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{{Short description|Medication used to treat erectile dysfunction}} |
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{{cs1 config|name-list-style=vanc|display-authors=6}} |
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{{Redirect|Cialis|the Central Asian kingdom|Karasahr}} |
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{{Redirect|Cialis|the Central Asian kingdom|Karasahr}} |
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{{Use dmy dates|date=October 2022}} |
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{{drugbox |
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{{Infobox drug |
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| Verifiedfields = changed |
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| Watchedfields = changed |
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| Watchedfields = changed |
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| verifiedrevid = 470476653 |
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| verifiedrevid = 635551343 |
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| image = Tadalafil.svg |
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| IUPAC_name = (6''R''-''trans'')-6-(1,3-benzodioxol-5-yl)- 2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino pyridoindole-1,4-dione |
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| width = 180 |
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| image = Tadalafil skeletal.svg |
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| width = 178 |
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| alt = |
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| caption = |
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| image2 = Tadalafil 3D 1XOZ.png |
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| image2 = Tadalafil 3D 1XOZ.png |
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| width2 = |
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<!--Clinical data--> |
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| alt2 = <!-- Clinical data --> |
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| pronounce = {{IPAc-en|t|ə|ˈ|d|æ|l|ə|f|ᵻ|l}} {{respell|tə|DAL|ə-fil}} |
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| tradename = Cialis |
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| tradename = Cialis, Adcirca, others |
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| Drugs.com = {{drugs.com|monograph|tadalafil}} |
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| Drugs.com = {{drugs.com|monograph|tadalafil}} |
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| MedlinePlus = a604008 |
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| MedlinePlus = a604008 |
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| DailyMedID = Tadalafil |
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| pregnancy_category = B |
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| legal_status = rx-only |
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| pregnancy_AU = B1 |
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| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Tadalafil Use During Pregnancy | website=Drugs.com | date=14 March 2019 | url=https://www.drugs.com/pregnancy/tadalafil.html | access-date=20 August 2020 | archive-date=1 December 2020 | archive-url=https://web.archive.org/web/20201201024307/https://www.drugs.com/pregnancy/tadalafil.html | url-status=live }}</ref> |
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| routes_of_administration = ] |
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| pregnancy_category = |
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| routes_of_administration = ] |
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| class = ] |
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| ATC_prefix = G04 |
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| ATC_suffix = BE08 |
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| ATC_supplemental = <!-- Legal status --> |
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| legal_AU = S4 |
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| legal_AU_comment = <ref name="Cialis tadalafil PI" /> |
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| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> |
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| legal_BR_comment = |
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| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --> |
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| legal_CA_comment = |
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| legal_DE = <!-- Anlage I, II, III or Unscheduled --> |
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| legal_DE_comment = |
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| legal_NZ = <!-- Class A, B, C --> |
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| legal_NZ_comment = |
