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  • CLASSES

    PDE4 Inhibitors For Asthma/COPD, Systemic

    DEA CLASS

    Rx

    DESCRIPTION

    Phosphodiesterase-4 (PDE4) inhibitor that may down-regulate inflammation via intracellular action
    Used to reduce COPD exacerbations in those with severe COPD, bronchitis, and history of COPD exacerbations
    Use caution in those with hepatic impairment, history of psychiatric issues, or on CYP3A4-inducers

    COMMON BRAND NAMES

    DALIRESP

    HOW SUPPLIED

    DALIRESP Oral Tab: 500mcg

    DOSAGE & INDICATIONS

    For the prevention of COPD exacerbations in patients with severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and a history of exacerbations.
    Oral dosage
    Adults

    500 mcg PO once daily. Roflumilast is not a bronchodilator and is not intended for the treatment of acute bronchospasm. It should be used to reduce exacerbations in patients with chronic bronchitis, a history of exacerbations, and severe to very severe COPD (GOLD class C or D patients with a high risk of exacerbation) whose frequent exacerbations are not controlled by long-acting bronchodilators. Roflumilast has been shown to decrease moderate and severe exacerbations requiring corticosteroids by 15—20% in these patients populations. Always use roflumilast in combination with at least one long-acting bronchodilator.

    MAXIMUM DOSAGE

    Adults

    500 mcg/day PO.

    Geriatric

    500 mcg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Caution is recommended in patients with mild hepatic impairment (Child-Pugh class A), but specific recommendations for roflumilast dosage adjustment are not available. Use is not recommended in patients with moderate to severe hepatic failure (Child-Pugh class B or C).

    Renal Impairment

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

    ADMINISTRATION

    Oral Administration

    Administer with or without food.

    STORAGE

    DALIRESP:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Hepatic disease

    Roflumilast is contraindicated in patients with moderate to severe hepatic disease (Child-Pugh B or C); consideration of potential benefit:risk is recommended prior to initiating therapy in patients with mild hepatic impairment (Child-Pugh A). In clinically study, 16 patients with Child-Pugh A or B hepatic impairment administered 250 mcg of roflumilast once daily for 14 days had increases in drug exposure parameters as compared to age-, weight- and gender-matched healthy patients. 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 over those of healthy patients. 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 patients.

    Labor, obstetric delivery, pregnancy

    No adequate and well controlled studies have been conducted with roflumilast in pregnant women. Use this medication during pregnancy only if the potential benefits to the mother outweigh the potential risk to the fetus. 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 maximum recommended human doses (MRHD) exhibited slowed delivery.

    Breast-feeding

    According to the manufacturer, roflumilast should not be used by women who are 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. Drug excretion into human milk and effect in a breast-fed infant is unknown. 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.

    Children, infants, neonates

    The safety and efficacy of roflumilast has not been established in neonates, infants, children, and adolescents.

    Acute bronchospasm

    Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm. However, improved lung function may occur with use over time. Statistically significant improvement in lung function, as measured by forced expiratory volume in 1 second (FEV1), has been demonstrated in roflumilast-treated patients as compared to placebo-treated ones in 4 clinical trials of 1-year duration. Two of these trials involved patients with severe COPD (FEV1 <= 50% 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.

    Anxiety, depression, insomnia, suicidal ideation

    Use 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 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 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.

