstat is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the exposure of roflumilast by 70%.
Bexarotene: (Major) Coadminister bexarotene and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Betaxortene induces CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Butalbital; Acetaminophen: (Major) Coadminister barbiturates and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Barbiturates induce CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Butalbital; Acetaminophen; Caffeine: (Major) Coadminister barbiturates and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Barbiturates induce CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Coadminister barbiturates and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Barbiturates induce CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Coadminister barbiturates and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Barbiturates induce CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Carbamazepine: (Major) Coadministration of carbamazepine and roflumilast is not recommended, as significantly reduced systemic exposure to roflumilast is expected. Carbamazepine is a strong CYP3A4 inducer; roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another strong CYP3A4 inducer, rifampicin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Ceritinib: (Moderate) Carefully weigh the risks of increased roflumilast exposure against the benefits of therapy if coadministration with ceritinib is necessary; monitor for roflumilast-related adverse reactions. Roflumilast is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
Cimetidine: (Moderate) Coadminister cimetidine and roflumilast cautiously as increased systemic exposure to roflumilast has been demonstrated in pharmacokinetic study. Increased roflumilast-induced adverse reactions may result. Cimetidine is an inhibitor of CYP3A4 and CYP1A2; roflumilast is a CYP3A4 and CYP1A2 substrate. In an open-label crossover study in 16 healthy volunteers, the coadministration of cimetidine (400 mg twice daily for 7 days) with a single oral dose of roflumilast 500 mcg resulted in a 46% and 85% increase in roflumilast Cmax and AUC; and a 4% decrease in Cmax and 27% increase in AUC for the active metabolite roflumilast N-oxide.
Cobicistat: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with cobicistat is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of roflumilast by 99%.
Conivaptan: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with conivaptan is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the exposure of roflumilast by 70%.
Crizotinib: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if coadministration with crizotinib is necessary; carefully weigh the risks and benefits of treatment. Roflumilast is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of roflumilast by 70%.
Darunavir; Cobicistat: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with cobicistat is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of roflumilast by 99%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with cobicistat is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of roflumilast by 99%.
Delavirdine: (Major) Coadminister delavirdine and roflumilast cautiously as this may lead to increased systemic exposure to roflumilast; roflumilast-induced adverse effects may occur. Delavirdine is a strong CYP3A4 inhibitor and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving one of several CYP3A4 inhibitors resulted in variably increased roflumilast Cmax and AUC, as well as decreased Cmax and increased AUC of the active metabolite roflumilast N-oxide.
Desogestrel; Ethinyl Estradiol: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Dienogest; Estradiol valerate: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Drospirenone: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Drospirenone; Estetrol: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Drospirenone; Estradiol: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Drospirenone; Ethinyl Estradiol: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Efavirenz: (Moderate) Coadminister efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Efavirenz induces CYP3A and roflumilast is a CYP3A substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadminister efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Efavirenz induces CYP3A and roflumilast is a CYP3A substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadminister efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Efavirenz induces CYP3A and roflumilast is a CYP3A substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Elbasvir; Grazoprevir: (Moderate) Administering roflumilast with elbasvir; grazoprevir may result in elevated roflumilast plasma concentrations. Roflumilast is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with cobicistat is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of roflumilast by 99%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with cobicistat is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of roflumilast by 99%.
Encorafenib: (Major) Concomitant use of roflumilast and encorafenib is not recommended. Concurrent use may decrease the systemic exposure to roflumilast which may reduce its efficacy. Roflumilast is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased roflumilast exposure by 80%; exposure to roflumilast N-oxide was decreased by 56%.
Enzalutamide: (Major) Coadministration of roflumilast with enzalutamide is not recommended due to decreased plasma concentrations of roflumilast. Roflumilast is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased roflumilast exposure by 80%; exposure to roflumilast N-oxide was decreased by 56%.
Erythromycin: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with erythromycin is necessary. Concurrent use may increase roflumilast exposure and the risk for roflumilast-related adverse reactions. Roflumilast is a CYP3A4 and CYP1A2 substrate. Erythromycin is a dual inhibitor of both CYP3A4 (moderate) and CYP1A2 (weak). Coadministration with erythromycin increased the exposure of roflumilast by 70%.