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| legal_UK = POM |
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| legal_UK_comment = <ref>{{cite web | title=Cialis 10mg film-coated tablets - Summary of Product Characteristics (SmPC) | website=(emc) | date=26 April 2017 | url=https://www.medicines.org.uk/emc/product/7431/smpc | access-date=20 August 2020 | archive-date=1 December 2020 | archive-url=https://web.archive.org/web/20201201121508/https://www.medicines.org.uk/emc/product/7431/smpc | url-status=live }}</ref> |
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| legal_US = Rx-only |
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| legal_US_comment = <ref name="Cialis FDA label" /><ref name="Adcirca FDA label">{{cite web | title=Adcirca- tadalafil tablet | website=DailyMed | date=23 June 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ff61b237-be8e-461b-8114-78c52a8ad0ae | access-date=10 April 2023 | archive-date=6 March 2023 | archive-url=https://web.archive.org/web/20230306224056/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ff61b237-be8e-461b-8114-78c52a8ad0ae | url-status=live }}</ref> |
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| legal_EU = Rx-only |
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| legal_EU_comment = <ref name="Cialis EPAR">{{cite web | title=Cialis EPAR | website=] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/cialis | access-date=20 August 2020 | archive-date=7 January 2021 | archive-url=https://web.archive.org/web/20210107012454/https://www.ema.europa.eu/en/medicines/human/EPAR/cialis | url-status=live }}</ref> |
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| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> |
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| legal_UN_comment = |
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| legal_status = Rx-only |
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<!--Pharmacokinetic data--> |
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<!-- Pharmacokinetic data -->| bioavailability = Varies |
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| bioavailability = varies |
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| protein_bound = 94% |
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| protein_bound = 94% |
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| metabolism = CYP3A4 (liver) |
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| metabolism = ] (predominantly ]) |
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| metabolites = ] metabolite |
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| elimination_half-life = 17.5 hours |
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| elimination_half-life = 17.5 hours |
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| duration_of_action = ≤ 36 hours |
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| excretion = feces (> 60%), urine (> 30%) |
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| onset = 30 minutes |
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| excretion = Feces (~61%), urine (~36%)<ref name="Cialis FDA label">{{cite web | title=Cialis- tadalafil tablet, film coated | website=DailyMed | date=12 June 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bcd8f8ab-81a2-4891-83db-24a0b0e25895 | access-date=20 August 2020 | archive-date=21 September 2019 | archive-url=https://web.archive.org/web/20190921074000/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bcd8f8ab-81a2-4891-83db-24a0b0e25895 | url-status=live }}</ref> |
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<!--Identifiers--> |
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<!-- Identifiers -->| CAS_number_Ref = {{cascite|correct|??}} |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 171596-29-5 |
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| CAS_number = 171596-29-5 |
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| ATC_prefix = G04 |
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| CAS_supplemental = |
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| ATC_suffix = BE08 |
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| ATC_supplemental = |
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| PubChem = 110635 |
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| PubChem = 110635 |
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| IUPHAR_ligand = 7299 |
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| ChEBI_Ref = {{ebicite|changed|EBI}} |
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| ChEBI = 71940 |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| DrugBank = DB00820 |
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| DrugBank = DB00820 |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D02008 |
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| KEGG = D02008 |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEBI = 71940 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 779 |
