Identification
- Summary
Avanafil is a phosphodiesterase-5 (PDE5) inhibitor used to treat erectile dysfunction.
- Brand Names
- Spedra, Stendra
- Generic Name
- Avanafil
- DrugBank Accession Number
- DB06237
- Background
Avanafil is a phosphodiesterase-5 (PDE5) inhibitor used in the treatment of erectile dysfunction. In comparison with other drugs of the same class, it shows greater selectivity for PDE5 over PDE6 than both sildenafil and vardenafil but less selectivity than tadalafil, suggesting a relatively lower risk of visual disturbances associated with off-target PDE6 inhibition.5
It first received FDA approval on April 27, 2012,4 with subsequent EMA approval in June 2013.5
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Avanafil (DB06237)
- Weight
- Average: 483.951
Monoisotopic: 483.17856544 - Chemical Formula
- C23H26ClN7O3
- Synonyms
- (S)-4-(3-Chloro-4-methoxybenzylamino)-2-(2-hydroxymethylpyrrolidin-1-yl)-N-pyrimidin-2-ylmethyl-5-pyrimidinecarboxamide
- Avanafil
- Avanafilo
- External IDs
- TA-1790
Pharmacology
- Indication
Avanafil is indicated for the treatment of erectile dysfunction.4
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Erectile dysfunction •••••••••••• ••••• •••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Avanafil is a strong competitive inhibitor of phosphodiesterase 5 (PDE5) with a demonstrated in vitro IC50 of 5.2 nM.5 Its inhibitory effects on PDE5 are 100-fold more potent than on PDE6 and >1000-fold more potent than on other PDE enzymes,4 meaning it is less likely to cause visual disturbances and cardiovascular adverse effects when compared with less selective PDE5 inhibitors such as sildenafil and vardenafil.5 It has a relatively quick onset of action allowing for administration as early as 15 minutes prior to sexual activity.4
PDE5 inhibitors like avanafil can cause significant drug interactions when administered alongside certain antihypertensive agents (e.g. alpha blockers, substantial amounts of alcohol).4 PDE5 inhibitors have also been associated with the development of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition that typically presents as sudden loss of vision in one or both eyes and appears to be more common in patients with a "crowded" optic disc. Patients presenting with any degree of vision loss should immediately discontinue use of all PDE5 inhibitors and seek medical attention.4 In some jurisdictions, a history of NAION or other degenerative retinal disorders is considered a contraindication to avanafil therapy.8
- Mechanism of action
Avanafil inhibits the cGMP-specific phosphodiesterase type 5 (PDE5) which is responsible for the degradation of cGMP in the corpus cavernosum located around the penis. Sexual arousal results in the local release of nitric oxide, which in turn stimulates the enzyme guanylate cyclase to produce cGMP. Elevated levels of cGMP result in local smooth muscle relaxation and increased blood flow to the penis (i.e. an erection).4,5
As PDE5 inhibitors like avanafil require the endogenous release of nitric oxide in order to exert their pharmacologic effect, they have no effect on the user in the absence of sexual stimulation/arousal.4,5
Target Actions Organism AcGMP-specific 3',5'-cyclic phosphodiesterase inhibitorHumans - Absorption
Avanafil is rapidly absorbed following oral administration (Tmax of 30-45 minutes)4 and appears to have low to moderate oral bioavailability, though formal studies have not been conducted.5 Administration with a meal results in a mean delay in Tmax of 1.12 to 1.25 hours, a 39% mean reduction in Cmax, and a negligible effect on AUC.4,5
- Volume of distribution
The apparent volume of distribution of avanafil is 47 to 83 L.5
- Protein binding
Avanafil and its two major metabolites, M4 and M16, are highly protein-bound in plasma at approximately 99%, 97%, and 81%, respectively. Binding occurs primarily to albumin (99%), with smaller contributions from γ-globulin (43%) and α1-acid glycoprotein (66%).5
- Metabolism
Avanafil is extensively metabolized, primarily by CYP3A4 and to a lesser extent by CYP2C9.4,8 There are two major metabolites formed, M4 and M16, which exist in the plasma at concentrations 23% and 29% that of the parent compound, respectively. The M16 metabolite lacks pharmacologic effect, but the M4 metabolite has an inhibitory potency for PDE5 18% that of avanafil and accounts for approximately 4% of the observed pharmacologic activity of avanafil.4
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- Route of elimination
Following oral administration, avanafil is extensively metabolized. Approximately 62% of a given dose is excreted as metabolites in the feces and approximately 21% as metabolites in the urine.4
- Half-life
Studies have demonstrated variability in the terminal elimination half-life of avanafil, with estimates ranging between 5 - 17 hours.5
- Clearance
Not Available
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Experience with avanafil overdose is limited. Single doses of up to 800mg and repeat doses of up to 300mg have been administered - these patients experienced adverse effects similar to those seen at therapeutic doses but with increased incidence and severity.8 Patients experiencing an overdosage of avanafil should be treated with standard symptomatic and supportive measures. Dialysis is unlikely to be of benefit in cases of overdose as avanafil is highly protein-bound in plasma.4
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The serum concentration of Avanafil can be increased when it is combined with 1,2-Benzodiazepine. Abaloparatide The risk or severity of hypotension can be increased when Avanafil is combined with Abaloparatide. Abametapir The serum concentration of Avanafil can be increased when it is combined with Abametapir. Abatacept The metabolism of Avanafil can be increased when combined with Abatacept. Abemaciclib The serum concentration of Avanafil can be increased when it is combined with Abemaciclib. - Food Interactions
- Avoid excessive or chronic alcohol consumption. Substantial alcohol consumption (e.g. >3 units) in combination with avanafil may increase the risk of hypotension.