Estradiol; Levonorgestrel: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Estradiol; Norethindrone: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Estradiol; Norgestimate: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Ethinyl Estradiol; Norelgestromin: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Ethinyl Estradiol; Norgestrel: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Etonogestrel; Ethinyl Estradiol: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Etravirine: (Moderate) Coadminister etravirine and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Etravirine induces CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Fedratinib: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if coadministration with fedratinib is necessary; carefully weigh the risks and benefits of treatment. Roflumilast is a CYP3A4 substrate and fedratinib is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of roflumilast by 70%.
Fluvoxamine: (Moderate) Coadminister fluvoxamine and roflumilast cautiously as increased systemic exposure to roflumilast has been demonstrated in pharmacokinetic study. Increased roflumilast-induced adverse reactions may result. Fluvoxamine is an inhibitor of CYP3A4 and CYP1A2; roflumilast is a CYP3A4 and CYP1A2 substrate. In an open-label crossover study in 16 healthy volunteers, the coadministration of fluvoxamine (50 mg daily for 14 days) with a single oral dose of roflumilast 500 mcg showed a 12% and 156% increase in roflumilast Cmax and AUC along with a 210% decrease and 52% increase in the active metabolite roflumilast N-oxide Cmax and AUC, respectively.
Fosamprenavir: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with fosamprenavir is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the exposure of roflumilast by 70%.
Fosphenytoin: (Major) Coadministration of phenytoin or fosphenytoin and roflumilast is not recommended, as significantly reduced systemic exposure to roflumilast is expected. Phenytoin is a strong CYP3A4 inducer; roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another strong CYP3A4 inducer, rifampicin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Indinavir: (Moderate) Coadminister indinavir and roflumilast cautiously as this may lead to increased systemic exposure to roflumilast; roflumilast-induced adverse effects may occur. Indinavir is a strong inhibitor of CYP3A4 and roflumilast is a CYP3A4 substrate. In a pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inhibitor resulted in variably increased roflumilast Cmax and AUC, as well as decreased Cmax and increased AUC of the active metabolite roflumilast N-oxide.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Coadministration of rifampin and roflumilast is not recommended, as significantly reduced systemic exposure to roflumilast has been demonstrated in pharmacokinetic study. Rifampin, known as rifampicin internationally, is a strong CYP3A4 inducer; roflumilast is a CYP3A4 substrate. In an open-label, three-period, fixed-sequence study in 15 healthy volunteers, coadministration of rifampin (600 mg once daily for 11 days) with a single oral dose of roflumilast 500 mcg resulted in reduction of roflumilast Cmax and AUC by 68% and 79%, respectively. The pharmacokinetics of the active metabolite roflumilast N-oxide were also affected; roflumilast N-oxide Cmax was increased by 30% and AUC was decreased by 56%.
Isoniazid, INH; Rifampin: (Major) Coadministration of rifampin and roflumilast is not recommended, as significantly reduced systemic exposure to roflumilast has been demonstrated in pharmacokinetic study. Rifampin, known as rifampicin internationally, is a strong CYP3A4 inducer; roflumilast is a CYP3A4 substrate. In an open-label, three-period, fixed-sequence study in 15 healthy volunteers, coadministration of rifampin (600 mg once daily for 11 days) with a single oral dose of roflumilast 500 mcg resulted in reduction of roflumilast Cmax and AUC by 68% and 79%, respectively. The pharmacokinetics of the active metabolite roflumilast N-oxide were also affected; roflumilast N-oxide Cmax was increased by 30% and AUC was decreased by 56%.
Itraconazole: (Moderate) Coadminister itraconazole and roflumilast cautiously as this may lead to increased systemic exposure to roflumilast; roflumilast-induced adverse effects may occur. Itraconazole is a strong inhibitor of CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inhibitor resulted in variably increased roflumilast Cmax and AUC, as well as decreased Cmax and increased AUC of the active metabolite roflumilast N-oxide.