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| ChEMBL = 779 |
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| NIAID_ChemDB = |
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| PDB_ligand = CIA |
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| PDB_ligand = CIA |
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| synonyms = <!-- Chemical and physical data --> |
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| IUPAC_name = (6''R'',12a''R'')-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino<br />pyridoindole-1,4-dione |
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<!--Chemical data--> |
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| C=22 | H=19 | N=3 | O=4 |
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| C = 22 |
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| H = 19 |
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| molecular_weight = 389.404 g/mol |
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| N = 3 |
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| smiles = O=C1N(CC(N21CC3=C(2C4=CC5=C(OCO5)C=C4)C6=C3C=CC=C6)=O)C |
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| O = 4 |
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| InChI = 1/C22H19N3O4/c1-24-10-19(26)25-16(22(24)27)9-14-13-4-2-3-5-15(13)23-20(14)21(25)12-6-7-17-18(8-12)29-11-28-17/h2-8,16,21,23H,9-11H2,1H3/t16-,21-/m1/s1 |
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| SMILES = CN1CC(=O)N2(Cc3c(c4ccccc34)2c2ccc3c(c2)OCO3)C1=O |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C22H19N3O4/c1-24-10-19(26)25-16(22(24)27)9-14-13-4-2-3-5-15(13)23-20(14)21(25)12-6-7-17-18(8-12)29-11-28-17/h2-8,16,21,23H,9-11H2,1H3/t16-,21-/m1/s1 |
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| StdInChI = 1S/C22H19N3O4/c1-24-10-19(26)25-16(22(24)27)9-14-13-4-2-3-5-15(13)23-20(14)21(25)12-6-7-17-18(8-12)29-11-28-17/h2-8,16,21,23H,9-11H2,1H3/t16-,21-/m1/s1 |
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| StdInChI_comment = |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = WOXKDUGGOYFFRN-IIBYNOLFSA-N |
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| StdInChIKey = WOXKDUGGOYFFRN-IIBYNOLFSA-N |
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| density = |
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| density_notes = |
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| melting_point = |
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| melting_notes = |
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| solubility = |
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| specific_rotation = |
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}} |
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}} |
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] |
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<!-- Definition and medical uses --> |
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'''Tadalafil''', sold under the brand name '''Cialis''' among others, is a ] used to treat ], ], and ].<ref name="Cialis FDA label" /><ref name="Adcirca FDA label" /><ref name=AHFS2019/> It is taken ].<ref name=AHFS2019>{{cite web |title=Tadalafil Monograph for Professionals |url=https://www.drugs.com/monograph/tadalafil.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=8 April 2019 |archive-date=20 September 2020 |archive-url=https://web.archive.org/web/20200920021716/https://www.drugs.com/monograph/tadalafil.html |url-status=live }}</ref> Onset is typically within half an hour and the duration is up to 36 hours.<ref name=AHFS2019/> |
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<!-- Side effects and mechanism --> |
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'''Tadalafil''' is ] marketed in pill form for treating ] (ED) under the name '''''Cialis''''', and under the name '''''Adcirca''''' for the treatment of ]. In October 2011 the ] (FDA) approved Cialis for treating the signs and symptoms of ] (BPH) as well as a combination of BPH and erectile dysfunction (ED) when the conditions coincide. It initially was developed by the ] company ], and then again developed and marketed world-wide by Lilly ICOS, LLC, the joint venture of ICOS Corporation and ]. ''Cialis'' tablets, in 2.5 mg, 5 mg, 10 mg, and 20 mg doses, are yellow, film-coated, and almond-shaped. The approved dose for pulmonary arterial hypertension is 40 mg (two 20-mg tablets) once daily. |
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Common side effects include ], muscle pain, flushed skin, and nausea.<ref name=AHFS2019/> Caution is advised in those with ].<ref name=AHFS2019/> Rare but serious side effects include a ] that can lead to damage to the ], vision problems, and ].<ref name=AHFS2019/> Tadalafil is not recommended in people taking ]s such as ], as this may result in a serious drop in ].<ref name=AHFS2019/> Tadalafil is a ] which increases blood flow to the penis.<ref name=AHFS2019/> It also dilates ] in the lungs, which lowers the ] pressure.<ref name=AHFS2019/> |
