Drug/Small Molecule:
sildenafil

PharmGKB contains no dosing guidelines for this drug/small molecule. To report known genotype-based dosing guidelines, or if you are interested in developing guidelines, click here.

PharmGKB gathers information regarding PGx on FDA drug labels from the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels", and from FDA-approved FDA and EMA-approved (European Medicines Agency) EMA labels brought to our attention. Excerpts from the label and downloadable highlighted label PDFs are manually curated by PharmGKB.

Please note that some drugs may have been removed from or added to the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" without our knowledge. We periodically check the table for additions to this table and update PharmGKB accordingly.

There is currently no such list for European drug labels - we are working with the EMA to establish a list of European Public Assessment Reports (EPAR)s that contain PGx information. We are constructing this list by initially searching for drugs for which we have PGx-containing FDA drug labels - of these 44 EMA EPARs were identified and are being curated for pgx information.

We welcome any information regarding drug labels containing PGx information approved by the FDA, EMA or other Medicine Agencies around the world - please contact feedback.


last updated 08/07/2014

European Medicines Agency (EMA) Label for sildenafil

Informative PGx

Summary

The EMA European Public Assessment Report (EPAR) for silenafil (Viagra) contains genetic information regarding its contraindication in patients with hereditary degenerative retinal disorders. It also mentions that the drug is metabolized by CYP3A4 and CYP2C9, and that a lower dose of silenafil should be considered in patients taking CYP3A4 inhibitors concomitantly.

Annotation

Silenafil (Viagra) is contraindicated in patients with hereditary degenerative retinal disorders, such as retinitis pigmentosa. Variants in different genes can underlie these disorders - see OMIM for more information.

Excerpts from the silenafil (Viagra) EPAR:

The safety of sildenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated: severe hepatic impairment, hypotension (blood pressure <90/50 mmHg), recent history of stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases).


Use in patients taking other medicinal products
With the exception of ritonavir for which co-administration with sildenafil is not advised (see section 4.4) a starting dose of 25 mg should be considered in patients receiving concomitant treatment with CYP3A4 inhibitors (see section 4.5).

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the silenafil (Viagra) EMA drug label.

*Disclaimer: The contents of this page have not been endorsed by the EMA and are the sole responsibility of PharmGKB.

Genes and/or phenotypes found in this label

  • Retinitis Pigmentosa
    • Contraindications section, other
    • source: European Medicines Agency (EMA) Label
  • CYP2C9
    • Drug interactions section, Pharmacokinetics section, metabolism/PK
    • source: European Medicines Agency (EMA) Label
  • CYP3A4
    • Dosage & administration section, Drug interactions section, Pharmacokinetics section, metabolism/PK
    • source: European Medicines Agency (EMA) Label

Links to Unannotated Labels

These links are to labels associated with sildenafil that have not been annotated by PharmGKB.

  1. DailyMed - DrugLabel PA166105247

PharmGKB contains no Clinical Variants that meet the highest level of criteria.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the page.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

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This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Gene?

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

Gene ? Variant?
(138)
Alternate Names / Tag SNPs ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available No Clinical Annotations available VA
rs1570360 -1154A>G, -614A>G, 43677830A>G, 43737830A>G, 4878A>G, VEGF -1154
A > G
5' Flanking
No VIP available No Clinical Annotations available VA
rs2070744 -51-762C>T, -786, -813C>T, 11285702C>T, 150690079C>T, 6933C>T, NOS3 -786T>C, NOS3:, T>C, eNOS -786T>C
C > T
5' Flanking
No VIP available CA VA
rs4343 16598G>A, 2328G>A, 26840183G>A, 606G>A, 61566031G>A, ACE:2350A>G in exon 17, ACE:Thr202Thr, Thr202=, Thr776=, tag SNP for ACE:I/D
G > A
Synonymous
Thr202Thr
No VIP available CA VA
rs5443 10501C>T, 47295C>T, 6894875C>T, 6954875C>T, 825C>T, GNB3:825C>T, GNB3:Ser275Ser, Ser275=
C > T
Synonymous
Ser275Ser
No VIP available CA VA
rs699947 -2055A>C, -2578, -2595A>C, 3437A>C, 43676389A>C, 43736389A>C, VEGF-A -2578 C/A, VEGFA:, VEGFA:C-2578A
A > C
5' Flanking
VIP No Clinical Annotations available No Variant Annotations available
rs776746 12083G>A, 219-237G>A, 321-1G>A, 37303382C>T, 581-237G>A, 689-1G>A, 99270539C>T, CYP3A5*1, CYP3A5*3, CYP3A5*3C, CYP3A5:6986A>G, g.6986A>G, intron 3 splicing defect, rs776746 A>G
C > T
Acceptor
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 138
2D structure from PubChem
provided by PubChem

Overview

Generic Names
  • Sildenafil Citrate
Trade Names
  • Revatio
  • Sildenafil Viagra
  • Viagra
Brand Mixture Names

PharmGKB Accession Id:
PA451346

Description

Sildenfail is a vasoactive agent used to treat erectile dysfunction and reduce symptoms in patients with pulmonary arterial hypertension (PAH). Sildenafil elevates levels of the second messenger, cGMP, by inhibiting its breakdown via phosphodiesterase type 5 (PDE5). PDE5 is found in particularly high concentrations in the corpus cavernosum, erectile tissue of the penis. It is also found in the retina and vascular endothelium. Increased cGMP results in vasodilation which facilitates generation and maintenance of an erection. The vasodilatory effects of sildenafil also help reduce symptoms of PAH.

