Identification

Summary

Roflumilast is a selective phosphodiesterase-4 inhibitor indicated to decrease the risk of exacerbations in patients with severe chronic obstructive pulmonary disease (COPD) and to treat plaque psoriasis.

Brand Names
Daliresp, Zoryve
Generic Name
Roflumilast
DrugBank Accession Number
DB01656
Background

Roflumilast is a highly selective phosphodiesterase-4 (PDE4) inhibitor first approved in the EU in April 2010 for the management of chronic obstructive pulmonary disease.7 PDE4 is a major cyclic-3',5′-adenosinemonophosphate (cyclic AMP, cAMP)-metabolizing enzyme8 expressed on nearly all immune and pro-inflammatory cells, in addition to structural cells like those of the smooth muscle or epithelium.7 The resultant increase in intracellular cAMP induced by roflumilast's inhibition of PDE4 is thought to mediate its disease-modifying effects, although its precise mechanism of action has yet to be elucidated.8,7

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 403.207
Monoisotopic: 402.034954148
Chemical Formula
C17H14Cl2F2N2O3
Synonyms
  • Roflumilast
  • Roflumilastum
External IDs
  • B-9302-107
  • B9302-107
  • BY-217
  • BY217
  • BYK-20869
  • BYK20869

Pharmacology

Indication

Administered orally, roflumilast is indicated to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.8 Administered topically, it is indicated for the treatment of plaque psoriasis in patients ≥12 years old.9

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Roflumilast and its active metabolite, roflumilast N-oxide, increase cyclic adenosine-3′, 5′-monophosphate (cAMP) in affected cells by inhibiting PDE4. They are highly selective for PDE4 and are effectively inactive against PDEs 1, 2, 3, 5, and 7.7

Mechanism of action

Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor which appears to have potential antiinflammatory and immunomodulatory effects in the pulmonary system. It is thought that the increased levels of intracellular cyclic AMP are responsible for the therapeutic actions of roflumilast.

TargetActionsOrganism
AcAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4)
inhibitor
Humans
Absorption

After a 500mcg dose, the bioavailability of roflumilast is about 80%.8 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.8

Applied topically, the mean systemic exposure for roflumilast and its N-oxide metabolite in adults was 72.7 ± 53.1 and 628 ± 648 h∙ng/mL, respectively.9 The mean systemic exposure for roflumilast and its N-oxide metabolite in adolescents was 25.1 ± 24.0 and 140 ± 179 h∙ng/mL, respectively.9

Volume of distribution

Following a single oral dose of 500 mcg, the volume of distribution of roflumilast is approximately 2.9 L/kg.8

Protein binding

Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively.8

Metabolism

Roflumilast is metabolized to roflumilast N-oxide, the active metabolite of roflumilast in humans, by CYP3A4 and CYP1A2.8 The N-oxide metabolite is less potent than its parent drug in regards to PDE4 inhibition, but its plasma AUC is approximately 10-fold greater.8

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Route of elimination

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

Half-life

Following oral administration, the plasma half-lives of roflumilast and roflumilast N-oxide are 17 hours and 30 hours, respectively.8

Clearance

Plasma clearance of roflumilast following short-term intravenous infusion is approximately 9.6 L/h.8

Adverse Effects
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Toxicity

There are no data regarding overdosage with orally administered roflumilast. Phase I studies in which roflumilast was administered at single doses up to 5000 mcg showed an increase in the incidence of headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess, and arterial hypotension.8 In the event of an overdose, administer support medical care as soon as possible. Hemodialysis is unlikely to be of benefit given the extensive protein binding of roflumilast.8

