Viagra ( Sildenafil )

Tadalafil

Tadalafil is a phosphodiesterase 5 inhibitor used to treat erectile dysfunction, benign prostatic hyperplasia, and pulmonary arterial hypertension.

Tadalafil is a selective phosphodiesterase-5 inhibitor that is used in the treatment of erectile dysfunction (ED), pulmonary arterial hypertension (PAH), and benign prostatic hypertrophy. 8,9 It was first approved in 2003 by the FDA for use in ED and later in 2009 for PAH. In contrast to other PDE5 inhibitors like sildenafil, tadalafil has greater selectivity for PDE5 and a longer half-life which has made it a more suitable option for chronic once-daily dosing in the treatment of PAH. 2

Type Small Molecule Groups Approved, Investigational Structure

Structure for Tadalafil (DB00820)

  • (6R-trans)-6-(1,3-Benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino(1′,2′:1,6)pyrido(3,4-b)indole-1,4-dione
  • (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-(methylenedioxy)phenyl) pyrazino(1′,2′:1,6)pyrido(3,4-b)indole-1,4-dione
  • Tadalafil
  • Tadalafilo
  • GF 196960
  • IC-351
  • IC351
  • ICOS 351

Pharmacology

Tadalafil is indicated for the treatment of erectile dysfunction (ED) and either alone or in combination with finasteride for the treatment of benign prostatic hypertrophy (BPH). 7,11 It is also indicated for the treatment of pulmonary arterial hypertension (PAH) both alone and in combination with macitentan or other endothelin-1 antagonists. 8,9

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Tadalafil exerts a therapeutic effect in ED by increasing sexual stimulation-dependant smooth muscle relaxation in the penis, allowing the corpus cavernosum to fill with blood to produce an erection. 2,3 Smooth muscle relaxation in the pulmonary vasculature helps to produce vasodilation in PAH which reduces blood pressure in the pulmonary arteries. 3 In BPH, tadalafil may contribute to decreased smooth muscle cell proliferation which may reduce the size of the prostate and relieve the anatomical obstruction which produces urinary symptoms of BPH. 4 The decreased affinity of tadalafil for PDE6 compared to other PDE5 inhibitors may explain the reduced incidence of visual side effects. 8,9,2

Mechanism of action

Tadalafil is a selective phosphodiesterase-5 (PDE5) inhibitor that produces several downstream effects with the most common therapeutic effect being smooth muscle relaxation. 7 Patients may experience ED due to a variety of causes including psychogenic, neurogenic, vasculogenic, iatrogenic, or endocrine. 6 These causes result in dysfunction of penile smooth muscle relaxation through either disrupted neuronal signaling or direct influence on smooth muscle cells. During sexual arousal, non-adrenergic non-cholinergic (NANC) neurons release nitric oxide (NO). Nitric oxide stimulates guanylate cyclase which converts guanosine triphosphate to cyclic guanosine monophosphate (cGMP). 2,3 cGMP activates the cGMP-dependent kinase (PKG) in a signal cascade which activates K+ channels leading to inhibition of Ca2+ channels, inhibits platelet activation, and inhibits smooth muscle cell proliferation while inducing apoptosis. This signal cascade is attenuated by PDE5 which breaks the phosphodiester bond of cGMP, converting it to GMP. Inhibition of PDE5 by tadalafil increases signaling via the PKG cascade which supports penile smooth muscle relaxation during sexual arousal by decreasing Ca2+ entry into smooth muscle cells. This smooth muscle relaxation allows blood to fill the corpus cavernosum thereby producing an erection.

In PAH, blood pressure in the pulmonary arteries is raised due to a variety of mechanisms stemming from endothelial dysfunction. 3 Decreased production of NO and prostacyclin reduce vasodilatory signaling while overproduction of endothelin-1 and thromboxane increase vasoconstriction. Inflammation, thromboses, and hypoxia later contribute to vascular remodeling which further reduces luminal size. The resultant increase in blood pressure reduces the capacity for gas exchange and increases afterload at the right ventricle, producing symptoms of dyspnea, fatigue, and dizziness as well as leading to right-sided heart failure. Tadalafil exerts its therapeutic effect in PAH through boosting NO-cGMP signaling to contribute to smooth muscle relaxation as with ED.

