Roflumilast

Synonyms :
Daliresp, ROF, Roflumilastum

Status : approved

Therapeutic Classification

OTHER SYSTEMIC DRUGS FOR OBSTRUCTIVE AIRWAY DISEASES

RESPIRATORY SYSTEM
DRUGS FOR OBSTRUCTIVE AIRWAY DISEASES
OTHER SYSTEMIC DRUGS FOR OBSTRUCTIVE AIRWAY DISEASES

Description

Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor. Due to its selective inhibition of the PDE4 isoenzyme in lung cells, roflumilast is indicated for the management of chronic obstrtuctive pulmonary disease (COPD) exacerbations. Treatment with Roflumilast is associated with an increase in psychiatric adverse reactions, including suicide and suicidal attempts.

Used

Roflumilast is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. Roflumilast is not a bronchodilator and is not indicated for the relief of acute bronchospasm.

Mechanism Of Action

Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor which, due to its selective inhibition of the PDE4 isoenzyme, has potential antiinflammatory and antimodulatory effects in the pulmonary system. It is thought that the increased levels of intracellular cyclic AMP are responsible for the therapeutic actions of Roflumilast.

Dosage

Form Route Strength
Tablet oral 500 ug
Tablet oral 500 mcg

Pharmacodynamics

Roflumilast (and its active metabolite, roflumilast N-oxide) increases cyclic adenosine-3′, 5′-monophosphate (cAMP) in lung cells by inhibiting PDE4. Increased cAMP activates PKA, which inactivates transcription factors involved in inflammation. Romflumilast also decreases the amount of sputum neutrophils and eosinophils in COPD patients.

Toxic Effect

Headache, weight loss, GI upset, insomnia, and loose stools.

Metabolism

Roflumilast is metabolized to roflumilast N-oxide, the active metabolite of roflumilast in humans, by CYP3A4 and CYP1A2.

Absorption

After a 500mcg dose, the bioavailability of roflumilast is about 80%. In the fasted state, maximum plasma concentrations are reached in 0.5 to 2 hours. While in the fed state, Cmax is reduced by 40%, Tmax is increased by one hour, and total absorption is unchanged.

Half Life

Plasma half-life of roflumilast is 17 hours and its metabolite is 30 hours (oral dose).

Protein Binding

Roflumilast is 99% plasma protein bound.

Elimination Route

Roflumilast is excreted 70% in the urine as roflumilast N-oxide.

Clearance

~9.6 L/hour.

Volume of Distribution

Roflumilast has a Vd of 2.9L/kg with a dose of 500mcg. Permeability of roflumilast across the blood-brain barrier appears to be poor in rat studies.

Chemical Classification

This compound belongs to the class of organic compounds known as n-arylamides. These are organic compounds that contain a carboxamide group that is N-linked to a aryl group. They have the generic structure RC(=O)N(R’)H, R = organyl group and R’= aryl group.

N-arylamides

Organic compounds

Organonitrogen compounds

N-arylamides

Chemical Name

Daliresp

Brands

name Dosage form Country
Daliresp tablet US
Daliresp tablet US
Daliresp tablet US
Daxas tablet Canada