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Roflumilast which could result in a higher serum level.
AbametapirThe serum concentration of Roflumilast can be increased when it is combined with Abametapir.
AbataceptRoflumilast may increase the immunosuppressive activities of Abatacept.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Roflumilast.
AbirateroneThe serum concentration of Roflumilast can be increased when it is combined with Abiraterone.
AcalabrutinibThe serum concentration of Roflumilast can be increased when it is combined with Acalabrutinib.
AceclofenacAceclofenac may decrease the excretion rate of Roflumilast which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Roflumilast which could result in a higher serum level.
AcenocoumarolThe metabolism of Acenocoumarol can be decreased when combined with Roflumilast.
AcetaminophenThe serum concentration of Roflumilast can be increased when it is combined with Acetaminophen.
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Food Interactions
  • Take with or without food. Administering roflumilast with a high-fat meal reduced and delayed the Cmax and Tmax, respectively, but did not impact the AUC of roflumilast or its active metabolite (roflumilast N‐oxide).

Products

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Product Images
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DalirespTablet500 ug/1OralAstraZeneca Pharmaceuticals LP2015-07-01Not applicableUS flag
DalirespTablet500 ug/1OralCardinal Health2011-02-282016-07-31US flag
DalirespTablet500 ug/1OralAllergan2011-02-282016-07-31US flag
DalirespTablet250 ug/1OralAstraZeneca Pharmaceuticals LP2015-07-01Not applicableUS flag
DaxasTablet500 mcgOralAstra Zeneca2010-12-30Not applicableCanada flag
DaxasTablet, film coated500 μgOralAstra Zeneca Ab2016-09-08Not applicableEU flag
DaxasTablet, film coated500 μgOralAstra Zeneca Ab2016-09-08Not applicableEU flag
DaxasTablet, film coated500 μgOralAstra Zeneca Ab2016-09-08Not applicableEU flag
DaxasTablet, film coated500 μgOralAstra Zeneca Ab2016-09-08Not applicableEU flag
DaxasTablet, film coated500 μgOralAstra Zeneca Ab2016-09-08Not applicableEU flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RoflumilastTablet500 ug/1OralZydus Pharmaceuticals (USA) Inc.2022-10-03Not applicableUS flag
RoflumilastTablet500 ug/1OralSolco Healthcare US, LLC.2022-05-10Not applicableUS flag
RoflumilastTablet500 ug/1OralMylan Pharmaceuticals Inc.2022-10-19Not applicableUS flag
RoflumilastTablet500 ug/1OralStrides Pharma Science Limited2022-10-13Not applicableUS flag
RoflumilastTablet250 ug/1OralNovadoz Pharmaceuticals Llc2022-09-07Not applicableUS flag
RoflumilastTablet500 ug/1OralTorrent Pharmaceuticals Limited2022-10-19Not applicableUS flag
RoflumilastTablet500 ug/1OralMicro Labs Limited2022-10-19Not applicableUS flag
RoflumilastTablet500 ug/1OralCadila Healthcare Limited2022-10-03Not applicableUS flag
RoflumilastTablet500 ug/1OralNovadoz Pharmaceuticals Llc2022-09-07Not applicableUS flag
RoflumilastTablet500 ug/1OralCamber Pharmaceuticals, Inc.2022-10-15Not applicableUS flag

Categories

ATC Codes
R03DX07 — Roflumilast
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as benzamides. These are organic compounds containing a carboxamido substituent attached to a benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzoic acids and derivatives
Direct Parent
Benzamides
Alternative Parents
Benzoyl derivatives / Phenol ethers / Phenoxy compounds / Polyhalopyridines / Alkyl aryl ethers / Aryl chlorides / Heteroaromatic compounds / Secondary carboxylic acid amides / Azacyclic compounds / Organopnictogen compounds
show 6 more
Substituents
Alkyl aryl ether / Alkyl fluoride / Alkyl halide / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzamide / Benzoyl / Carboxamide group
show 19 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organofluorine compound, aromatic ether, benzamides, cyclopropanes, chloropyridine (CHEBI:47657)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
0P6C6ZOP5U
CAS number
162401-32-3
InChI Key
MNDBXUUTURYVHR-UHFFFAOYSA-N
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)
IUPAC Name
3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide
SMILES
FC(F)OC1=C(OCC2CC2)C=C(C=C1)C(=O)NC1=C(Cl)C=NC=C1Cl

References

Synthesis Reference

王朝阳, 马静君, 郭培良, 黄耀宗, 王利春, 沈芃, 梁隆, & 程志鹏. (2015, March 25). Method for synthesizing roflumilast. CN103012256B.