Source: Drug Bank

Indication

For the treatment of erectile dysfunction and to relieve symptoms of pulmonary arterial hypertension (PAH).

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Sildenafil inhibits the cGMP-specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) by sildenafil enhances erectile function by increasing the amount of cGMP.

Source: Drug Bank

Pharmacology

Erections are controlled by the parasympathetic nervous system. Upon sexual stimulation, a decrease in vascular resistance is mediated by acetylcholine and nitric oxide resulting in vasodilation. The hemodynamic mechanism of an erection is comprised of five stages. During the latent stage, arterial and carvernous smooth muscle relaxation occurs. Vasodilation results in high levels of blood flow causing the penis to grow to its full size. This stage is called tumescence. During the full-erection stage, blood flow fills penis sinusoids and outflow is restricted. This is followed by the rigid-erection phase during which the cavernous muscles contract causing the penis to become rigid. Little blood flow occurs during this stage. During the final stage, detumescence, the cavernous muscles relax and blood flows out of the penis. Erectile dysfunction may occur when there is insufficient blood supply to the penis or when the penis is unable to prevent outflow of blood from the penis. Sildenafil is a specific inhibitor of PDE5, an enzyme responsible for the breakdown of cGMP to 5'-GMP. Increased levels of cGMP stimulate vasodilation and facilitate the generation and maintenance of erections. These vasodilatory effects also help decrease symptoms of PAH. Sildenfail also exhibits some activity against PDE6 (10 times less potentcy compared to PDE5), a PDE isoform found predmoninantly in the retina. This activity is responsible for the blue tinged vision experienced by users of sildenafil.

Source: Drug Bank

Food Interaction

Take on empty stomach: 1 hour before or 2 hours after meals.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Sildenafil appears to be completely metabolized in the liver to 16 metabolites. Its metabolism is mediated mainly by cytochrome P450 microsomal isozymes 3A4 (major route) and 2C9 (minor route). The major circulating metabolite, N-demethylated metabolite, has PDE selectivity similar to the parent drug and ~50% of its in vitro potency. The N-demethylated metabolite is further metabolized to an N-dealkylated N,N-de-ethylated metabolite. Sildenafil also undergoes N-dealkylation followed by N-demethylation of the piperazine ring.

Source: Drug Bank

Protein Binding

96%

Source: Drug Bank

Absorption

>90% absorbed with ~40% reaching systemic circulation unchanged following first-pass metabolism

Source: Drug Bank

Half-Life

4 hours

Source: Drug Bank

Route of Elimination

Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).

Source: Drug Bank

Volume of Distribution

  • 105 L

Source: Drug Bank

Chemical Properties

Chemical Formula

C22H30N6O4S

Source: Drug Bank

Isomeric SMILES

CCCc1c2c(c(=O)[nH]c(n2)c3cc(ccc3OCC)S(=O)(=O)N4CCN(CC4)C)n(n1)C

Source: OpenEye

Canonical SMILES

CCCC1=NN(C)C2=C1NC(=NC2=O)C1=C(OCC)C=CC(=C1)S(=O)(=O)N1CCN(C)CC1

Source: Drug Bank

Average Molecular Weight

474.576

Source: Drug Bank

Monoisotopic Molecular Weight

474.204924168

Source: Drug Bank

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

Drug Targets

Gene Description
PDE2A (source: Drug Bank)
PDE5A (source: Drug Bank)
PDE6G (source: Drug Bank)
PDE6H (source: Drug Bank)

