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.
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- FDA Approved Drug Products: Cialis (tadalafil) tablets [Link]
- FDA Approved Drug Products: Adcirca (tadalafil) tablets [Link]
- DPD Approved Drug Products: Opsynvi (tadalafil/macitentan) combination tablets [Link]
- Medisca: Tadalafil MSDS [Link]
- 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)