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<!-- History and culture --> |
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Tadalafil is also manufactured and sold under the name of ''Tadacip'' by the Indian pharmaceutical company ] in doses of 10 mg and 20 mg. |
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Tadalafil was approved for medical use in the United States in 2003.<ref name=AHFS2019/> It is available as a ].<ref name=BNF76>{{cite book|title=British national formulary: BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=978-0-85711-338-2|pages=796|edition=76}}</ref> In 2022, it was the 172nd most commonly prescribed medication in the United States, with more than 3{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Tadalafil Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Tadalafil | access-date = 30 August 2024 }}</ref> |
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==Medical uses== |
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On November 21, 2003 the FDA approved tadalafil (as Cialis) for sale in the United States as the third ED prescription drug pill (after ] (Viagra) and ] (Levitra)). Like sildenafil and vardenafil, tadalafil is recommended as an 'as needed' medication. Cialis is the only one of the three that is also offered as a once-daily medication. |
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] |
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Tadalafil is used to treat ], ], and ].<ref name=AHFS2019/> In the US, tadalafil (as Cialis) is ] for the treatment of erectile dysfunction and the signs and symptoms of benign prostatic hyperplasia;<ref name="Cialis FDA label" /> and (as Adcirca) for the treatment of pulmonary arterial hypertension to improve exercise ability.<ref name="Adcirca FDA label" /> |
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===Benign prostatic hyperplasia=== |
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Moreover, tadalafil was approved in May 2009 in the United States for the treatment of pulmonary arterial hypertension <ref> {{cite web| url=http://www.drugs.com/newdrugs/fda-approves-adcirca-tadalafil-pulmonary-arterial-hypertension-1366.html| | accessdate=2014-11-13 | publisher= Drugs.com | title = FDA approves tadalafil for pulmonary arterial hypertension}} </ref> and is under regulatory review in other regions for this condition. In late November 2008, Eli Lilly sold the exclusive rights to commercialize tadalafil for pulmonary arterial hypertension in the United States to ] for an upfront payment of $150 million. |
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A meta‐analysis found that tadalafil is an effective treatment for ] due to benign prostatic hyperplasia and that such treatment had a low rate of adverse effects.<ref>{{cite journal | vauthors = Wang Y, Bao Y, Liu J, Duan L, Cui Y | title = Tadalafil 5 mg Once Daily Improves Lower Urinary Tract Symptoms and Erectile Dysfunction: A Systematic Review and Meta-analysis | journal = Lower Urinary Tract Symptoms | volume = 10 | issue = 1 | pages = 84–92 | date = January 2018 | pmid = 29341503 | doi = 10.1111/luts.12144 | s2cid = 23929021 }}</ref> Tadalafil is FDA-approved for males as a therapy to treat and prevent symptoms of benign prostatic hyperplasia, such as urinary urgency, hesitancy, weak stream, dribbling, and incontinence. Tadalafil was found to have similar benefits for lower urinary tract symptoms as the usually prescribed ].<ref>{{cite journal | vauthors = Hatzimouratidis K | title = A review of the use of tadalafil in the treatment of benign prostatic hyperplasia in men with and without erectile dysfunction | journal = Therapeutic Advances in Urology | volume = 6 | issue = 4 | pages = 135–147 | date = August 2014 | pmid = 25083163 | pmc = 4054509 | doi = 10.1177/1756287214531639 | publisher = SAGE Publications | doi-access = free }}</ref> |
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===Pulmonary arterial hypertension=== |
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==History== |
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Tadalafil is approved in the United States, Canada, and Japan to improve exercise ability in people with pulmonary arterial hypertension.<ref>{{Cite press release |title=Ppsynvi (macitentan and tadalafil) Becomes the First and Only Health Canada-Approved Once Daily Fixed Dose Combination Treatment for Patients with Pulmonary Arterial Hypertension (PAH) |url=https://www.jnj.com/opsynvi-macitentan-and-tadalafil-becomes-the-first-and-only-health-canada-approved-once-daily-fixed-dose-combination-treatment-for-patients-with-pulmonary-arterial-hypertension-pah |access-date=26 November 2021 |website=Johnson & Johnson |archive-date=26 November 2021 |archive-url=https://web.archive.org/web/20211126103807/https://www.jnj.com/opsynvi-macitentan-and-tadalafil-becomes-the-first-and-only-health-canada-approved-once-daily-fixed-dose-combination-treatment-for-patients-with-pulmonary-arterial-hypertension-pah |url-status=live }}</ref><ref>{{cite journal | vauthors = Galiè N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, Shapiro S, White RJ, Chan M, Beardsworth A, Frumkin L, Barst RJ | title = Tadalafil therapy for pulmonary arterial hypertension | journal = Circulation | volume = 119 | issue = 22 | pages = 2894–2903 | date = June 2009 | pmid = 19470885 | doi = 10.1161/CIRCULATIONAHA.108.839274 | s2cid = 9916876 | doi-access = free }}</ref> |
