Roflumilast

Pronunciation: roe-FLUE-mi-last
Class: Phosphodiesterase inhibitor

Trade Names

Daliresp
- Tablets, oral 500 mcg

Pharmacology

Selectively inhibits phosphodiesterase 4 (PDE4), leading to an accumulation of intracellular cyclic AMP within inflammatory and structural cells important in the pathogenesis of COPD.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Absolute bioavailabilty is 80%. T max of roflumilast and the N-oxide metabolite occur approximately 1 and 8 h after dosing, respectively. Steady-state plasma concentrations are reached for roflumilast and N-oxide in approximately 4 and 6 days, respectively. Food delays T max of roflumilast by 1 h and reduces C max by 40%.

Distribution

Protein binding of roflumilast and the N-oxide metabolite is 99% and 97%, respectively. Vd is 2.9 L/kg.

Metabolism

Extensively metabolized in the liver via phase I (CYP-450) and phase II (conjugate) reactions. N-oxide is the major metabolite and accounts for the majority of the dose (87.5%) in plasma.

Elimination

Plasma half-life of roflumilast and the N-oxide are approximately 17 and 30 h, respectively. Excreted in the urine (approximately 70% as unchanged drug).

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 C max was reduced 16% and 12%, respectively. No dosage adjustment is necessary.

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 C max 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).

Elderly

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

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.

Race

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

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.

Indications and Usage

To reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.

Contraindications

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

Dosage and Administration

Chronic Obstructive Pulmonary Disease
Adults

PO 500 mcg/day.

General Advice

  • Administer with or without food.

Storage/Stability

Store between 68° and 77°F; excursions are permitted between 59° and 86°F.

Drug Interactions

Contraceptives, oral (eg, gestodene, ethinyl estradiol)

Coadministration with oral contraceptives containing gestodene and ethinyl estradiol may increase roflumilast systemic exposure, increasing the risk of adverse effects. The risk of concurrent use should be weighed carefully against benefit.

CYP3A4 inhibitors or drugs that inhibit both CYP3A4 and CYP1A2 simultaneously (eg, cimetidine, erythromycin, fluvoxamine, ketoconazole)

Coadministration may elevate roflumilast plasma concentrations, increasing drug exposure and the risk of adverse reactions. The risk of concurrent use should be weighed carefully against the benefits.

CYP3A4 strong inducers (eg, carbamazepine, phenobarbital, phenytoin, rifampin)

CYP3A4 inducers reduce roflumilast plasma concentrations, decreasing drug exposure, and may result in decreased efficacy. Avoid coadministration.

Adverse Reactions

CNS

Headache (4%); dizziness, insomnia (2%); anxiety, depression, tremor (1% to 2%).

EENT

Rhinitis, sinusitis (1% to 2%).

GI

Diarrhea (10%); weight decreased (8%); nausea (5%); decreased appetite (2%); abdominal pain, dyspepsia, gastritis, vomiting (1% to 2%); acute pancreatitis.

Genitourinary

UTI (1% to 2%); acute renal failure, prostate cancer.

Musculoskeletal

Back pain (3%); muscle spasms (1% to 2%).

Miscellaneous

Influenza (3%); atrial fibrillation, lung cancer.

Precautions

Monitor

Monitor weight regularly during treatment. Monitor for new or worsening depressive symptoms and/or development of suicidality.


Pregnancy

Category C.

Lactation

Undetermined; however, excretion into human breast milk is probable.

Children

Safety and efficacy not established.

Elderly

Greater sensitivity cannot be ruled out.

Hepatic Function

Contraindicated for use in patients with moderate or severe liver impairment (Child Pugh class B or C). Consider the risks and benefits when using in patients with mild liver impairment.

Acute bronchospasm

Not indicated for the relief of acute bronchospasm.

CNS effects

Neuropsychiatric effects (eg, anxiety, depression, insomnia) have been reported with use; rarely, suicidal behavior/ideation and completed suicide were reported. Carefully weigh the benefits and risks of treatment in patients with a history of depression with suicidal behavior/ideation.

Weight loss

May occur. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of roflumilast.

Overdosage

Symptoms

Arterial hypotension, clamminess, dizziness, headache, GI disorders, light-headedness, palpitations.

Patient Information

  • Advise patient to read the Medication Guide before using product for the first time and to reread it with each refill.
  • Inform patient that roflumilast is not a bronchodilator, and not to use it for the relief of acute bronchospasm.
  • Advise patient, caregiver, and family 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 health care provider.
  • Inform patients that weight loss is a common adverse effect and that they will have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of therapy.

Copyright © 2009 Wolters Kluwer Health.

Hide
(web4)