Lastly, tadalafil is used to treat BPH. 7 BPH produces urinary dysfunction through hyperproliferation of the epithelial and smooth muscle layers of the prostate. 4 The increased size of the prostate blocks urine flow through the urethra resulting in higher residual volumes due to incomplete emptying. Tadalafil does not appear to exert its benefit via smooth muscle relaxation of the prostate. It may instead exert its effect through a mix of increased oxygenation and decreased inflammation, which decreases tissue remodeling, and inhibition of cell proliferation through the cGMP cascade.

The decreased affinity for PDE6 compared to other PDE5 inhibitors may explain the decreased incidence of visual side effects as PDE6 is present in the eye and contributes to color vision. 8,9,2

Tadalafil has a tmax of 0.5-6h with a median of 2h in healthy adults. 1,7 The tmax in adults with PAH is reported as 2-8h with a median of 4h. 8 There does not appear to be a significant effect on absorption when tadalafil is taken with food. 1

Volume of distribution

Tadalafil has a mean apparent volume of distribution of 63L in healthy adults. 1,7 The mean apparent volume of distribution is reported as 77L in adults with PAH. 8

Tadalafil is 94% bound to plasma proteins. 1,7,8

Tadalafil undergoes hepatic metabolism via CYP3A4 to a catechol metabolite. 1,5,7,8 This catechol metabolite undergoes subsequent methylation and glucuronidation with the methyl-glucuronide metabolite becoming the primary metabolite in circulation. None of the known metabolites are considered to be active.

Hover over products below to view reaction partners

Tadalafil is primarily eliminated via hepatic metabolism. 1,7,8 These metabolites are mainly excreted in the feces (61%) and to a lesser extent in the urine (36%)

The mean half-life of elimination of tadalafil is 15-17.5h in healthy adults. 1,7,8 The mean half-life of elimination in adults with PAH is reported as 35h. 8

The mean apparent oral clearance of tadalafil is 2.5-3.4L/h in healthy adults. 1,7,8 The mean apparent oral clearance in adults with PAH is reported as 3.5L/h

With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.

Symptoms of overdose are expected to be similar to typical adverse effects which may include headache, dyspepsia, back pain, myalgia, nasopharyngitis, and dizziness. 7,8 Standard supportive care is recommended. Hemodialysis is not expected to contribute significantly to tadalafil clearance.

Pathways Not Available Pharmacogenomic Effects/ADRs

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.

  • Avoid excessive or chronic alcohol consumption. Ingesting excess amounts of alcohol (more than four drinks in a short time) may potentiate the hypotension and dizziness caused by tadalafil.
  • Avoid grapefruit products. Tadalafil is metabolized by CYP3A4, and grapefruit products are CYP3A4 inhibitors; therefore, coadministration may increase serum levels of tadalafil and result in increased hypotension.
  • Take with or without food.

Products

Our datasets provide approved product information including: dosage, form, labeller, route of administration, and marketing period.

Brand Name Prescription Products

Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image
Act Tadalafil Tablet 20 mg Oral TEVA Canada Limited 2016-07-12 Not applicable Canada
Act Tadalafil Tablet 2.5 mg Oral TEVA Canada Limited 2016-07-12 Not applicable Canada
Act Tadalafil Tablet 10 mg Oral TEVA Canada Limited 2016-07-12 Not applicable Canada
Act Tadalafil Tablet 5 mg Oral TEVA Canada Limited 2016-07-12 Not applicable Canada
Adcirca Tablet 20 mg/1 Oral United Therapeutics Corporation 2009-05-22 Not applicable US
Adcirca Tablet, film coated 20 mg Oral Eli Lilly Nederland B.V. 2016-09-07 Not applicable EU
Adcirca Tablet 20 mg/1 Oral Aphena Pharma Solutions – Tennessee, LLC 2009-05-22 Not applicable US
Adcirca Tablet, film coated 20 mg Oral Eli Lilly Nederland B.V. 2016-09-07 Not applicable EU
Adcirca Tablet 20 mg Oral Eli Lilly & Co. Ltd. 2010-01-19 Not applicable Canada
Adcirca Tablet 20 mg/1 Oral Avera McKennan Hospital 2015-10-28 2017-05-24 US