- Take with or without food. High-fat meals slow absorption, but not to a clinically significant extent.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Images
- International/Other Brands
- Spedra (A. Menarini Farmaceutica Internazionale SRL)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Spedra Tablet 100 mg Oral Menarini International Operations Luxembourg S.A. 2021-02-11 Not applicable EU 
Spedra Tablet 50 mg Oral Menarini International Operations Luxembourg S.A. 2021-02-11 Not applicable EU Spedra Tablet 200 mg Oral Menarini International Operations Luxembourg S.A. 2016-09-08 Not applicable EU Spedra Tablet 200 mg Oral Menarini International Operations Luxembourg S.A. 2016-09-08 Not applicable EU Spedra Tablet 100 mg Oral Menarini International Operations Luxembourg S.A. 2016-09-08 Not applicable EU
Categories
- ATC Codes
- G04BE10 — Avanafil
- Drug Categories
- BCRP/ABCG2 Inhibitors
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Drugs Used in Erectile Dysfunction
- Genito Urinary System and Sex Hormones
- P-glycoprotein substrates
- Phosphodiesterase 5 Inhibitors
- Phosphodiesterase Inhibitors
- Urologicals
- Vasodilating Agents
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as pyrimidinecarboxamides. These are compounds containing a pyrimidine ring which bears a carboxamide.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Diazines
- Sub Class
- Pyrimidines and pyrimidine derivatives
- Direct Parent
- Pyrimidinecarboxamides
- Alternative Parents
- Anisoles / Benzylamines / Phenoxy compounds / Dialkylarylamines / Methoxybenzenes / Alkyl aryl ethers / Aminopyrimidines and derivatives / Secondary alkylarylamines / Chlorobenzenes / Aryl chlorides show 12 more
- Substituents
- Alcohol / Alkyl aryl ether / Amine / Amino acid or derivatives / Aminopyrimidine / Anisole / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle show 30 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- monocarboxylic acid amide, organochlorine compound, pyrimidines, aromatic amide, prolinols (CHEBI:66876)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- DR5S136IVO
- CAS number
- 330784-47-9
- InChI Key
- WEAJZXNPAWBCOA-INIZCTEOSA-N
- InChI
- InChI=1S/C23H26ClN7O3/c1-34-19-6-5-15(10-18(19)24)11-27-21-17(22(33)28-13-20-25-7-3-8-26-20)12-29-23(30-21)31-9-2-4-16(31)14-32/h3,5-8,10,12,16,32H,2,4,9,11,13-14H2,1H3,(H,28,33)(H,27,29,30)/t16-/m0/s1
- IUPAC Name
- 4-{[(3-chloro-4-methoxyphenyl)methyl]amino}-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-[(pyrimidin-2-yl)methyl]pyrimidine-5-carboxamide
- SMILES
- COC1=C(Cl)C=C(CNC2=C(C=NC(=N2)N2CCC[C@H]2CO)C(=O)NCC2=NC=CC=N2)C=C1
References
- General References
- Gur S, Sikka SC, Hellstrom WJ: Novel phosphodiesterase-5 (PDE5) inhibitors in the alleviation of erectile dysfunction due to diabetes and ageing-induced oxidative stress. Expert Opin Investig Drugs. 2008 Jun;17(6):855-64. doi: 10.1517/13543784.17.6.855 . [Article]
- Bruzziches R, Francomano D, Gareri P, Lenzi A, Aversa A: An update on pharmacological treatment of erectile dysfunction with phosphodiesterase type 5 inhibitors. Expert Opin Pharmacother. 2013 Jul;14(10):1333-44. doi: 10.1517/14656566.2013.799665. Epub 2013 May 16. [Article]
- Kedia GT, Uckert S, Assadi-Pour F, Kuczyk MA, Albrecht K: Avanafil for the treatment of erectile dysfunction: initial data and clinical key properties. Ther Adv Urol. 2013 Feb;5(1):35-41. doi: 10.1177/1756287212466282. [Article]
- FDA Approved Drug Products: Stendra (avanafil) tablets for oral use [Link]
- EMA CHMP Assessment Report: Avanafil (INN) [Link]
- CaymanChem: Avanafil M4 metabolite [Link]
- CaymanChem: Avanafil M16 metabolite [Link]
- EMA Summary of Product Characteristics: Spedra (avanafil) oral tablets [Link]
- FDA Approved Drug Products: Stendra (avanafil) tablets for oral use 2022 [Link]
- External Links
- KEGG Drug
- D03217
- PubChem Compound
- 9869929
- PubChem Substance
- 175427065
- ChemSpider
- 8045620
- BindingDB
- 235766
- 1291301
- ChEBI
- 66876
- ChEMBL
- CHEMBL1963681
- ZINC
- ZINC000011677857
- PDBe Ligand
- E6L
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Avanafil
- PDB Entries
- 6l6e
- FDA label
- Download (465 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Treatment Erectile Dysfunction 3 4 Completed Treatment Vision 1 4 Unknown Status Treatment Erectile Dysfunction 1 3 Completed Treatment Erectile Dysfunction 6 3 Completed Treatment Sexual Function and Fertility Disorders NEC-Erectile Dysfunction 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet, coated Oral 100 mg Tablet Oral 100 mg Tablet Oral 200 mg Tablet Oral 50 mg Tablet Oral 100 mg/1 Tablet Oral 200 mg/1 Tablet Oral 50 mg/1 Tablet Oral - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US6656935 No 2003-12-02 2020-09-13 US 