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The FDA's approval of Viagra (]) on March 27, 1998<ref>{{cite web|url=http://www.history.com/this-day-in-history/fda-approves-viagra| title=FDA approves Viagra| publisher=History.com| accessdate=2014-11-12}}</ref> was a ground-breaking commercial event for the treatment of ED, with sales exceeding ]1 billion. Subsequently, the FDA approved Levitra (]) on August 19, 2003, and Cialis (tadalafil) on November 21, 2003. |
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==Adverse effects== |
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Cialis was discovered by Glaxo Wellcome (now ]) under a partnership between Glaxo and ICOS to develop new drugs that began in August 1991. <ref name="tadalafil">{{cite journal |last=Daugan |first=A |coauthors=Grondin P, Ruault C, Le Monnier de Gouville AC, Coste H, Kirilovsky J, Hyafil F, Labaudinière R |date=October 9, 2003 |title=The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 1: 5,6,11,11a-tetrahydro-1H-imidazopyridoindole-1,3(2H)-dione analogues |journal=] |volume=46 |issue=21 |pages=4525–32 |pmid=14521414 |doi=10.1021/jm030056e}}</ref><ref>{{cite news |first=Rhonda |last=Richards |title=ICOS At A Crest On Roller Coaster |work=] |page=3B |date=September 17, 1991}}</ref> In 1993, the ] biotechnology company ICOS Corporation began studying compound IC351, a ] (PDE5) ]. In 1994, Pfizer scientists discovered that sildenafil, which also inhibits the PDE5 enzyme, caused penile erection in men participating in a clinical study of a heart medicine. Although ICOS scientists were not testing compound IC351 for treating ED, they recognized its potential usefulness for treating that disorder. Soon, in 1994, ICOS received a patent for compound IC351 (structurally unlike sildenafil and vardenafil), and Phase 1 clinical trials began in 1995. In 1997, the Phase 2 clinical studies were initiated for men experiencing ED, then progressed to the Phase 3 trials that supported the drug's FDA approval. Although Glaxo had an agreement with ICOS to share profits 50/50 for drugs resulting from the partnership, Glaxo let the agreement lapse in 1996 as the drugs developed were not in the company's core markets.<ref name="ervin">{{cite news |first=Keith |last=Ervin |title=Deep Pockets + Intense Research + Total Control = The Formula -- Bothell Biotech Icos Keeps The Pipeline Full Of Promise |work=] |page=F1 |date=June 21, 1998 |accessdate=January 10, 2009 |url=http://community.seattletimes.nwsource.com/archive/?date=19980621&slug=2757327}}</ref> |
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The most common potential ] when using tadalafil are ], stomach discomfort or pain, indigestion, ], ], ], ] (pain in limbs and extremities), ], ] (or uncommonly ]), and ]/].<ref name=AHFS2019/> Also common are ], ], ], and ] or ]; both ] and ] have been reported.<ref name=AHFS2019/> Diarrhea was reported more frequently in patients 65 or older than in younger subjects.<ref name="Cialis FDA label" /> These side effects reflect the ability of PDE5 inhibition to cause vasodilation (causing blood vessels to widen) and usually resolve after a few hours.<ref>{{cite journal | vauthors = Rajfer J, Aliotta PJ, Steidle CP, Fitch WP, Zhao Y, Yu A | title = Tadalafil dosed once a day in men with erectile dysfunction: a randomized, double-blind, placebo-controlled study in the US | journal = International Journal of Impotence Research | volume = 19 | issue = 1 | pages = 95–103 | date = January 2007 | pmid = 16871272 | doi = 10.1038/sj.ijir.3901496 | s2cid = 21494857 }}</ref> |
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===Vision=== |
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In 1998, ICOS Corporation and Eli Lilly and Company formed the Lilly ICOS, LLC, joint venture company to further develop and commercialize tadalafil as a treatment for ED. Two years later, Lilly ICOS, LLC, filed a new drug application with the FDA for compound IC351 (under the tadalafil generic name, and the Cialis brand name). In May 2002, Lilly ICOS reported to the ] that clinical trial testing demonstrated that tadalafil was effective for up to 36 hours, and one year later, the FDA approved tadalafil. One advantage Cialis has over Viagra and Levitra is its 17.5-hour ] (thus Cialis is advertised to work for up to 36 hours, after which time there remains approximately 25 percent of the absorbed dose in the body) when compared to the four-hour half–life of sildenafil (Viagra). |
