roflumilast (Rx)

1-10%

Diarrhea (9.5%)

Weight loss (7.5%)

Nausea (4.7%)

Headache (4.4%)

Back pain (3.2%)

Insomnia (2.4%)

Decreased appetite (2.1%)

Dizziness (2.1%)

1-10%

Abdominal pain (1-2%)

Anxiety (1-2%)

Depression (1-2%)

Dyspepsia (1-2%)

Gastritis (1-2%)

Muscle spasms (1-2%)

Rhinitis (1-2%)

Sinusitis (1-2%)

Tremor (1-2%)

Urinary tract infection (1-2%)

Vomiting (1-2%)

Frequency Not Defined

Suicidality

Postmarketing Reports

Hypersensitivity reactions including angioedema, urticaria, rash

Gynecomastia

Contraindications

Hypersensitivity

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

Cautions

Not indicated for relief of acute bronchospasm; drug is not bronchodilator

Psychiatric events, including suicidality, reported (monitor for emergence or worsening of insomnia, mood disturbance, or anxiety)

Monitor for clinically significant weight loss; this may be reversible upon discontinuance

Drug interaction overview

• Strong CYP3A4 inducers may reduce therapeutic effectiveness of roflumilast; coadministration not recommended

• CYP P450 enzyme inhibitors

  • CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously may increase roflumilast systemic exposure and increase risk for adverse effects

Pregnancy

Data are not available regarding use in pregnant women

Lactation

Probable that roflumilast, its metabolites, or both are excreted into milk; avoid use

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Selective phosphodiesterase (PDE)-4 inhibitor; PDE-4 inhibition leads to accumulation of intracellular cyclic adenosine monophosphate (cAMP) in lung tissue and is thought to be underlying mechanism of action

Absorption

80% absorbed

Peak plasma time: 1 hr (range, 0.5-2 hr); active metabolite, 8 hr

Distribution

Protein bound: 99%

Vd: 2.9 L/kg

Metabolism

Extensively metabolized via phase I (CYP450) and phase II (conjugation) reactions; N-oxide metabolite is only major metabolite observed in human plasma; together, roflumilast and roflumilast N-oxide account for 87.5% of total dose administered in plasma

Biotransformation of roflumilast to N-oxide metabolite is mediated by CYP1A2 and CYP3A4

Elimination

Half-life: Roflumilast, 17 hr; N-oxide metabolite, 30 hr

Clearance: 9.6 L/hr

Excretion: Urine (70%)

Oral Administration

May take with or without food

May titrate dose from 250 mcg/day to 500 mcg/day (therapeutic dose) over 4 weeks to improve tolerability (see Dosing)