DALIRESP

Systemic Phosphodiesterase-4 (PDE4) Inhibitors for Reactive and Obstructive Airway Diseases
Topical Antipsoriasis Agents

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.

Severe

suicidal ideation / Delayed / Incidence not known
angioedema / Rapid / Incidence not known

Moderate

depression / Delayed / 1.0-2.0
gastritis / Delayed / 1.0-2.0

Mild

weight loss / Delayed / 7.0-20.0
diarrhea / Early / 3.1-9.5
nausea / Early / 1.2-4.7
headache / Early / 2.4-4.4
back pain / Delayed / 3.2-3.2
infection / Delayed / 1.0-2.8
influenza / Delayed / 2.8-2.8
insomnia / Early / 1.4-2.4
anorexia / Delayed / 2.1-2.1
dizziness / Early / 2.1-2.1
anxiety / Delayed / 1.0-2.0
dyspepsia / Early / 1.0-2.0
vomiting / Early / 1.0-2.0
abdominal pain / Early / 1.0-2.0
tremor / Early / 1.0-2.0
rhinitis / Early / 1.0-2.0
sinusitis / Delayed / 1.0-2.0
muscle cramps / Delayed / 1.0-2.0
urticaria / Rapid / 0-1.0
application site reaction / Early / 1.0-1.0
rash / Early / Incidence not known
gynecomastia / Delayed / Incidence not known

Daliresp, ZORYVE

Rx

Phosphodiesterase-4 (PDE4) inhibitor that reduces inflammation via an intracellular action
Used orally to reduce COPD exacerbations in adults with severe COPD, chronic bronchitis, and history of COPD exacerbations; topically to treat plaque psoriasis, including intertriginous areas, in adults and children 12 years of age and older
GOLD guidelines recommend use with a long-acting bronchodilator

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 the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for COPD, roflumilast is used in chronic bronchitis patients with severe to very severe COPD whose frequent exacerbations are not controlled by long-acting bronchodilators. In these patients, roflumilast decreases moderate and severe COPD exacerbations requiring corticosteroids by 15% to 20%. 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 Adults

Apply topically to the affected area(s) once daily.

Children and Adolescents 12 to 17 years

Apply topically to the affected area(s) once daily.

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): Caution is recommended, but specific recommendations are not available.
Moderate to severe hepatic impairment (Child-Pugh class B or C): Use is contraindicated.

Renal Impairment

No roflumilast dosage adjustments are needed for patients with renal impairment.

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%.
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.
Butabarbital: (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: (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%.
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.
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%.

Daliresp/Roflumilast Oral Tab: 250mcg, 500mcg
ZORYVE Topical Cream: 0.3%

Adults

500 mcg/day PO; 1 application per day topically.

Geriatric

500 mcg/day PO; 1 application per day topically.

Adolescents

1 application per day topically; safety and efficacy have not been established for the oral tablet.

Children

12 years: 1 application per day topically; safety and efficacy have not been established for the oral tablet.
1 to 11 years: Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

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 two- to three-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 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.

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 one hour after dosing (range, 0.5 to 2 hours) while plateau-like maximum concentrations of the N-oxide metabolite are reached in approximately eight hours (range, 4 to 13 hours). Food has no affect on total drug absorption, but delays time to maximum concentration (Tmax) of roflumilast by one hour and reduces Cmax of roflumilast by approximately 40%; the Cmax and Tmax of roflumilast N-oxide are unaffected.

Topical Route

In a small study of 18 adults and 6 adolescents (aged 13 to 16 years of age) with plaque psoriasis and a mean +/- body surface area involvement of 26.8 +/- 6.8% and 13 +/- 3.58%, respectively, an average topical application of 3 to 6.5 g of roflumilast 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 for roflumilast and 628 +/- 648 hour x ng/mL for the N-oxide metabolite. In adolescents, the mean systemic exposure (AUC0 to 24) was 25.1 +/- 24 hour x ng/mL for roflumilast and 140 +/- 179 hour x ng/mL for the N-oxide metabolite.

Pregnancy

There is no information regarding the presence of roflumilast in human milk, the effects on the breastfed infant, or the effects on milk production. According to the manufacturer, oral roflumilast should not be used during breast-feeding. The drug and/or its metabolites are excreted into the milk of lactating rats and the manufacturer states that such excretion into human milk is probable. To minimize potential exposure to the breastfed infant, 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 infant exposure. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.