General References
  1. Meyers JA, Taverna J, Chaves J, Makkinje A, Lerner A: Phosphodiesterase 4 inhibitors augment levels of glucocorticoid receptor in B cell chronic lymphocytic leukemia but not in normal circulating hematopoietic cells. Clin Cancer Res. 2007 Aug 15;13(16):4920-7. [Article]
  2. Sanz MJ, Cortijo J, Taha MA, Cerda-Nicolas M, Schatton E, Burgbacher B, Klar J, Tenor H, Schudt C, Issekutz AC, Hatzelmann A, Morcillo EJ: Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability. Br J Pharmacol. 2007 Oct;152(4):481-92. Epub 2007 Aug 20. [Article]
  3. Barone FC, Barton ME, White RF, Legos JJ, Kikkawa H, Shimamura M, Kuratani K, Kinoshita M: Inhibition of phosphodiesterase type 4 decreases stress-induced defecation in rats and mice. Pharmacology. 2008;81(1):11-7. Epub 2007 Aug 28. [Article]
  4. Chong J, Poole P, Leung B, Black PN: Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011 May 11;(5):CD002309. doi: 10.1002/14651858.CD002309.pub3. [Article]
  5. Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D, Bethke TD, Hiemstra PS, Rabe KF: Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax. 2007 Dec;62(12):1081-7. Epub 2007 Jun 15. [Article]
  6. Thappali SR, Varanasi KV, Veeraraghavan S, Vakkalanka SK, Mukkanti K: Simultaneous quantitation of IC87114, roflumilast and its active metabolite roflumilast N-oxide in plasma by LC-MS/MS: application for a pharmacokinetic study. J Mass Spectrom. 2012 Dec;47(12):1612-9. doi: 10.1002/jms.3103. [Article]
  7. Giembycz MA, Field SK: Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD. Drug Des Devel Ther. 2010 Jul 21;4:147-58. doi: 10.2147/dddt.s7667. [Article]
  8. FDA Approved Drug Products: Daliresp (roflumilast) tablets for oral use [Link]
  9. FDA Approved Drug Products: Zoryve (roflumilast) cream for topical use [Link]
  10. Arcutis Biotherapeutics: FDA Approves Arcutis’ ZORYVE™ (Roflumilast) Cream 0.3% For the Treatment of Plaque Psoriasis in Individuals Age 12 and Older [Link]
KEGG Drug
D05744
PubChem Compound
449193
PubChem Substance
175426853
ChemSpider
395793
BindingDB
14774
RxNav
1091836
ChEBI
47657
ChEMBL
CHEMBL193240
ZINC
ZINC000000592419
PharmGKB
PA165948052
PDBe Ligand
ROF
Drugs.com
Drugs.com Drug Page
Wikipedia
Roflumilast
PDB Entries
1xmu / 1xoq / 3g4l
FDA label
Download (255 KB)
MSDS
Download (569 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedNot AvailableChronic Obstructive Pulmonary Disease (COPD)2
4CompletedTreatmentChronic Bronchitis / Chronic Obstructive Pulmonary Disease (COPD) / Emphysema1
4CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)2
4CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD) / Exacerbation of COPD / Lung Disorder / Respiratory Disorders1
4CompletedTreatmentChronic Obstructive Pulmonary Disease and Allied Conditions1
4CompletedTreatmentObesity / Polycystic Ovarian Syndrome (PCOS)2
4Unknown StatusTreatmentChronic Obstructive Pulmonary Disease (COPD)2
4Unknown StatusTreatmentSarcoidosis1
3CompletedTreatmentAsthma4
3CompletedTreatmentBronchial Asthma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
TabletOral250 ug/1
TabletOral500 ug/1
TabletOral250 MCG
TabletOral250 ?g
TabletOral500 mcg
Tablet, film coatedOral500 μg
Tablet, film coatedOral500 mcg
Tablet, film coatedOral
Powder, for solutionOral
CreamTopical3 mg/1g
Tablet, film coatedOral0.5 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8536206No2013-09-172024-03-08US flag
US8604064No2013-12-102024-03-08US flag
US5712298No1998-01-272020-01-27US flag
US8618142No2013-12-312024-03-08US flag
US8431154No2013-04-302023-02-19US flag
US9468598No2016-10-182023-02-19US flag
US9907788No2018-03-062037-06-07US flag
US11129818No2021-09-282037-08-25US flag
US10940142No2021-03-092037-06-07US flag
US9884050No2018-02-062037-06-07US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)158 Giembycz MA, Field SK: Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD. Drug Des Devel Ther. 2010 Jul 21;4:147-58. doi: 10.2147/dddt.s7667.
water solubilitySparingly soluble Giembycz MA, Field SK: Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD. Drug Des Devel Ther. 2010 Jul 21;4:147-58. doi: 10.2147/dddt.s7667.
pKa8.74Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0062 mg/mLALOGPS
logP4.47ALOGPS
logP4.45Chemaxon
logS-4.8ALOGPS
pKa (Strongest Acidic)13.3Chemaxon
pKa (Strongest Basic)2.4Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area60.45 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity93.92 m3·mol-1Chemaxon
Polarizability35.9 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9874
Caco-2 permeable+0.5235
P-glycoprotein substrateNon-substrate0.7295
P-glycoprotein inhibitor INon-inhibitor0.5775
P-glycoprotein inhibitor IINon-inhibitor0.622
Renal organic cation transporterNon-inhibitor0.8057
CYP450 2C9 substrateNon-substrate0.8082
CYP450 2D6 substrateNon-substrate0.7705
CYP450 3A4 substrateSubstrate0.5821
CYP450 1A2 substrateInhibitor0.7732
CYP450 2C9 inhibitorInhibitor0.5686
CYP450 2D6 inhibitorNon-inhibitor0.7204
CYP450 2C19 inhibitorInhibitor0.7813
CYP450 3A4 inhibitorInhibitor0.6242
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8602
Ames testNon AMES toxic0.5216
CarcinogenicityNon-carcinogens0.8843
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.3522 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9704
hERG inhibition (predictor II)Non-inhibitor0.6336
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (81 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0f76-0950700000-9d3dc26457cb82e9e2af