Drug Interactions

Drug Description
sildenafil The protease inhibitor increases the effect and toxicity of sildenafil (source: Drug Bank)
sildenafil The protease inhibitor, amprenavir, may increase the effect and toxicity of sildenafil. (source: Drug Bank)
sildenafil Increases the effect and toxicity of sildenafil (source: Drug Bank)
sildenafil Increases the effect and toxicity of sildenafil (source: Drug Bank)
sildenafil Increases the effect and toxicity of sildenafil (source: Drug Bank)
sildenafil Increases the effect and toxicity of sildenafil (source: Drug Bank)
sildenafil The quinolone increases sildenafil levels (source: Drug Bank)
sildenafil The quinolone increases sildenafil levels (source: Drug Bank)
sildenafil Increases the effect and toxicity of sildenafil (source: Drug Bank)
sildenafil Increases the effect and toxicity of sildenafil (source: Drug Bank)
sildenafil The macrolide increases the effect and toxicity of sildenafil (source: Drug Bank)
sildenafil The macrolide, erythromycin, may increase the effect and toxicity of sildenafil. (source: Drug Bank)
sildenafil The protease inhibitor increases the effect and toxicity of sildenafil (source: Drug Bank)
sildenafil The protease inhibitor, fosamprenavir, may increase the effect and toxicity of sildenafil. (source: Drug Bank)
sildenafil The protease inhibitor increases the effect and toxicity of sildenafil (source: Drug Bank)
sildenafil The protease inhibitor, indinavir, may increase the effect and toxicity of sildenafil. (source: Drug Bank)
sildenafil Possible significant hypotension with this combination (source: Drug Bank)
sildenafil Possible significant hypotension with this combination (source: Drug Bank)
sildenafil Possible significant hypotension with this combination (source: Drug Bank)
sildenafil Possible significant hypotension with this combination (source: Drug Bank)
sildenafil The imidazole increases the effect and toxicity of sildenafil (source: Drug Bank)
sildenafil The imidazole increases the effect and toxicity of sildenafil (source: Drug Bank)
sildenafil The imidazole increases the effect and toxicity of sildenafil (source: Drug Bank)
sildenafil The imidazole increases the effect and toxicity of sildenafil (source: Drug Bank)
sildenafil The protease inhibitor increases the effect and toxicity of sildenafil (source: Drug Bank)
sildenafil The protease inhibitor, nelfinavir, may increase the effect and toxicity of sildenafil. (source: Drug Bank)
sildenafil Possible significant hypotension with this combination (source: Drug Bank)
sildenafil Possible significant hypotension with this combination (source: Drug Bank)
sildenafil Telithromycin may reduce clearance of Sildenafil. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Sildenafil if Telithromycin is initiated, discontinued or dose changed. (source: Drug Bank)
sildenafil Increased risk of hypotension. (source: Drug Bank)
sildenafil Tipranavir, co-administered with Ritonavir, may increase the concentration of Sildenafil. Alternate therapy should be considered. (source: Drug Bank)
sildenafil Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of sildenafil by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of sildenafil if voriconazole is initiated, discontinued or dose changed. (source: Drug Bank)

Curated Information ?

EvidenceDisease
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Erectile Dysfunction

Relationships from National Drug File - Reference Terminology (NDF-RT)

May Treat
Contraindicated With

Publications related to sildenafil: 13

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Cystic fibrosis: Toward personalized therapies. The international journal of biochemistry & cell biology. 2014. Ikpa Pauline T, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Cystic fibrosis transmembrane regulator correctors and potentiators. Cold Spring Harbor perspectives in medicine. 2013. Rowe Steven M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Cystic fibrosis: insight into CFTR pathophysiology and pharmacotherapy. Clinical biochemistry. 2012. Lubamba Bob, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
VEGF genetic polymorphisms affect the responsiveness to sildenafil in clinical and postoperative erectile dysfunction. The pharmacogenomics journal. 2012. Lacchini R, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
PharmGKB summary: very important pharmacogene information for CYP3A5. Pharmacogenetics and genomics. 2012. Lamba Jatinder, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Endothelial nitric oxide synthase genotypes and haplotypes modify the responses to sildenafil in patients with erectile dysfunction. The pharmacogenomics journal. 2011. Muniz J J, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
A dosing/cross-development study of the multikinase inhibitor sorafenib in patients with pulmonary arterial hypertension. Clinical pharmacology and therapeutics. 2010. Gomberg-Maitland M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Analytical and bioanalytical chemistry. 2008. Zanger Ulrich M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Machine learning methods and docking for predicting human pregnane X receptor activation. Chemical research in toxicology. 2008. Khandelwal Akash, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
ACE gene I/D and NOS3 G894T polymorphisms and response to sildenafil in men with erectile dysfunction. Urology. 2003. Eisenhardt Andreas, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Sildenafil response is influenced by the G protein beta 3 subunit GNB3 C825T polymorphism: a pilot study. The Journal of urology. 2003. Sperling Herbert, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides. The Journal of biological chemistry. 2000. Jedlitschky G, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Effects of sildenafil on human penile blood vessels. Urology. 2000. Medina P, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
0069-4190-68
DrugBank:
DB00203
ChEBI:
9139
KEGG Compound:
C07259
KEGG Drug:
D02229
PubChem Compound:
5212
PubChem Substance:
205034
46508371
Drugs Product Database (DPD):
2239766
BindingDB:
14390
ChemSpider:
5023
Therapeutic Targets Database:
DAP000614
FDA Drug Label at DailyMed:
f158fe10-d5dc-4432-b2c9-fc665401291b

Clinical Trials

These are trials that mention sildenafil and are related to either pharmacogenetics or pharmacogenomics.

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Sources for PharmGKB drug information: DrugBank, Open Eye Scientific Software.