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In May 2005, the US ] (FDA) found that tadalafil (along with other PDE5 inhibitors) was associated with vision impairment related to NAION (]).<ref>{{Cite web|title=Non-Arteritic Anterior Ischemic Optic Neuropathy - Brigham and Women's Hospital|url=https://www.brighamandwomens.org/neurology/neuro-ophthalmology/non-arteritic-anterior-ischemic-optic-neuropathy|access-date=13 October 2021|website=www.brighamandwomens.org|archive-date=28 October 2021|archive-url=https://web.archive.org/web/20211028170209/https://www.brighamandwomens.org/neurology/neuro-ophthalmology/non-arteritic-anterior-ischemic-optic-neuropathy|url-status=live}}</ref> Most, but not all, of these patients, had underlying anatomic or vascular risk factors for the development of NAION, unrelated to PDE5 inhibitor use.<ref name=AHFS2019/> The FDA concluded that they were not able to draw a cause and effect relationship, only an association; the label of all three PDE5 inhibitors was changed to alert clinicians to that fact. A 2019 meta-analysis found that tadalafil exposure was ''not'' associated with NAION.<ref>{{cite journal | vauthors = Penedones A, Alves C, Batel Marques F | title = Risk of nonarteritic ischaemic optic neuropathy with phosphodiesterase type 5 inhibitors: a systematic review and meta-analysis | journal = Acta Ophthalmologica | volume = 98 | issue = 1 | pages = 22–31 | date = February 2020 | pmid = 31559705 | doi = 10.1111/aos.14253 | doi-access = free }}</ref> |
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In 2007, Eli Lilly and Company bought the ICOS Corporation for $2.3 billion. As a result, Eli Lilly owned Cialis and then closed the ICOS operations, ending the joint venture and firing most of ICOS's approximately 500 employees, except for 127 employees of the ICOS biologics facility, which subsequently was bought by CMC Biopharmaceuticals A/S (CMC). |
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===Hearing=== |
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Persons surnamed "Cialis" objected to Eli Lilly and Company's so naming the drug, but the company has maintained that the drug's trade name is unrelated to the surname.<ref>{{cite news | url = http://observer.guardian.co.uk/sex/story/0,12550,887478,00.html | title = Drugs giant says its new pill will pack more punch than rival Viagra | last = Revill | first = Jo | date = February 2, 2003 | accessdate = 2007-04-06 | work = ]}}</ref> |
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In October 2007, the FDA announced that the labeling for all ]s, including tadalafil, requires a more prominent warning of the potential risk of ] as the result of post-marketing reports of temporary deafness associated with use of PDE5 inhibitors.<ref name="FDA PDE5">{{cite web| url= https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109012.htm| title= FDA Announces Revisions to Labels for Cialis, Levitra and Viagra| date= 18 October 2007| publisher= U.S. ] (FDA) | access-date= 28 September 2009| archive-url= https://web.archive.org/web/20161022203200/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109012.htm| archive-date= 22 October 2016| url-status= dead}}</ref> |
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==Metabolism== |
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On October 6, 2011, the U.S. FDA approved tadalafil <ref>http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm274642.htm</ref> to treat the signs and symptoms of benign prostatic hyperplasia (BPH). BPH is a condition in males in which the prostate gland becomes enlarged, obstructing the free flow of urine. Symptoms may include sudden urges to urinate (urgency), difficulty in starting urination (hesitancy), a weak urine stream, and more frequent urination- especially at night. The FDA has also approved tadalafil for treatment of both BPH and erectile dysfunction (ED) where the two conditions co-exist. |
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Tadalafil is metabolized predominantly<ref>{{Cite journal| vauthors = Lemma GL, Desta Z, Jones DR, Gorski JC, Hall SD |date=February 2003|title=Droperidol is predominantly metabolized by human CYP3A enzymes. |journal=Clinical Pharmacology & Therapeutics|volume=73|issue=2|pages=P16|doi=10.1016/s0009-9236(03)90413-9|s2cid=71353631 |issn=0009-9236}}</ref> by the ] ] enzyme system. |
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==Mechanism of action== |
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==Mechanism of action== |
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Penile ] during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of ] and the smooth muscle of the ].{{medcn|date=April 2023}} This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of ] (more commonly known as cyclic GMP or cGMP) in smooth muscle cells.{{medcn|date=April 2023}} cGMP relaxes smooth muscle and increases blood flow to the corpus cavernosum.{{medcn|date=April 2023}} |
