Skip to Content

Roflumilast

Pronunciation

(roe FLUE mi last)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Daliresp: 500 mcg

Brand Names: U.S.

  • Daliresp

Pharmacologic Category

  • Phosphodiesterase-4 Enzyme Inhibitor

Pharmacology

Roflumilast and its active N-oxide metabolite selectively inhibit phosphodiesterase-4 (PDE4) leading to an accumulation of cyclic AMP (cAMP) within inflammatory and structural cells important in the pathogenesis of COPD. Anti-inflammatory effects include suppression of cytokine release and inhibition of lung infiltration by neutrophils and other leukocytes. Pulmonary remodeling and mucociliary malfunction are also attenuated.

Distribution

Vd: 2.9 L/kg

Metabolism

Hepatic via CYP3A4 and CYP1A2 to active N-oxide metabolite; also undergoes conjugation

Excretion

Urine (~70% as metabolites)

Time to Peak

~1 hour (delayed by food); N-oxide metabolite: ~8 hours

Half-Life Elimination

17 hours; N-oxide metabolite: 30 hours

Protein Binding

99%; N-oxide metabolite: 97%

Special Populations: Renal Function Impairment

In patients with severe renal impairment, roflumilast and N-oxide metabolite AUCs were decreased by 21% and 7%, respectively, and Cmax was reduced 16% and 12%, respectively. No dosage adjustment is necessary.

Special Populations: Hepatic Function Impairment

The AUC of roflumilast and the N-oxide metabolite were increased by 51% and 24%, respectively, in Child-Pugh class A subjects and by 92% and 41%, respectively, in Child-Pugh class B subjects as compared with healthy subjects. The Cmax of roflumilast and the N-oxide metabolite was increased by 3% and 26%, respectively, in Child-Pugh class A subjects and by 26% and 40%, respectively, in Child-Pugh class B subjects. Roflumilast is contraindicated in patients with moderate or severe liver impairment (Child-Pugh class B or C).

Special Populations: Elderly

The roflumilast AUC and Cmax increased 27% and 16%, respectively, and the N-oxide metabolite AUC and Cmax increased 19% and 13%, respectively, in elderly patients. No dosage adjustment is necessary.

Special Populations: Gender

The roflumilast and N-oxide metabolite AUC increased 39% and 33%, respectively, in healthy women when compared to healthy men. No dosage adjustment is necessary.

Special Populations: Race

The AUC and Cmax of roflumilast and the N-oxide metabolite increased in white, black, Hispanic, and Japanese patients. No dosage adjustment is necessary.

Special Populations Note

Smoking

The AUC of roflumilast in smokers was 13% less than in nonsmokers while the AUC of the N-oxide metabolite in smokers was 17% more than in nonsmokers.

Use: Labeled Indications

Chronic obstructive pulmonary disease: 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

Contraindications

Moderate or severe hepatic impairment (Child-Pugh class B or C)

Canadian labeling: Additional contraindication (not in U.S. labeling): Hypersensitivity to roflumilast or any component of the formulation

Dosage

Oral: Adults: COPD: 500 mcg once daily

Dosage adjustment in renal impairment: No dosage adjustment necessary.

Dosage adjustment in hepatic impairment:

Mild impairment (Child-Pugh class A): No dosage adjustment necessary. Use with caution; 500 mcg once daily dose has not been evaluated in mild impairment.

Moderate-to-severe impairment (Child-Pugh class B or C): Use is contraindicated.

Administration

Administer without regard to meals.

Storage

Store at 20°C to 25°C (68°F to 77°F), excursions permitted from 15°C to 30°C (59°F to 86°F).