Ketoconazole: (Moderate) Coadminister ketoconazole and roflumilast cautiously as increased systemic exposure to roflumilast has been demonstrated in pharmacokinetic study. Increased roflumilast-induced adverse reactions may result. Ketoconazole is a strong CYP3A4 inhibitor; roflumilast is a CYP3A4 substrate. In an open-label crossover study in 16 healthy volunteers, the coadministration of ketoconazole (200 mg twice daily for 13 days) with a single oral dose of roflumilast 500 mcg resulted in 23% and 99% increase in Cmax and AUC for roflumilast, respectively, and a 38% reduction in Cmax and 3% increase in AUC for the active metabolite roflumilast N-oxide.
Lefamulin: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if coadministration with oral lefamulin is necessary; carefully weigh the risks and benefits of treatment. Roflumilast is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of roflumilast by 70%.
Lenacapavir: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with lenacapavir is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the exposure of roflumilast by 70%.
Letermovir: (Moderate) An increase in the plasma concentration of roflumilast may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. The risk of such concurrent use should be weighed carefully against benefit. Roflumilast is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, concurrent administration with another strong CYP3A4 inhibitor increased the maximum plasma concentration (Cmax) and exposure (AUC) of roflumilast by 23% and 99%, respectively. In addition, the Cmax of the metabolite, roflumilast N-oxide, was decrease by 38% and the AUC was increased by 3%. Similarly, when administered with another moderate CYP3A4 inhibitor the Cmax and AUC of roflumilast increased by 40% and 70%, respectively; while the Cmax of roflumilast N-oxide decreased by 34% and the AUC increased by 4%.
Leuprolide; Norethindrone: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Levoketoconazole: (Moderate) Coadminister ketoconazole and roflumilast cautiously as increased systemic exposure to roflumilast has been demonstrated in pharmacokinetic study. Increased roflumilast-induced adverse reactions may result. Ketoconazole is a strong CYP3A4 inhibitor; roflumilast is a CYP3A4 substrate. In an open-label crossover study in 16 healthy volunteers, the coadministration of ketoconazole (200 mg twice daily for 13 days) with a single oral dose of roflumilast 500 mcg resulted in 23% and 99% increase in Cmax and AUC for roflumilast, respectively, and a 38% reduction in Cmax and 3% increase in AUC for the active metabolite roflumilast N-oxide.
Levonorgestrel: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Levonorgestrel; Ethinyl Estradiol: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Lonafarnib: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with lonafarnib is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of roflumilast by 99%.
Lopinavir; Ritonavir: (Major) Patients receiving roflumilast may have altered serum concentrations if coadministered with ritonavir. Ritonavir is a potent inhibitor and an inducer of CYP3A4, and roflumilast is a CYP3A4 substrate. Specific pharmacokinetic study of this potential interaction has not been conducted.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may reduce the efficacy of roflumilast by decreasing its systemic exposure; concomitant use is not recommended. Roflumilast is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Coadministration of roflumilast and rifampicin, another strong CYP3A inducer, resulted in a reduction of roflumilast Cmax and AUC by 68% and 79%, respectively, and a 30% increase and 56% decrease in the Cmax and AUC for the active metabolite roflumilast N-oxide, respectively.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may reduce the efficacy of roflumilast by decreasing its systemic exposure; concomitant use is not recommended. Roflumilast is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Coadministration of roflumilast and rifampicin, another strong CYP3A inducer, resulted in a reduction of roflumilast Cmax and AUC by 68% and 79%, respectively, and a 30% increase and 56% decrease in the Cmax and AUC for the active metabolite roflumilast N-oxide, respectively.
Methohexital: (Major) Coadminister barbiturates and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Barbiturates induce CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Mitotane: (Major) Concomitant use of mitotane with roflumilast is not recommended; if coadministration cannot be avoided, monitor for decreased efficacy of roflumilast. Mitotane is a strong CYP3A4 inducer and roflumilast is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of roflumilast. In an open-label, three-period, fixed-sequence study in 15 healthy volunteers, coadministration of another strong CYP3A inducer, rifampin (600 mg once daily for 11 days), with a single oral dose of roflumilast 500 mcg resulted in reduction of roflumilast Cmax and AUC by 68% and 79%, respectively. The pharmacokinetics of the active metabolite roflumilast N-oxide were also affected; roflumilast N-oxide Cmax was increased by 30% and AUC was decreased by 56%.