Generic Prescription Products

Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image
Ach-tadalafil Tablet 5 mg Oral Accord Healthcare Inc Not applicable Not applicable Canada
Ach-tadalafil Tablet 20 mg Oral Accord Healthcare Inc Not applicable Not applicable Canada
Ach-tadalafil Tablet 2.5 mg Oral Accord Healthcare Inc Not applicable Not applicable Canada
Ach-tadalafil Tablet 10 mg Oral Accord Healthcare Inc Not applicable Not applicable Canada
Ag-tadalafil Tablet 20 mg Oral Angita Pharma Inc. 2019-11-21 Not applicable Canada
Ag-tadalafil Tablet 2.5 mg Oral Angita Pharma Inc. Not applicable Not applicable Canada
Ag-tadalafil Tablet 10 mg Oral Angita Pharma Inc. Not applicable Not applicable Canada
Ag-tadalafil Tablet 5 mg Oral Angita Pharma Inc. 2022-03-16 Not applicable Canada
Alyq Tablet, film coated 20 mg/1 Oral Teva Pharmaceuticals USA, Inc. 2019-02-06 Not applicable US
Alyq Tablet, film coated 20 mg/1 Oral AvKARE 2019-02-18 Not applicable US

Mixture Products

Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image
Entadfi Tadalafil (5 mg/1) + Finasteride (5 mg/1) Capsule Oral Veru Inc. 2021-12-12 Not applicable US
Opsynvi Tadalafil (40 mg) + Macitentan (10 mg) Tablet Oral Janssen Pharmaceuticals 2021-11-25 Not applicable Canada
TADA PLUS 30/20 MG FILM KAPLI TABLET ,4 ADET Tadalafil (20 mg) + Dapoxetine (30 mg) Tablet, coated NEUTEC İLAÇ SAN. TİC. A.Ş. 2020-08-14 Not applicable Turkey
TADA PLUS 30/20 MG FILM KAPLI TABLET ,8 ADET Tadalafil (20 mg) + Dapoxetine (30 mg) Tablet, coated NEUTEC İLAÇ SAN. TİC. A.Ş. 2020-08-14 Not applicable Turkey

Categories

show 8 more Substituents 1,4-diazinane / 2,5-dioxopiperazine / 3-alkylindole / Acetal / Alpha-amino acid or derivatives / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Benzodioxole / Beta-carboline / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Dioxopiperazine / Heteroaromatic compound / Hydrocarbon derivative / Indole / Lactam / N-alkylpiperazine / N-methylpiperazine / Organic nitrogen compound / Organic oxide / Organic oxygen compound / Organonitrogen compound / Organooxygen compound / Organopnictogen compound / Oxacycle / Piperazine / Pyrrole / Tertiary carboxylic acid amide

Chemical Identifiers

References

Ben-Zion Dolitzky, Dov Diller, “Preparation of tadalafil intermediates.” U.S. Patent US20060276652, issued December 07, 2006.

