Roflumilast (roflumilast)

The recommended adult dosage of roflumilast to reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations is 500 mcg once daily.

Roflumilast is administered orally once daily without regard to meals.

In vitro, roflumilast and roflumilast N-oxide do not inhibit the P-glycoprotein transport system.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Apremilast; Roflumilast/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of apremilast(1) and roflumilast(2,3) by CYP3A4.

CLINICAL EFFECTS: Concurrent or recent use of strong CYP3A4 inducers may reduce the clinical effectiveness of apremilast(1) and roflumilast.(2,3)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Monitor patients receiving concurrent CYP3A4 inducers for decreased apremilast(1) and roflumilast(2,3) efficacy. Concurrent use is not recommended.(1,2) The dosage of roflumilast may need to be adjusted or additional COPD therapy may need to be adjusted during and for up to two weeks after therapy with a CYP3A4 inducer has been completed.

DISCUSSION: Pretreatment with rifampin (600 mg daily for 15 days) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of apremilast by 43% and 72%, respectively.(1) In an open-label study in 16 healthy males, rifampin (600 mg daily) decreased AUC and Cmax of a single dose of roflumilast (500 mcg) by 80% and 68%, respectively. The AUC and Cmax of roflumilast N-oxide decreased by 56% and 30%, respectively.(2) The total PDE4 inhibitory activity of roflumilast decreased by 60%.(2-4) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, rifampin, rifapentine and St. John's wort.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Roflumilast/Strong Or Mod 3A4 Inh; Dual 3A4 And 1A2 Inhibit

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that are either strong or moderate CYP3A4 inhibitors or dual inhibitors of CYP1A2 and CYP3A4 may inhibit the metabolism of roflumilast.(1)

CLINICAL EFFECTS: The coadministration of roflumilast with strong or moderate CYP3A4 inhibitors or dual inhibitors of CY3A4 and CYP1A2 may increase roflumilast systemic exposure and may result in increased adverse reactions.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of roflumilast states concurrent use with CYP3A4 inhibitors or dual inhibitors of CYP3A4 and CYP1A2 should be approached with caution and the risk should be weighed carefully against the benefit. Consider alternatives with no or minimal enzyme inhibition.(1)

DISCUSSION: In healthy subjects, concurrent use of roflumilast (500 mcg single dose) with erythromycin, a moderate CYP3A4 inhibitor, (500 mg three times daily for 15 days) increased the area-under-curve (AUC) and concentration maximum (Cmax) of roflumilast by 70% and 40%, respectively, and decreased the AUC and Cmax of roflumilast N-oxide by 4% and 34%, respectively.(1,2) In healthy subjects, concurrent use of roflumilast (500 mcg single dose) with ketoconazole, a strong CYP3A4 inhibitor, (200 mg twice daily for 13 days) increased the AUC and Cmax of roflumilast by 99% and 23%, respectively, and decreased the AUC and Cmax of roflumilast N-oxide by 3% and 38%, respectively.(1) In healthy subjects, concurrent use of roflumilast (500 mcg single dose) with fluvoxamine, a dual CYP3A4 and CYP1A2 inhibitor, (50 mg daily for 14 days) increased the AUC and Cmax of roflumilast by 156% and 12%, respectively, and decreased the AUC and Cmax of roflumilast N-oxide by 52% and 210%, respectively.(1) In healthy subjects, concurrent use of roflumilast (500 mcg single dose) with cimetidine, a dual CYP3A4 and CYP1A2 inhibitor, (400 mg twice daily for 14 days) increased the AUC and Cmax of roflumilast by 85% and 46%, respectively, and increased the AUC and decreased Cmax of roflumilast N-oxide by 27% and 4%, respectively.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, saquinavir, telaprevir, tipranavir, tucatinib, and voriconazole.(3,4) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazole, lefamulin (oral), lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, schisandra, stiripentol, tofisopam, treosulfan, and voxelotor.(3,4) Dual CYP3A4 and CYP1A2 inhibitors linked to this monograph include: belumosudil, cannabidiol, cimetidine, ciprofloxacin, fluvoxamine, glecaprevir/pibrentasvir, grapefruit, osilodrostat, piperine, ribociclib, rucaparib, simeprevir, telithromycin, troleandomycin, verapamil, and viloxazine.(3,4)

Moderate or severe hepatic impairment (Child-Pugh class B or C). (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

• Child-pugh class B hepatic impairment
• Child-pugh class C hepatic impairment
• Lactation

• Depression
• Suicidal
• Suicidal ideation

• Weight loss

Adverse effects reported in 2% or more of patients receiving roflumilast include diarrhea, weight loss, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite.

Rare or Very Rare

• Angioedema
• Suicidal
• Suicidal ideation

More Frequent

• Back pain
• Diarrhea
• Headache disorder
• Nausea
• Weight loss

Less Frequent

• Acute abdominal pain
• Anorexia
• Dizziness
• Dyspepsia
• Gastritis
• Influenza
• Insomnia
• Muscle spasm
• Rhinitis
• Sinusitis
• Symptoms of anxiety
• Tremor
• Urinary tract infection
• Vomiting

Rare or Very Rare

• Depression
• Gynecomastia
• Skin rash
• Urticaria

No enhanced messaging available.

Safety and efficacy of roflumilast have not been established in pediatric patients; chronic obstructive pulmonary disease (COPD) does not occur in children.

Category C. (See Users Guide.)

Roflumilast should not be used during labor and delivery. The effect of roflumilast on preterm labor or labor at term in humans is unknown; however, disruption of labor and delivery has occurred in animals receiving the drug.

Roflumilast and/or its metabolites are distributed into milk in rats. Roflumilast and/or its metabolites are likely distributed into human milk. The effects of roflumilast on breast-fed infants have not been established. Roflumilast should not be used in nursing women.

Approximately 46% of patients with COPD who received roflumilast in clinical studies have been older than 65 years of age and about 11% have been older than 75 years of age. Although no substantial differences in safety and efficacy relative to younger adults have been observed, and other clinical experience revealed no evidence of age-related differences, the possibility of increased sensitivity in some older patients cannot be ruled out. Dosage adjustment is not necessary in geriatric patients.