Modafinil: (Major) Coadminister modafinil and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Modafinil induces CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Nirmatrelvir; Ritonavir: (Major) Patients receiving roflumilast may have altered serum concentrations if coadministered with ritonavir. Ritonavir is a potent inhibitor and an inducer of CYP3A4, and roflumilast is a CYP3A4 substrate. Specific pharmacokinetic study of this potential interaction has not been conducted.
Nirogacestat: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with nirogacestat is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the exposure of roflumilast by 70%.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Norethindrone: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Norethindrone; Ethinyl Estradiol: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Norgestimate; Ethinyl Estradiol: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Norgestrel: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Omeprazole; Amoxicillin; Rifabutin: (Major) Coadminister rifabutin and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Rifabutin is a CYP3A4 inducer and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide. Specific pharmacokinetic study of this potential interaction has not been conducted.
Oral Contraceptives: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Pentobarbital: (Major) Coadminister barbiturates and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Barbiturates induce CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Phenobarbital: (Major) Coadminister barbiturates and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Barbiturates induce CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Coadminister barbiturates and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Barbiturates induce CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Phenytoin: (Major) Coadministration of phenytoin and roflumilast is not recommended, as significantly reduced systemic exposure to roflumilast is expected. Phenytoin is a strong CYP3A4 inducer; roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another strong CYP3A4 inducer, rifampicin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Primidone: (Major) Coadminister barbiturates and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Barbiturates induce CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
Ribociclib: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if coadministration with ribociclib is necessary; carefully weigh the risk against the benefit. Roflumilast is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased roflumilast exposure by 99%.
Ribociclib; Letrozole: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if coadministration with ribociclib is necessary; carefully weigh the risk against the benefit. Roflumilast is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased roflumilast exposure by 99%.
Rifabutin: (Major) Coadminister rifabutin and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Rifabutin is a CYP3A4 inducer and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide. Specific pharmacokinetic study of this potential interaction has not been conducted.
Rifampin: (Major) Coadministration of rifampin and roflumilast is not recommended, as significantly reduced systemic exposure to roflumilast has been demonstrated in pharmacokinetic study. Rifampin, known as rifampicin internationally, is a strong CYP3A4 inducer; roflumilast is a CYP3A4 substrate. In an open-label, three-period, fixed-sequence study in 15 healthy volunteers, coadministration of rifampin (600 mg once daily for 11 days) with a single oral dose of roflumilast 500 mcg resulted in reduction of roflumilast Cmax and AUC by 68% and 79%, respectively. The pharmacokinetics of the active metabolite roflumilast N-oxide were also affected; roflumilast N-oxide Cmax was increased by 30% and AUC was decreased by 56%.
Rifapentine: (Major) Concomitant use of roflumilast and rifapentine is not recommended. Concurrent use may decrease the systemic exposure to roflumilast which may reduce its efficacy. Roflumilast is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased roflumilast exposure by 80%; exposure to roflumilast N-oxide was decreased by 56%.
Riociguat: (Moderate) Coadministration of riociguat and phosphodiesterase inhibitors, including specific phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil) and nonspecific phosphodiesterase inhibitors (dipyridamole or theophylline, aminophylline) is contraindicated due to the risk of hypotension. Clinical experience with other phosphodidesterase inhibitors (e.g., milrinone, cilostazol, and roflumilast) is limited. The addition of riociguat to a stable sildenafil regimen (20 mg three times a day) resulted in additive hemodynamic effects in an exploratory interaction study in 7 patients with pulmonary arterial hypertension (PAH). Among patients with PAH on stable sildenafil treatment and riociguat there was one death, possibly related to the combination of these drugs, and a high rate of discontinuation for hypotension.
Ritlecitinib: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with ritlecitinib is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A and CYP1A2 substrate and ritlecitinib is a CYP3A/CYP1A2 inhibitor. Coadministration with other dual CYP3A/CYP1A2 inhibitors increased the exposure of roflumilast by 85% to 156%.
Ritonavir: (Major) Patients receiving roflumilast may have altered serum concentrations if coadministered with ritonavir. Ritonavir is a potent inhibitor and an inducer of CYP3A4, and roflumilast is a CYP3A4 substrate. Specific pharmacokinetic study of this potential interaction has not been conducted.
