Roflumilast

R03D - Other systemic drugs for obstructive airway diseases ATC R03DX07 Small molecule approved 2010 Oral Topical First-in-class

JFDA label: Lemitat 500mcg

Mechanism of Action

Inhibitor of Phosphodiesterase 4 — Phosphodiesterase 4 inhibitor

Target	Action	Gene / class
Phosphodiesterase 4 efficacy	INHIBITOR

Indications

Approved

COPD

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): Hypersensitivity to roflumilast or any component of the formulation Absolute
Moderate to severe hepatic impairment (Child-Pugh class B or C) Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (3)

Common dizziness · Headache · insomnia

Metabolism and nutrition disorders (1)

Common Weight loss

Gastrointestinal disorders (3)

Common decreased appetite · Diarrhea · nausea

Musculoskeletal and connective tissue disorders (1)

Common Back pain

Infections and infestations (1)

Common Influenza

Dosing

Source: Lexicomp

COPD: Oral: 250 mcg once daily for 4 weeks, followed by 500 mcg once daily. Note: An initial dose of 250 mcg once daily is recommended for the first 4 weeks of treatment in an attempt to improve tolerability. However, this is not considered a therapeutic dose and the effect of this approach on long-term tolerability is uncertain.

Refer to adult dosing.

No dosage adjustment necessary.

Mild impairment (Child-Pugh class A): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution. Moderate to severe impairment (Child-Pugh class B or C): Use is contraindicated.

Warnings & Precautions

Source: Lexicomp

Neuropsychiatric

Neuropsychiatric effects (eg, anxiety, depression, insomnia) have been reported with use; rarely, suicidal behavior/ideation and completed suicide were reported. Assess risk versus benefits before prescribing 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.

Weight loss

Weight loss has occurred; monitor weight regularly. If unexplained or significant weight loss occurs, discontinuation should be considered. 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

Use with caution in patients with mild impairment (systemic exposure may be increased); use in moderate to severe impairment is contraindicated. Other warnings/precautions:

Appropriate use

Not indicated for relieving acute bronchospasm.

Pregnancy & Lactation

Pregnancy

Adverse events were observed in some animal reproduction studies.

Lactation

Avoid

It is not known if roflumilast is present in breast milk; however, excretion into human breast milk is likely. Breastfeeding is not recommended by the manufacturer.

Monitoring

Clinical pearl	Liver function tests; weight (regularly during therapy); new or worsening insomnia, anxiety, depression, suicidal thoughts, or other mood changes.

Chemistry & Properties

Formula	C17H14Cl2F2N2O3
Molecular weight	403.21 g/mol
IUPAC name	3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)benzamide
CAS	162401-32-3
PubChem CID	449193
InChIKey	`MNDBXUUTURYVHR-UHFFFAOYSA-N`
logP	5.03 (XLogP 4.6)
Polar surface area	60.45 Å²
H-bond acceptors / donors	4 / 1
Drug-likeness (QED)	0.70
Lipinski violations	1

SMILES

O=C(Nc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Inhibitor	—
CYP1A2	Substrate	—
CYP2B6	Inhibitor	—
CYP2B6	Substrate	—
CYP2C19	Inhibitor	—
CYP2C8	Inhibitor	—
CYP3A4	Inhibitor	—
CYP3A4	Substrate	—

Receptor binding (top 1)

Target	Action	Affinity
phosphodiesterase 4B (PDE4B)	Inhibitor	pIC50 9.4

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Cladribine	major
Abametapir (topical)	moderate
Abatacept	moderate
Abemaciclib	moderate
Acalabrutinib	moderate
Adalimumab	moderate
Aflibercept	moderate
Aldesleukin	moderate
Alefacept	moderate
Alemtuzumab	moderate
Altretamine	moderate
Amiodarone	moderate
Anagrelide	moderate
Anakinra	moderate
Antilymphocyte immunoglobulin (horse)	moderate
Antithymocyte immunoglobulin (rabbit)	moderate
Apalutamide	moderate
Asparaginase Escherichia coli	moderate
Atezolizumab	moderate
Avapritinib	moderate
Axicabtagene ciloleucel	moderate
Azacitidine	moderate
Azathioprine	moderate
Baricitinib	moderate
Basiliximab	moderate
Belantamab mafodotin	moderate
Belatacept	moderate
Belimumab	moderate
Belinostat	moderate
Bendamustine	moderate
Berotralstat	moderate
Betamethasone	moderate
Bexarotene	moderate
Bleomycin	moderate
Blinatumomab	moderate
Bortezomib	moderate
Bosutinib	moderate
Brentuximab vedotin	moderate
Brexucabtagene autoleucel	moderate
Brigatinib	moderate

Showing 40 of 100+.

Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Lemitat	Tablet 500 mcg	30 tab	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	35.940