    ADVERSE REACTIONS

    Severe

    suicidal ideation / Delayed / 0-1.0
    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 / 9.5-9.5
    nausea / Early / 4.7-4.7
    headache / Early / 4.4-4.4
    back pain / Delayed / 3.2-3.2
    influenza / Delayed / 2.8-2.8
    insomnia / Early / 2.4-2.4
    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
    infection / Delayed / 1.0-2.0
    rhinitis / Early / 1.0-2.0
    sinusitis / Delayed / 1.0-2.0
    muscle cramps / Delayed / 1.0-2.0
    rash (unspecified) / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    gynecomastia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (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.
    Acetaminophen; 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.
    Acetaminophen; Butalbital; 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.
    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.
    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.
    Aspirin, ASA; Butalbital; 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.
    Atropine; Hyoscyamine; Phenobarbital; 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.
    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.
    Belladonna Alkaloids; Ergotamine; 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.
    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.
    Bosentan: (Major) Coadminister bosentan and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Bosentan 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.
    Brigatinib: (Moderate) Monitor for decreased efficacy of roflumilast if coadministration with brigatinib is necessary. Roflumilast is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of roflumilast may decrease. In an open-label, three-period, fixed-sequence study (n = 15), coadministration with a strong CYP3A4 inducer decreased the Cmax and AUC of roflumilast by 68% and 79%, respectively; the AUC of metabolite roflumilast N-oxide was reduced by 56%.
    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.
    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 and benefits of concomitant use of roflumilast with ceritinib prior to administration; monitor for roflumilast-related adverse reactions. Ceritinib is a CYP3A4 inhibitor. A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. Coadministration with a strong CYP3A4 inhibitor increased the AUC of roflumilast by 99%; the AUC of Roflumilast N-oxide was unchanged. Concomitant use with a moderate CYP3A4 inhibitor increased the roflumilast AUC by 70%; the AUC of Roflumilast N-oxide was unchanged. The degree of CYP3A4 inhibition by ceritinib is unknown.
    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.
    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 CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of roflumilast by 70%.
    Dalfopristin; Quinupristin: (Moderate) Coadminister dalfopristin; quinupristin and roflumilast cautiously as this may lead to increased systemic exposure to roflumilast; roflumilast-induced adverse effects may occur. Quinupristin 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.
    Dasabuvir; Ombitasvir; Paritaprevir; 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.
    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.
    Dexamethasone: (Major) Coadminister dexamethasone and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Dexamethasone 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.
    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; 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 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.
    Efavirenz; Emtricitabine; Tenofovir: (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 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.
    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.
    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) Coadminister erythromycin and roflumilast cautiously as increased systemic exposure to roflumilast has been demonstrated in pharmacokinetic study. Increased roflumilast-induced adverse reactions may result. Erythromycin is a strong CYP3A4 inhibitor; roflumilast is a CYP3A4 substrate. In an open-label crossover study in 16 healthy volunteers, the coadministration of erythromycin (500 mg three times daily for 13 days) with a single oral dose of roflumilast 500 mcg resulted in 40% and 70% increase in Cmax and AUC for roflumilast, respectively, and a 34% decrease in Cmax and a 4% increase AUC for the active metabolite roflumilast N-oxide.
    Erythromycin; Sulfisoxazole: (Moderate) Coadminister erythromycin and roflumilast cautiously as increased systemic exposure to roflumilast has been demonstrated in pharmacokinetic study. Increased roflumilast-induced adverse reactions may result. Erythromycin is a strong CYP3A4 inhibitor; roflumilast is a CYP3A4 substrate. In an open-label crossover study in 16 healthy volunteers, the coadministration of erythromycin (500 mg three times daily for 13 days) with a single oral dose of roflumilast 500 mcg resulted in 40% and 70% increase in Cmax and AUC for roflumilast, respectively, and a 34% decrease in Cmax and a 4% increase AUC for the active metabolite roflumilast N-oxide.
    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.
    Ethanol: (Major) Consumption of ethanol during roflumilast therapy may reduce systemic exposure to roflumilast. Ethanol 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.
    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.
    Ethinyl Estradiol; Desogestrel: (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; Ethynodiol Diacetate: (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; Etonogestrel: (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; 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.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; 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.
    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; Norethindrone Acetate; 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.
    Ethinyl 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.
    Ethinyl Estradiol; Norethindrone; 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.
    Ethinyl 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; 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.
    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.
    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: (Major) Patients receiving roflumilast may have altered serum concentrations if coadministered with fosamprenavir. Fosamprenavir is both an inhibitor and inducer of CYP3A4, and roflumilast is a CYP3A4 substrate. Specific pharmacokinetic study of this potential interaction has not been conducted.
    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: (Moderate) Coadminister isoniazid, INH and roflumilast cautiously as this may lead to increased systemic exposure to roflumilast; roflumilast-induced adverse effects may occur. Isoniazid 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.
    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%. (Moderate) Coadminister isoniazid, INH and roflumilast cautiously as this may lead to increased systemic exposure to roflumilast; roflumilast-induced adverse effects may occur. Isoniazid 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.
    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%. (Moderate) Coadminister isoniazid, INH and roflumilast cautiously as this may lead to increased systemic exposure to roflumilast; roflumilast-induced adverse effects may occur. Isoniazid 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.
    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.
    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.
    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.
    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.
    Mephobarbital: (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.
    Mestranol; 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.
    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.
    Metyrapone: (Major) Coadminister metyrapone and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Metyrapone 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.
    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.
    Nevirapine: (Major) Coadminister nevirapine and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Nevirapine 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.
    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.
    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.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as roflumilast. Therapeutic monitoring is recommended with coadministration.
    Ombitasvir; Paritaprevir; 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.
    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.
    Oxcarbazepine: (Major) Coadminister oxcarbazepine and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Oxcarbazepine 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.
    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.
    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.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with roflumilast is necessary, as the systemic exposure of roflumilast may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and roflumilast is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with roflumilast is necessary, as the systemic exposure of roflumilast may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and roflumilast is a CYP3A4 substrate.
    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%.
    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.
    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.
    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.
    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.
    Streptogramins: (Moderate) Coadminister dalfopristin; quinupristin and roflumilast cautiously as this may lead to increased systemic exposure to roflumilast; roflumilast-induced adverse effects may occur. Quinupristin 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.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and roflumilast is necessary, as the systemic exposure of roflumilast may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of roflumilast; consider increasing the dose of roflumilast if necessary. Roflumilast is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    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).
    Thiopental: (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.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    No adequate and well controlled studies have been conducted with roflumilast in pregnant women. Use this medication during pregnancy only if the potential benefits to the mother outweigh the potential risk to the fetus. 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 maximum recommended human doses (MRHD) exhibited slowed delivery.

    MECHANISM OF ACTION

    Roflumilast and the active metabolite, roflumilast N-oxide, selectively inhibit the actions of phosphodiesterase-4 (PDE4). This medication 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.

    PHARMACOKINETICS

    Roflumilast is administered orally. 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 an oral dose, the median plasma effective half-life of roflumilast and its N-oxide metabolite are approximately 17 and 30 hours, respectively. With once daily 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.