Roflumilast (Monograph)

Brand name: Daliresp
Drug class: Phosphodiesterase Type 4 Inhibitors
Chemical name: 3-(Cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-benzamide
Molecular formula: C₁₇H₁₄Cl₂F₂N₂O₃
CAS number: 162401-32-3

Introduction

A selective phosphodiesterase type 4 (PDE4) inhibitor.

Uses for Roflumilast

COPD

Reduction of risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.

Not a bronchodilator and not indicated for relief of acute bronchospasm.

Effects on COPD exacerbations when added to a fixed-combination preparation containing a long-acting β₂-adrenergic agonist and orally inhaled corticosteroid not established.

Roflumilast Dosage and Administration

Administration

Oral Administration

Administer orally once daily without regard to meals.

Dosage

Adults

COPD

Oral

500 mcg once daily.

Special Populations

Dosage adjustment not necessary based on gender or race.

Hepatic Impairment

Dosage of 500 mcg once daily not studied in patients with hepatic impairment. Consider the risks and benefits of using roflumilast in patients with mild hepatic impairment (Child-Pugh class A). Contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C). (See Special Populations under Pharmacokinetics.)

Renal Impairment

Dosage adjustment not necessary.

Geriatric Patients

Dosage adjustment not necessary.

Cautions for Roflumilast

Contraindications

• Moderate or severe hepatic impairment (Child-Pugh class B or C). (See Hepatic Impairment under Cautions and also Special Populations under Pharmacokinetics.)

Warnings/Precautions

Acute Bronchospasm

Not a bronchodilator; do not use for relief of acute bronchospasm.

Psychiatric Events and Suicidality

Increased risk of adverse psychiatric effects; insomnia, anxiety, and depression most frequently reported. Suicidal ideation or behavior, including completed suicide and suicide attempts, also reported.

Carefully weigh the risks and benefits before using the drug in patients with a history of depression and/or suicidal thoughts or behavior. Carefully evaluate the risks and benefits of continuing therapy with roflumilast if such effects occur. Some clinicians recommend avoiding the drug in patients with depression. (See Advice to Patients.)

Weight Loss

Moderate or severe weight loss (defined as 5–10% or >10% of body weight, respectively) reported. Most patients regained some of the lost weight following treatment discontinuance.

Regularly monitor patient’s weight. If unexplained or clinically important weight loss occurs, evaluate weight loss and consider discontinuing roflumilast. Some clinicians avoid use of roflumilast therapy in underweight patients.

Interactions

Concomitant use with potent CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin) not recommended. (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Category C.

Do not use during labor and delivery. Effect on preterm labor or labor at term in humans unknown; however, labor and delivery disrupted in animals.

Lactation

Roflumilast and/or its metabolites distributed into milk in rats. Distribution likely into human milk. Effects in breast-fed infants not established. Do not use in nursing women.

Pediatric Use

Safety and efficacy not established in pediatric patients; COPD does not occur in children.

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults. Clinical experience has not revealed age-related differences, but increased sensitivity cannot be ruled out. Dosage adjustment not necessary.

Hepatic Impairment

Consider the risks and benefits of using roflumilast in patients with mild hepatic impairment (Child-Pugh class A). Contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C). (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Diarrhea, weight loss, nausea, headache, back pain, influenza, insomnia, dizziness, decreased appetite.

Drug Interactions

Metabolized by CYP3A4 and CYP1A2 to roflumilast N-oxide; roflumilast N-oxide metabolized mainly by CYP3A4, to a lesser extent by CYP2C19 and extrahepatic CYP1A, and glucuronidated.

Roflumilast and roflumilast N-oxide do not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11.

Roflumilast does not induce CYP isoenzymes 1A2, 2A6, 2C9, 2C19, or 3A4/5 and is a weak inducer of CYP2B6.

Roflumilast and roflumilast N-oxide do not inhibit the P-glycoprotein transport system.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inducers: Decrease systemic exposure and may reduce the therapeutic efficacy of roflumilast. Concomitant use not recommended.

CYP3A4 inhibitors or inhibitors of both CYP3A4 and CYP1A2: May result in increased systemic exposure to roflumilast and increased adverse effects. Carefully weigh risk of concurrent use against benefit.

Specific Drugs

Roflumilast Pharmacokinetics

Absorption

Bioavailability

Roflumilast: Absolute bioavailability is approximately 80%. Peak plasma concentrations attained in approximately 1 hour (range: 0.5–2 hours). Steady-state plasma concentrations attained after approximately 4 days.

Roflumilast N-oxide: Peak concentrations attained in approximately 8 hours (range: 4–13 hours). Steady-state plasma concentrations attained after approximately 6 days.

Food

Roflumilast: No effect on total drug absorption. Time to peak plasma concentrations delayed by 1 hour and peak plasma concentrations reduced by approximately 40%.

Roflumilast N-oxide: Peak plasma concentrations and time to peak plasma concentrations unaffected.