Drug Drug Interactions

  •  Abatacept  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Adalimumab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  ado-trastuzumab emtansine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Alemtuzumab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Altretamine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Amsacrine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Anakinra  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Anti-thymocyte Globulin (Rabbit)  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Azacitidine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Azathioprine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Basiliximab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Belatacept  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Belimumab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Betamethasone  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Bleomycin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Blinatumomab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Bosentan  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Brentuximab vedotin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Busulfan  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Cabazitaxel  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Canakinumab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Capecitabine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Carbamazepine  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast.
  •  Carboplatin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Carmustine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Certolizumab pegol  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Chlorambucil  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Cimetidine  : May increase serum concentrations of the active metabolite(s) of Roflumilast. Cimetidine may increase the serum concentration of Roflumilast.
  •  Ciprofloxacin  : Ciprofloxacin (Systemic) may increase the serum concentration of Roflumilast.
  •  Cisplatin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Cladribine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Clofarabine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Corticotropin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Cortisone acetate  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Cyclophosphamide  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Cyclosporine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Cytarabine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Dabrafenib  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Dacarbazine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Dactinomycin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Dasatinib  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Daunorubicin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Deferasirox  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Dexamethasone  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Dinutuximab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Docetaxel  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Doxorubicin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Eculizumab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Enzalutamide  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast.
  •  Epirubicin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Estramustine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Etanercept  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Etoposide  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Everolimus  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Fingolimod  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Floxuridine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Fludarabine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Fludrocortisone  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Fluorouracil  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Fluvoxamine  : May increase serum concentrations of the active metabolite(s) of Roflumilast. Fluvoxamine may increase the serum concentration of Roflumilast.
  •  Fosphenytoin  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast.
  •  Gemcitabine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Gemtuzumab ozogamicin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Glatiramer Acetate  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  golimumab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Hydrocortisone  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Hydroxyurea  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Ibritumomab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Ibrutinib  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Idarubicin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Idelalisib  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Ifosfamide  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Imatinib  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Imiquimod  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Infliximab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Irinotecan  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  L-Phenylalanine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Leflunomide  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Lenalidomide  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Lomustine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Loxapine  : Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine.
  •  Mechlorethamine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Melphalan  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Mercaptopurine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Methotrexate  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Methylprednisolone  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Mitomycin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Mitotane  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast.
  •  Mitoxantrone  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Mycophenolate mofetil  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Mycophenolic acid  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Natalizumab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Nelarabine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Nilotinib  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Obinutuzumab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Oxaliplatin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Paclitaxel  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Palbociclib  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Panobinostat  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Pazopanib  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Pegaspargase  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Pemetrexed  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Pentostatin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Phenobarbital  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast.
  •  Phenytoin  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast.
  •  Pomalidomide  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Pralatrexate  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Prednisolone  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Prednisone  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Primidone  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast.
  •  Procarbazine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Rifabutin  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast.
  •  Rifampicin  : May decrease the serum concentration of Roflumilast.
  •  Rifapentine  : CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast.
  •  Rilonacept  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Riociguat  : Roflumilast may enhance the hypotensive effect of Riociguat.
  •  Rituximab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Ruxolitinib  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Secukinumab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Siltuximab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Sirolimus  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Sorafenib  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Streptozocin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Sunitinib  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Tacrolimus  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Temozolomide  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Temsirolimus  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Teniposide  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Teriflunomide  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Thalidomide  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Thiotepa  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Tioguanine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Tocilizumab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Tofacitinib  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Topotecan  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Tositumomab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Trabectedin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Tretinoin  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Triamcinolone  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Ustekinumab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Vedolizumab  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Vinblastine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Vincristine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Vindesine  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Vinorelbine  : May enhance the immunosuppressive effect of Immunosuppressants.

Calculated Property

kind Value Source
logP 4.47 ALOGPS
logS -4.8 ALOGPS
Water Solubility 6.20e-03 g/l ALOGPS
logP 4.45 ChemAxon
IUPAC Name 3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide ChemAxon
Traditional IUPAC Name roflumilast ChemAxon
Molecular Weight 403.207 ChemAxon
Monoisotopic Weight 402.034954148 ChemAxon
SMILES FC(F)OC1=C(OCC2CC2)C=C(C=C1)C(=O)NC1=C(Cl)C=NC=C1Cl ChemAxon
Molecular Formula C17H14Cl2F2N2O3 ChemAxon
InChI InChI=1S/C17H14Cl2F2N2O3/c18-11-6-22-7-12(19)15(11)23-16(24)10-3-4-13(26-17(20)21)14(5-10)25-8-9-1-2-9/h3-7,9,17H,1-2,8H2,(H,22,23,24) ChemAxon
InChIKey InChIKey=MNDBXUUTURYVHR-UHFFFAOYSA-N ChemAxon
Polar Surface Area (PSA) 60.45 ChemAxon
Refractivity 93.92 ChemAxon
Polarizability 35.9 ChemAxon
Rotatable Bond Count 7 ChemAxon
H Bond Acceptor Count 4 ChemAxon
H Bond Donor Count 1 ChemAxon
pKa (strongest acidic) 8.18 ChemAxon
pKa (strongest basic) 2.4 ChemAxon
Physiological Charge 0 ChemAxon
Number of Rings 3 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 1 ChemAxon
Ghose Filter 1 ChemAxon
MDDR-Like Rule 1 ChemAxon

Affected organism

Humans and other mammals

Target within organism

  • cAMP-specific 3′,5′-cyclic phosphodiesterase 4D : in Human
  • cAMP-specific 3′,5′-cyclic phosphodiesterase 4A : in Human
  • cAMP-specific 3′,5′-cyclic phosphodiesterase 4B : in Human
  • cAMP-specific 3′,5′-cyclic phosphodiesterase 4C : in Human