Rucaparib: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if coadministration with rucaparib is necessary. A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. Rucaparib is a moderate CYP1A2 inhibitor and a weak inhibitor of CYP3A4. Dual inhibitors of CYP3A4 and CYP1A2 may increase roflumilast exposure.
Secobarbital: (Major) Coadminister barbiturates and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Barbiturates induce CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) Coadminister oral contraceptives containing gestodene and ethinyl estradiol and roflumilast cautiously, as the combination has resulted in increased drug exposure to roflumilast in pharmacokinetic study. In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single dose of oral roflumilast 500 mcg with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state resulted in a 38% increase in Cmax of roflumilast and a 12% decrease in Cmax of the active metabolite roflumilast N-oxide. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively. A similar interaction is expected with oral contraceptives and ethinyl estradiol; etonogestrel.
St. John's Wort, Hypericum perforatum: (Major) Coadminister roflumilast and St. John's wort, Hypericum perforatum cautiously as this may lead to reduced systemic exposure to roflumilast. St. John's wort induces CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Theophylline, Aminophylline: (Major) Drug interaction studies were performed with roflumilast and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. No significant drug interactions were observed when 500 mcg oral roflumilast was administered with theophylline, aminophylline. While a pharmacokinetic interaction did not occur, patients were prohibited from taking theophylline in roflumilast clinical trials. Current guidelines in the management of patients with COPD do not recommend co-use of theophylline or aminophylline with roflumilast, presumably due to a pharmacodynamic effect (additive actions on cyclic AMP) and the potential for similar side effect profiles (e.g., diarrhea, weight loss, appetite changes, nausea, headache). (Major) Drug interaction studies were performed with roflumilast and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. No significant drug interactions were observed when 500 mcg oral roflumilast was administered with theophylline, aminophylline. While a pharmacokinetic interaction did not occur, patients were prohibited from taking theophylline in roflumilast clinical trials. Current guidelines in the management of patients with COPD do not recommend the routine co-use of theophylline or aminophylline with roflumilast, presumably due to a pharmacodynamic effect (additive actions on cyclic AMP) and the potential for similar side effect profiles (e.g., diarrhea, weight loss, appetite changes, nausea, headache).
Tipranavir: (Moderate) Coadminister tipranavir and roflumilast cautiously as this may lead to increased systemic exposure to roflumilast; roflumilast-induced adverse effects may occur. Tipranavir is a strong inhibitor of CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving one of several CYP3A4 inhibitors, including cimetidine, enoxacin, erythromycin, fluvoxamine, or ketoconazole, resulted in variably increased roflumilast Cmax and AUC, as well as decreased Cmax and increased AUC of the active metabolite roflumilast N-oxide.
Tucatinib: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if coadministration with tucatinib is necessary; carefully weigh the risk against the benefit. Roflumilast is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased roflumilast exposure by 99%.
Viloxazine: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with viloxazine is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A4 and CYP1A2 substrate and viloxazine is a strong CYP1A2 inhibitor and weak CYP3A4 inhibitor. Coadministration of roflumilast with other dual CYP3A4/CYP1A2 inhibitors increased the exposure of roflumilast by 85% to 156%.
Voriconazole: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if coadministration with voriconazole is necessary; carefully weigh the risk against the benefit. Roflumilast is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased roflumilast exposure by 99%.
Voxelotor: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with voxelotor is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased the exposure of roflumilast by 70%.
Roflumilast and the active metabolite, roflumilast N-oxide, selectively inhibit the actions of phosphodiesterase-4 (PDE4). Oral roflumilast is not a bronchodilator. Instead, inhibition of the PDE4 enzyme blocks the hydrolyses and inactivation of cyclic adenosine monophosphate (cAMP), resulting in intracellular cAMP accumulation. This is thought to decrease inflammatory activity, though the exact mechanism of action is not fully elucidated. Study has suggested PDE4 inhibition affects the migration and actions of pro-inflammatory cells including neutrophils and other leukocytes, T-lymphocytes, monocytes, macrophages, and fibroblasts.