Targets

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insights and accelerate drug research.
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Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.

Components:
References
  1. Giembycz MA, Field SK: Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD. Drug Des Devel Ther. 2010 Jul 21;4:147-58. doi: 10.2147/dddt.s7667. [Article]
  2. FDA Approved Drug Products: Daliresp (roflumilast) tablets for oral use [Link]
  3. FDA Approved Drug Products: Zoryve (roflumilast) cream for topical use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Kelly Freeman ML: Clinical Considerations for Roflumilast: A New Treatment for COPD. Consult Pharm. 2012 Mar;27(3):189-93. doi: 10.4140/TCP.n.2012.189. [Article]
  2. Baye J: Roflumilast (daliresp): a novel phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease. P T. 2012 Mar;37(3):149-61. [Article]
  3. Rabe KF: Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol. 2011 May;163(1):53-67. doi: 10.1111/j.1476-5381.2011.01218.x. [Article]
  4. FDA Approved Drug Products: Daliresp (roflumilast) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Giembycz MA, Field SK: Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD. Drug Des Devel Ther. 2010 Jul 21;4:147-58. doi: 10.2147/dddt.s7667. [Article]
  2. FDA Approved Drug Products: Daliresp (roflumilast) tablets for oral use [Link]

Drug created at June 13, 2005 13:24 / Updated at December 01, 2022 23:18