  1. Forgue ST, Patterson BE, Bedding AW, Payne CD, Phillips DL, Wrishko RE, Mitchell MI: Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol. 2006 Mar;61(3):280-8. doi: 10.1111/j.1365-2125.2005.02553.x. [Article]
  2. Andersson KE: PDE5 inhibitors – pharmacology and clinical applications 20 years after sildenafil discovery. Br J Pharmacol. 2018 Jul;175(13):2554-2565. doi: 10.1111/bph.14205. Epub 2018 Apr 25. [Article]
  3. Arif SA, Poon H: Tadalafil: a long-acting phosphodiesterase-5 inhibitor for the treatment of pulmonary arterial hypertension. Clin Ther. 2011 Aug;33(8):993-1004. doi: 10.1016/j.clinthera.2011.06.008. Epub 2011 Jul 16. [Article]
  4. Monica FZ, De Nucci G: Tadalafil for the treatment of benign prostatic hyperplasia. Expert Opin Pharmacother. 2019 Jun;20(8):929-937. doi: 10.1080/14656566.2019.1589452. Epub 2019 Mar 22. [Article]
  5. Dalvie D, Obach RS, Kang P, Prakash C, Loi CM, Hurst S, Nedderman A, Goulet L, Smith E, Bu HZ, Smith DA: Assessment of three human in vitro systems in the generation of major human excretory and circulating metabolites. Chem Res Toxicol. 2009 Feb;22(2):357-68. doi: 10.1021/tx8004357. [Article]
  6. Yafi FA, Jenkins L, Albersen M, Corona G, Isidori AM, Goldfarb S, Maggi M, Nelson CJ, Parish S, Salonia A, Tan R, Mulhall JP, Hellstrom WJ: Erectile dysfunction. Nat Rev Dis Primers. 2016 Feb 4;2:16003. doi: 10.1038/nrdp.2016.3. [Article]
  7. FDA Approved Drug Products: Cialis (tadalafil) tablets [Link]
  8. FDA Approved Drug Products: Adcirca (tadalafil) tablets [Link]
  9. DPD Approved Drug Products: Opsynvi (tadalafil/macitentan) combination tablets [Link]
  10. Medisca: Tadalafil MSDS [Link]
  11. FDA Approved Drug Products: Entadfi (finasteride/tadalafil) capsules for oral use [Link]

Clinical Trials

Phase Status Purpose Conditions Count
4 Active Not Recruiting Treatment Benign Prostatic Hyperplasia (BPH) / Overactive Bladder Syndrome (OABS) 1
4 Active Not Recruiting Treatment Lower Ureteric Stones 1
4 Completed Not Available Sexual impotency 1
4 Completed Basic Science Becker’s Muscular Dystrophy (BMD) 1
4 Completed Diagnostic Erectile Dysfunction / Erectile Dysfunction With Diabetes Mellitus 1
4 Completed Treatment Becker’s Muscular Dystrophy (BMD) 1
4 Completed Treatment Benign Prostatic Hyperplasia (BPH) 1
4 Completed Treatment Connective Tissue Diseases / Pulmonary Arterial Hypertension (PAH) / Pulmonary Hypertension (PH) / Scleroderma Spectrum of Diseases / Systemic Sclerosis (SSc) 1
4 Completed Treatment Diabetic Cardiomyopathies / Type 2 Diabetes Mellitus 1
4 Completed Treatment Erectile Dysfunction 10

Pharmacoeconomics

  • Eli lilly co
  • Eli lilly and co
  • Eli Lilly and Company
  • A-S Medication Solutions LLC
  • Bryant Ranch Prepack
  • Diversified Healthcare Services Inc.
  • Eli Lilly & Co.
  • Lake Erie Medical and Surgical Supply
  • Lilly Del Caribe Inc.
  • Nucare Pharmaceuticals Inc.
  • Physicians Total Care Inc.
  • Rebel Distributors Corp.
  • Redpharm Drug
  • Southwood Pharmaceuticals
  • United Therapeutics Corp.

Dosage Forms

Form Route Strength
Film, soluble Oral 20 mg
Film, soluble Oral 5 mg
Tablet Oral 10 mg
Tablet Oral 2.5 mg
Tablet Oral 5 mg
Tablet, film coated Oral 10 mg/1
Tablet, film coated Oral 2.5 mg/1
Tablet, film coated Oral 20 mg/1
Tablet, film coated Oral 5 mg/1
Tablet, coated Oral 10 mg
Tablet, coated Oral 5 mg
Tablet, coated Oral
Film, soluble Oral
Tablet, soluble Oral 10 mg
Tablet, orally disintegrating Oral
Capsule Oral
Tablet, orally disintegrating Oral 10 mg
Tablet, film coated Oral 20 mg
Tablet, film coated Oral
Tablet Oral
Tablet, coated
Tablet, film coated Oral 10.000 mg
Tablet, film coated Oral 2.500 mg
Tablet, film coated Oral 20.000 mg
Tablet, film coated Oral 5.000 mg
Tablet, chewable Oral 20 mg
Tablet Oral 10 mg/1
Tablet Oral 2.5 mg/1
Tablet Oral 20 mg/1
Tablet Oral 5 mg/1
Tablet, coated Oral 10 mg/1
Tablet, coated Oral 2.5 mg/1
Tablet, coated Oral 20 mg/1
Tablet, coated Oral 5 mg/1
Tablet Oral
Tablet, film coated Oral 2.5 MG
Tablet, orally disintegrating Oral 20 mg
Tablet, soluble Oral 5 mg
Tablet, chewable Oral 5 mg
Tablet Oral 20 mg
Solution Oral 20 mg/1mL
Tablet, effervescent 10 mg
Tablet, effervescent
Film, soluble Oral 10 Mg
Tablet, film coated Oral 10 mg
Tablet, film coated Oral 5 mg
Tablet, orally disintegrating Oral 5 mg
Tablet, coated Oral 20 mg

