roflumilast topical (Rx)

1-10%

Diarrhea (3.1%)

Headache (2.4%)

Insomnia (1.4%)

Nausea (1.2%)

Application site pain (1%)

Upper respiratory tract infection (1%)

Urinary tract infection (1%)

Contraindications

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

Cautions

Hepatic impairment

• Contraindicated with moderate-to-severe impairment (Child-Pugh B or C)
• No studies were conducted with topical roflumilast in patients with hepatic impairment; however, oral roflumilast 250 mcg/day for 14 days was studied in mild-to-moderate hepatic impairment (Child-Pugh A and B)
• AUC of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively, in Child-Pugh A and by 92% and 41%, respectively, in Child-Pugh B, as compared to age-, weight-, and gender-matched healthy individuals
• Peak plasma concentration of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively, in Child-Pugh A and by 26% and 40%, respectively, in Child-Pugh B, as compared to healthy individuals

Drug interaction overview

• No formal drug-drug interaction studies were conducted with topical roflumilast

• CYP Inhibitors

  • Caution, monitor
  • Coadministration of roflumilast with systemic CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously (eg, erythromycin, ketoconazole, fluvoxamine, cimetidine) may increase roflumilast systemic exposure

• Oral contraceptives

  • Caution, monitor
  • Coadministration of roflumilast with oral contraceptives containing ethinyl estradiol may increase roflumilast systemic exposure

Pregnancy

There are no randomized clinical trials of oral or topical roflumilast in pregnant females

Animal studies

• Oral administration to pregnant rats and rabbits during organogenesis produced no fetal structural abnormalities at doses up to 9 and 8 times the maximum recommended human dose (MRHD), respectively
• Roflumilast induced post-implantation loss in rats at oral doses ≥3x MRHD
• Roflumilast induced stillbirth and decreased pup viability in mice at oral doses 5x and 15x MRHD, respectively
• Shown to adversely affect pup post-natal development when dams were treated with oral dose 15x MRHD during pregnancy and lactation periods in mice

Clinical considerations

• Do not use during labor and delivery
• There are no human studies that have investigated effects on preterm labor or labor at term; however, animal studies showed roflumilast PO disrupted labor and delivery process in mice

Lactation

Data are not available regarding presence in human milk, effects on breastfed infants, or effects on milk production

Roflumilast and/or its metabolites are excreted into the milk of lactating rats; when a drug is present in animal milk, it is likely that to be present in human milk

Consider developmental and health benefits of breastfeeding along with the mother’s clinical need for treatment and any potential adverse effects on the breastfed infant

Clinical considerations

• Minimize potential exposure to breastfeeding infants via breast milk by applying to smallest area of skin and for the shortest duration possible
• Advise breastfeeding women not to apply cream directly to the nipple and areola to avoid direct infant exposure

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

Roflumilast and its active metabolite (roflumilast N-oxide) are inhibitors of phosphodiesterase (PDE)-4

Inhibition of PDE4 (a major cyclic 3′,5′-adenosine monophosphate (cyclic AMP) metabolizing enzyme) activity leads to accumulation of intracellular cyclic AMP

Specific mechanism(s) by which roflumilast exerts its therapeutic action is not well defined

Absorption

Following application of mean BSA 26.8% and 13% in adults (n = 18) and adolescents (n = 6) respectively, plasma concentrations were quantifiable in all but 2 individuals at Day 15

AUC (adults): 72.7 h⋅ng/mL (roflumilast); 628 h⋅ng/mL (N-oxide metabolite)

AUC (adolescents): 25.1 h⋅ng/mL (roflumilast); 140 h⋅ng/mL (N-oxide metabolite)

Distribution

Protein bound: 99% (roflumilast); 97% (N-oxide metabolite)

Metabolism

Extensively metabolized by cytochrome P450, then it undergoes conjugation

Elimination

Half-life (topical): 4 days (roflumilast); 4.6 days (N-oxide metabolite)

Plasma clearance (IV): 9.6 L/hr

Topical Administration

For topical use only

Not for ophthalmic, oral, or intravaginal use

Wash hands after application, unless application is for treatment of hands

Storage

Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)