US7501409 No 2009-03-10 2023-05-05 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Practically insoluble https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202276s018lbl.pdf - Predicted Properties
Property Value Source logP 2.78 Chemaxon pKa (Strongest Acidic) 12.35 Chemaxon pKa (Strongest Basic) 5.55 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 9 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 125.39 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 131.75 m3·mol-1 Chemaxon Polarizability 50.87 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9958 Blood Brain Barrier - 0.7165 Caco-2 permeable - 0.61 P-glycoprotein substrate Substrate 0.672 P-glycoprotein inhibitor I Non-inhibitor 0.6724 P-glycoprotein inhibitor II Inhibitor 0.9038 Renal organic cation transporter Non-inhibitor 0.5282 CYP450 2C9 substrate Non-substrate 0.7215 CYP450 2D6 substrate Non-substrate 0.795 CYP450 3A4 substrate Substrate 0.6184 CYP450 1A2 substrate Non-inhibitor 0.5 CYP450 2C9 inhibitor Non-inhibitor 0.5841 CYP450 2D6 inhibitor Non-inhibitor 0.7495 CYP450 2C19 inhibitor Non-inhibitor 0.5892 CYP450 3A4 inhibitor Non-inhibitor 0.549 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5277 Ames test Non AMES toxic 0.6096 Carcinogenicity Non-carcinogens 0.8809 Biodegradation Not ready biodegradable 0.9929 Rat acute toxicity 2.5077 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.6671 hERG inhibition (predictor II) Inhibitor 0.8671
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-001i-0001900000-5f7140d1a11a65c68b04 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0ue9-1013900000-d431ff0234a0af134a00 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0fc0-0004900000-fd4377c73a274ef01fef Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0560-2228900000-fb50403c630139e0288c Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-056r-0912200000-209000a6d8f121ede0fa Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-3977600000-f7c0b9b026e37353c46c Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 207.86842 predictedDeepCCS 1.0 (2019) [M+H]+ 210.26398 predictedDeepCCS 1.0 (2019) [M+Na]+ 216.17651 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Metal ion binding
- Specific Function
- Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP (PubMed:9714779, ...
- Gene Name
- PDE5A
- Uniprot ID
- O76074
- Uniprot Name
- cGMP-specific 3',5'-cyclic phosphodiesterase
- Molecular Weight
- 99984.14 Da
References
- Kedia GT, Uckert S, Assadi-Pour F, Kuczyk MA, Albrecht K: Avanafil for the treatment of erectile dysfunction: initial data and clinical key properties. Ther Adv Urol. 2013 Feb;5(1):35-41. doi: 10.1177/1756287212466282. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- 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
- Bruzziches R, Francomano D, Gareri P, Lenzi A, Aversa A: An update on pharmacological treatment of erectile dysfunction with phosphodiesterase type 5 inhibitors. Expert Opin Pharmacother. 2013 Jul;14(10):1333-44. doi: 10.1517/14656566.2013.799665. Epub 2013 May 16. [Article]
- FDA Approved Drug Products: Stendra (avanafil) tablets for oral use [Link]
- EMA CHMP Assessment Report: Avanafil (INN) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid 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 oxidizes a variety of structurally un...
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- EMA Summary of Product Characteristics: Spedra (avanafil) oral tablets [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binder
- General Function
- Toxic substance binding
- Specific Function
- Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Serum albumin
- Molecular Weight
- 69365.94 Da
References
- EMA CHMP Assessment Report: Avanafil (INN) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Binder
- General Function
- Not Available
- Specific Function
- Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
- Gene Name
- ORM1
- Uniprot ID
- P02763
- Uniprot Name
- Alpha-1-acid glycoprotein 1
- Molecular Weight
- 23511.38 Da
References
- EMA CHMP Assessment Report: Avanafil (INN) [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- ATP-binding cassette sub-family G member 2
- Molecular Weight
- 72313.47 Da
References
- EMA Summary of Product Characteristics: Spedra (avanafil) oral tablets [Link]
Drug created at March 19, 2008 16:18 / Updated at October 27, 2022 02:24