Prices

Unit description Cost Unit
Cialis 30 5 mg tablet Box 140.77USD box
Cialis 10 mg tablet 20.92USD tablet
Cialis 20 mg tablet 20.92USD tablet
Cialis 2.5 mg tablet 4.76USD tablet
Cialis 5 mg tablet 4.76USD tablet

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number Pediatric Extension Approved Expires (estimated) Region
CA2379948 No 2008-03-25 2020-04-26 Canada
CA2181377 No 2002-05-28 2015-01-19 Canada
US6140329 No 2000-10-31 2016-07-11 US
US6821975 Yes 2004-11-23 2021-05-19 US
US6943166 Yes 2005-09-13 2020-10-26 US
US7182958 Yes 2007-02-27 2020-10-26 US
US5859006 Yes 1999-01-12 2018-05-21 US
US11382917 No 2018-12-24 2038-12-24 US

Properties

State Solid Experimental Properties

Property Value Source
melting point (°C) 301-302 °C Medisca: Tadalafil MSDS
water solubility Practically insoluble in water Medisca: Tadalafil MSDS
logP 2.89 Medisca: Tadalafil MSDS

Predicted Properties

Property Value Source
Water Solubility 0.25 mg/mL ALOGPS
logP 2.36 ALOGPS
logP 1.64 ChemAxon
logS -3.2 ALOGPS
pKa (Strongest Acidic) 15.17 ChemAxon
pKa (Strongest Basic) -4.2 ChemAxon
Physiological Charge 0 ChemAxon
Hydrogen Acceptor Count 4 ChemAxon
Hydrogen Donor Count 1 ChemAxon
Polar Surface Area 74.87 Å 2 ChemAxon
Rotatable Bond Count 1 ChemAxon
Refractivity 104.08 m 3 ·mol -1 ChemAxon
Polarizability 40.92 Å 3 ChemAxon
Number of Rings 6 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five Yes ChemAxon
Ghose Filter Yes ChemAxon
Veber’s Rule No ChemAxon
MDDR-like Rule No ChemAxon

Predicted ADMET Features

Property Value Probability
Human Intestinal Absorption + 0.9933
Blood Brain Barrier + 0.7821
Caco-2 permeable + 0.5
P-glycoprotein substrate Substrate 0.6581
P-glycoprotein inhibitor I Non-inhibitor 0.59
P-glycoprotein inhibitor II Non-inhibitor 0.775
Renal organic cation transporter Non-inhibitor 0.7165
CYP450 2C9 substrate Non-substrate 0.8742
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.7407
CYP450 1A2 substrate Non-inhibitor 0.7447
CYP450 2C9 inhibitor Inhibitor 0.5566
CYP450 2D6 inhibitor Non-inhibitor 0.6788
CYP450 2C19 inhibitor Inhibitor 0.6998
CYP450 3A4 inhibitor Non-inhibitor 0.6981
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7235
Ames test Non AMES toxic 0.6466
Carcinogenicity Non-carcinogens 0.931
Biodegradation Not ready biodegradable 0.8906
Rat acute toxicity 2.6521 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.976
hERG inhibition (predictor II) Non-inhibitor 0.8734

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)