Roflumilast is 2 to 3 times more potent than roflumilast N-oxide at inhibition of the PDE4 enzyme in vitro; however, the plasma AUC of roflumilast N-oxide on average is about 10-fold greater than the plasma AUC of roflumilast.
Roflumilast is administered orally and topically. Plasma protein binding is approximately 99% for roflumilast and 97% for its N-oxide metabolite. Rat studies indicate low penetration across the blood-brain barrier. Roflumilast is extensively metabolized in the liver via cytochrome P450 (CYP) and conjugation reactions. Metabolism by CYP3A4 and CYP1A2 yields the active metabolite roflumilast N-oxide. Comparatively, this metabolite has an in vitro PDE4 inhibitory activity of approximately one-third and an AUC of approximately 10 times that of the parent compound following oral administration and 7 to 8 times higher following topical administration. Following an oral dose, the median plasma effective half-life of roflumilast and its N-oxide metabolite are approximately 17 and 30 hours, respectively. After topical application, the half-life of roflumilast and its N-oxide metabolite are approximately 4 and 4.6 days, respectively. With once daily oral dosing steady state plasma concentrations are reached after approximately 4 days for roflumilast and 6 days for roflumilast N-oxide. Following intravenous or oral administration of radiolabeled roflumilast, about 70% of the radioactivity was recovered in the urine.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4, CYP1A2
Because roflumilast is metabolized by CYP3A4 and CYP1A2, clinically significant drug interactions are possible if another drug inhibits or induces these enzymes.
-Route-Specific Pharmacokinetics
Oral Route
Following oral administration, roflumilast 500 mcg tablets have an approximately 80% absolute bioavailability. In the fasted state, maximum plasma concentrations (Cmax) of roflumilast typically occur approximately 1 hour after dosing (range, 0.5 to 2 hours), while plateau-like maximum concentrations of the N-oxide metabolite are reached in approximately 8 hours (range, 4 to 13 hours). Food has no effect on total drug absorption, but delays time to maximum concentration (Tmax) of roflumilast by 1 hour and reduces Cmax of roflumilast by approximately 40%; the Cmax and Tmax of roflumilast N-oxide are unaffected.
Topical Route
Topical cream
In a small study that included 18 adults and 6 adolescents (aged 13 to 16 years) with plaque psoriasis and a mean +/- body surface area (BSA) involvement of 26.8 +/- 6.8% and 13 +/- 3.58%, respectively, an average topical application of 3 to 6.5 g of roflumilast cream once daily for 15 days resulted in quantifiable plasma concentrations in all but 2 patients on day 15. The plasma concentration versus time profile was relatively flat, with a peak-to-trough ratio less than 2. In adults, the mean systemic exposure (AUC0 to 24) was 72.7 +/- 53.1 hour x ng/mL and 628 +/- 648 hour x ng/mL for roflumilast and the N-oxide metabolite, respectively. In adolescents, the mean AUC0 to 24 was 25.1 +/- 24 hour x ng/mL and 140 +/- 179 hour x ng/mL for roflumilast and the N-oxide metabolite, respectively. In another study involving 10 pediatric patients (aged 6 to 12 years) with at least mild plaque psoriasis and a mean +/- BSA involvement of 10.9 +/- 6.56%, the 14-day mean AUC0 to 24 was 75.6 +/- 87.3 and 693 +/- 986 hour x ng/mL for roflumilast and the N-oxide metabolite, respectively. In a third study, the pharmacokinetics of roflumilast cream were evaluated in 9 pediatric patients (aged 2 to 5 years) with at least mild plaque psoriasis and a mean +/- BSA involvement of 9.44 +/- 5.57%. The 14-day mean AUC0 to 24 for roflumilast and the N-oxide metabolite was 51.6 +/- 29.9 and 539 +/- 372 hour x ng/mL, respectively.