Special Populations

Mild hepatic impairment (Child-Pugh class A): Following roflumilast 250 mcg once daily for 14 days, AUCs of roflumilast and roflumilast N-oxide were 51 and 24% higher, respectively, and peak plasma concentrations were 3 and 26% higher, respectively, compared with values for healthy individuals matched for age, weight, and gender. (See Hepatic Impairment under Dosage and Administration.)

Moderate hepatic impairment (Child-Pugh class B): Following roflumilast 250 mcg once daily for 14 days, AUCs of roflumilast and roflumilast N-oxide were 92 and 41% higher, respectively, and peak plasma concentrations were 26 and 40% higher, respectively, compared with values for healthy individuals matched for age, weight, and gender. (See Hepatic Impairment under Dosage and Administration.)

Severe renal impairment: Following single 500-mcg dose of roflumilast, AUCs of roflumilast and roflumilast N-oxide were reduced by 21 and 7%, respectively, and peak plasma concentrations were reduced by 16 and 12%, respectively.

Geriatric patients: AUCs of roflumilast and roflumilast N-oxide were 27 and 19% higher, respectively, and peak plasma concentrations were 16 and 13% higher, respectively, in geriatric individuals (>65 years of age) compared with younger adults (18–45 years of age). (See Geriatric Use under Cautions.)

Gender: AUCs of roflumilast and roflumilast N-oxide were 39 and 33% higher, respectively, in healthy women compared with healthy men. (See Special Populations under Dosage and Administration.)

Race: In African-American, Hispanic, and Japanese individuals, AUCs were 16, 41, and 15% higher, respectively, for roflumilast and 43, 27, and 16% higher, respectively, for roflumilast N-oxide compared with white individuals. In African-American, Hispanic, and Japanese individuals, peak plasma concentrations were 8, 21, and 5% higher, respectively, for roflumilast and 43, 27, and 17% higher, respectively, for roflumilast N-oxide compared with white individuals. (See Special Populations under Dosage and Administration.)

Smoking: Pharmacokinetics of roflumilast and roflumilast N-oxide were similar in smokers and nonsmokers.

Distribution

Extent

Low penetration across blood-brain barrier.

Roflumilast and/or its metabolites distributed into milk in rats. Distribution likely into human milk.

Plasma Protein Binding

Roflumilast: Approximately 99%.

Roflumilast N-oxide: Approximately 97%.

Elimination

Metabolism

Extensively metabolized via CYP and conjugation reactions; metabolized mainly by CYP3A4 and 1A2 to roflumilast N-oxide. Roflumilast N-oxide metabolized mainly by CYP3A4, to a lesser extent by CYP2C19 and extrahepatic CYP1A, and glucuronidated.

Roflumilast and roflumilast N-oxide together account for most (87.5%) of the administered dose present in plasma.

N-oxide metabolite is the only major metabolite detected in human plasma. While potency of roflumilast is 3 times that of roflumilast N-oxide with respect to PDE4 inhibition, AUC of roflumilast N-oxide is about 10 times that of roflumilast. N-oxide metabolite appears to account for about 90% of the biologic action of roflumilast.

Elimination Route

Roflumilast not detected in urine; trace amount (<1%) of roflumilast N-oxide detected in urine. Other conjugated metabolites detected in urine. About 70% of radioactivity recovered in urine following IV or oral administration of radiolabeled roflumilast.

Half-life

Roflumilast: Approximately 17 hours.

Roflumilast N-oxide: Approximately 30 hours.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

• Selective inhibitor of PDE4, a major enzyme involved in the metabolism of cyclic adenosine-3′,5′-monophosphate (cAMP) in lung tissue.

• Exact mechanism(s) of therapeutic action in patients with COPD not fully elucidated; thought to be related to the effects of increased cAMP in lung cells.

• Increased cAMP concentrations can lead to activation of protein kinase A, resulting in phosphorylation and inactivation of target transcription factors and reduction of cellular inflammatory activity. Anti-inflammatory effect may account for efficacy of roflumilast; available data are limited and inconclusive regarding such effects in humans.

• Reduced number of neutrophils and eosinophils in sputum of patients with COPD and number of total cells, neutrophils, and eosinophils in bronchoalveolar lavage fluid in healthy individuals; clinical importance unknown.

• Not a bronchodilator.

Advice to Patients

• Importance of patients reading the manufacturer’s patient information (medication guide) prior to initiation of therapy and each time the prescription is refilled.

• Importance of informing patients that roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.

• Risk of adverse psychiatric effects (e.g., insomnia, anxiety, depression, suicidal ideation or behavior). Importance of advising patients, their families, and caregivers to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts, or other mood changes, and to contact a clinician if such changes occur.

• Risk of weight loss. Importance of patients being regularly monitored for weight loss. Importance of patients informing a clinician if weight loss occurs.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, vitamins, and herbal supplements, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Reload page with references included

Medical Disclaimer