Drug Interactions

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Cimetidine: May increase serum concentrations of the active metabolite(s) of Roflumilast. Cimetidine may increase the serum concentration of Roflumilast. Monitor therapy

Ciprofloxacin (Systemic): May increase the serum concentration of Roflumilast. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Roflumilast. Management: Roflumilast U.S. prescribing information recommends against combining strong CYP3A4 inducers with roflumilast. The Canadian product monograph makes no such recommendation but notes that such agents may reduce roflumilast therapeutic effects. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

FluvoxaMINE: May increase serum concentrations of the active metabolite(s) of Roflumilast. FluvoxaMINE may increase the serum concentration of Roflumilast. Monitor therapy

Immunosuppressants: Roflumilast may enhance the immunosuppressive effect of Immunosuppressants. Exceptions: Beclomethasone (Oral Inhalation); Cytarabine (Liposomal); Fluticasone (Oral Inhalation). Consider therapy modification

Loxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine. Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation. This does not apply to non-inhaled formulations of loxapine. Avoid combination

Rifampin: May decrease the serum concentration of Roflumilast. Management: Roflumilast U.S. prescribing information recommends against combining rifampin with roflumilast. The Canadian product monograph makes no such recommendation but notes that rifampin may reduce roflumilast therapeutic effects. Avoid combination

Riociguat: Roflumilast may enhance the hypotensive effect of Riociguat. Management: Riociguat is contraindicated with nonselective phosphodiesterase (PDE) inhibitors and PDE type 5 inhibitors. Other types of PDE inhibitors are not contraindicated, but caution is advised and patients should be monitored for hypotension. Monitor therapy

St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Adverse Reactions

2% to 10%:

Central nervous system: Headache (4%), dizziness (2%), insomnia (2%)

Endocrine & metabolic: Weight loss (5% to 10% of body weight: 8% to 20%; >10% loss: 7%)

Gastrointestinal: Diarrhea (10%), nausea (5%), decreased appetite (2%)

Infection: Influenza (3%)

Neuromuscular & skeletal: Back pain (3%)

<2% (Limited to important or life-threatening): Abdominal pain, anemia, arthritis, atrial fibrillation, depression, dysgeusia, epistaxis, gastritis, gastroesophageal reflux disease, gynecomastia, hematochezia, hypersensitivity, increased gamma-glutamyl transferase, increased lactate dehydrogenase, increased serum AST, lung carcinoma, muscle spasm, myalgia, myasthenia, pancreatitis, paresthesia, prostate carcinoma, renal failure, respiratory tract infection, rhinitis, sinusitis, suicidal ideation, suicidal tendencies, suicide completed, supraventricular cardiac arrhythmia, urinary tract infection

Warnings/Precautions

Concerns related to adverse effects:

• Arrhythmia: Supraventricular arrhythmias including atrial fibrillation have been reported.

• Gastrointestinal effects: May cause weight loss and/or diarrhea (sometimes severe); weight loss usually observed within 6 months of initiating therapy and diarrhea within 4 weeks. Instruct patients to monitor weight regularly. Avoid initiation of therapy or discontinue therapy with unexplained/pronounced weight loss.

• Neuropsychiatric: Neuropsychiatric effects (eg, anxiety, depression) have been reported with use; rarely, suicidal behavior/ideation and completed suicide were reported. Avoid use in patients with a history of depression with suicidal behavior/ideations; instruct patients/caregivers to report psychiatric symptoms and consider discontinuation of therapy in such patients.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Disease-related concerns:

• Hepatic impairment: Systemic exposure may be increased in patients with mild hepatic impairment; use in moderate to severe impairment is contraindicated.

Dosage form specific issues:

• Lactose: May contain lactose; the Canadian labeling recommends avoiding use in patients with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Other warnings/precautions:

• Appropriate use: Not indicated for relieving acute bronchospasms or for use as monotherapy of COPD; use only as adjunctive therapy to bronchodilator therapy.

• Canadian labeling recommendations (not in U.S. labeling): Avoid use in patients with cancer (excluding basal cell carcinoma), heart failure (NYHA III/IV), severe acute infection, immunosuppression, or immunosuppressive therapy (excludes short-term systemic corticosteroid use for COPD exacerbation).

Monitoring Parameters

Liver function tests. Measure weight regularly during therapy

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. The Canadian labeling recommends avoiding use during pregnancy and in women of childbearing potential not using adequate contraception.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, dyspepsia, diarrhea, headache, back pain, flu-like symptoms, insomnia, or lack of appetite. Have patient report immediately to prescriber severe anxiety, tremors, excessive weight loss, suicidal ideation, depression, anxiety, akathisia, irritability, panic attacks, or mood changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Hide