Topical foam
The pharmacokinetics of roflumilast foam were evaluated in 10 adults and 10 pediatric patients (aged 11 to 16 years) with seborrheic dermatitis. In this study, a mean dose of approximately 4.1 grams of roflumilast foam was applied once daily for 15 days to a mean BSA involvement of 6.5 +/- 1.08% and 5.5 +/- 1.27% in adult and pediatric patients, respectively. At Day 15, plasma concentrations of roflumilast were quantifiable in all but 2 patients, while roflumilast N-oxide concentrations were quantifiable in all patients. The plasma concentration versus time profile was relatively flat, with mean peak-to-trough ratios of 1.68 and 1.62 for roflumilast and the metabolite, respectively. In adults, the mean maximum plasma concentration (Cmax) was 2.2 +/- 1.6 and 13.8 +/- 9 ng/mL for roflumilast and the metabolite, respectively. The mean AUC0 to 24 was 36.6 +/- 23.7 and 261 +/- 190 ng x hour/mL for roflumilast and the metabolite, respectively. In pediatric patients, the extrapolated mean AUC0 to 24 was 25.1 +/- 30.2 and 253 +/- 404 ng x hour/mL for roflumilast and roflumilast N-oxide, respectively.
-Special Populations
Hepatic Impairment
In a clinical study in 16 patients with mild to moderate (Child-Pugh A or B) hepatic impairment administered roflumilast 250 mcg PO once daily for 14 days, increases in drug exposure parameters were observed. The AUCs of roflumilast and the active metabolite roflumilast N-oxide were increased by 51% and 24%, respectively, in Child-Pugh A patients and by 92% and 41%, respectively, in Child-Pugh B patients, as compared to age-, weight- and gender-matched healthy subjects. Similarly, the Cmax of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively in Child-Pugh A patients and by 26% and 40%, respectively in Child-Pugh B patients, as compared to healthy subjects. Topical roflumilast has not been studied in patients with hepatic impairment.
Renal Impairment
Twelve subjects with severe renal impairment received a single roflumilast oral dose of 500 mcg, 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 studies have been conducted with topical roflumilast in patients with renal impairment.
Pediatrics
Following topical application, no clinically significant differences in the pharmacokinetics of roflumilast and roflumilast N-oxide were observed based on age (2 years and older). Oral roflumilast has not been studied in pediatric patients.
Geriatric
Based on available data for roflumilast, no dosage adjustment in elderly patients is warranted. No overall differences in safety or effectiveness were observed between study patients older than 65 years of age and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. Following 15 days of roflumilast 500 mcg PO once daily to young, middle-aged, and elderly healthy individuals, the AUC and Cmax were 27% and 16% higher, respectively, for roflumilast, and 19% and 13% higher, respectively, for roflumilast-N-oxide in geriatric subjects (greater than 65 years of age) compared to younger subjects (18 to 45 years of age). Following topical application, no clinically significant differences in the pharmacokinetics of roflumilast and roflumilast N-oxide were observed based on age (up to 88 years).
Gender Differences
No dosage adjustment is necessary based on sex. In a Phase I study evaluating the effect of gender on the pharmacokinetics of roflumilast and roflumilast N-oxide, a 39% and 33% increase in roflumilast and roflumilast N-oxide AUC, respectively, was noted in healthy female subjects as compared to healthy male subjects. Following topical application, no clinically significant differences in the pharmacokinetics of roflumilast and roflumilast N-oxide were observed based on sex.
Ethnic Differences
No dosage adjustment is necessary for race. As compared to white patients, the AUC of oral roflumilast and roflumilast N-oxide were increased by 16% and 43%, respectively, in Black patients, 41% and 27%, respectively, in Hispanic patients, and 15% and 16%, respectively, in Japanese patients. Similarly, compared to white patients, the Cmax of oral roflumilast and roflumilast N-oxide were increased by 8% and 43%, respectively, in Black patients, 21% and 27%, respectively, in Hispanic patients, and 5% and 17%, respectively, in Japanese patients. Following topical application, no clinically significant differences in the pharmacokinetics of roflumilast and roflumilast N-oxide were observed based on race or ethnicity.
Other
Smokers
The pharmacokinetics of oral roflumilast and roflumilast N-oxide were comparable in smokers and non-smokers. There was no difference in Cmax when 500 mcg PO was administered as a single dose to 12 smokers and 12 non-smokers. The roflumilast AUC in smokers was 13% less than that in non-smokers and the AUC of roflumilast N-oxide in smokers was 17% more than that in non-smokers.