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{{unreferenced section|date=February 2011}} |
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Although ] (]), ] (]), and tadalafil (Cialis) all work by inhibiting PDE5, tadalafil's pharmacologic distinction is its longer half-life (17.50 hours) <ref>{{cite book|title= Medicinal Chemistry| page=635| author= Sriram D | publisher= Pearson Education India, 2010}} </ref> – compared to sildenafil and vardenafil (both 4.0–5.0 hours)<ref>{{cite web| publisher= Medscape| title=Tadalafil (Cialis) and Vardenafil (Levitra) Recently Approved Drugs for Erectile Dysfunction| author= Kaye K. Gaines}}</ref> – resulting in longer duration of action, and so partly responsible for "The Weekend Pill" sobriquet. Furthermore, the longer half-life is the basis for current investigation of tadalafil's daily therapeutic use in relieving pulmonary arterial hypertension. Sildenafil is approved in several world regions as a thrice-daily therapy for pulmonary arterial hypertension. |
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The ] (PDE5) enhances erectile function by increasing the amount of cGMP.{{medcn|date=April 2023}} Tadalafil (and sildenafil and vardenafil) inhibits PDE5. However, because ] is required to initiate the local penile release of nitric oxide, tadalafil's inhibition of PDE5 will have no effect without sexual stimulation.<ref name="Cialis tadalafil PI">{{Cite web|title=Cialis tadalafil PI|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06346-3|access-date=19 August 2020|website=Therapeutic Goods Administration|archive-date=20 January 2021|archive-url=https://web.archive.org/web/20210120142402/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06346-3|url-status=live}}</ref> |
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Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and the smooth muscle of the ]. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of ] (more commonly known as Cyclic GMP or cGMP) in smooth muscle cells. cGMP relaxes smooth muscle and increases blood flow to the corpus cavernosum. |
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===Duration of action=== |
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The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Tadalafil (and sildenafil and vardenafil) inhibits PDE5. However, because sexual stimulation is required to initiate the local penile release of nitric oxide, tadalafil's inhibition of PDE5 will have no effect without direct sexual stimulation of the penis. The recommended tadalafil starting dose for most men is 10 mg, taken as needed before sexual activity (but not more than once daily). The dose may be increased to 20 mg or decreased to 5 mg, per its efficacy and the man's personal tolerance of the drug.In June 2007, the European Commission approved low-dose (2.5 mg and 5 mg) Cialis to be used as single-daily ED therapy. |
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Although ], ], and tadalafil all work by inhibiting PDE5, tadalafil's pharmacologic distinction is its longer half-life (17.5 hours),<ref>{{cite book|title= Medicinal Chemistry| page=635| author= Sriram D | publisher= Pearson Education India, 2010}}</ref> compared to sildenafil and vardenafil, which are both 4–5 hours.<ref>{{cite web| publisher= Medscape| title= Tadalafil (Cialis) and Vardenafil (Levitra) Recently Approved Drugs for Erectile Dysfunction| author= Kaye K. Gaines| url= http://www.medscape.com/viewarticle/471785| access-date= 30 September 2016| archive-date= 14 July 2016| archive-url= https://web.archive.org/web/20160714120754/http://www.medscape.com/viewarticle/471785| url-status= live}}</ref> This translates to a longer duration of action, which is partly responsible for "The Weekend Pill" nickname. Furthermore, the longer half-life is the basis for tadalafil's daily therapeutic use in treating pulmonary arterial hypertension. |
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Although available since 2003 in 5, 10, 20 mg dosage, in late 2008/early 2009, the U.S. FDA approved the commercial sale of Cialis in 2.5 mg dosage as a one-a-day treatment for ED. The 2.5 mg dose avoids earlier dispensing restrictions on higher dosages. The price of the 5 mg and 2.5 mg are often similar, so some people score and split the pill.<ref>https://www.consumerreports.org/health/resources/pdf/best-buy-drugs/money-saving-guides/english/PillSplitting-FINAL.pdf</ref> Both physicians and the manufacturer warn against splitting the pill, especially since it is enterically coated and splitting might impact absorption. |
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===Comparison with actions of other PDE5 inhibitors=== |
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Moreover, tadalafil (Adcirca) 40 mg was approved in 2009 in the United States and Europe (and 2010 in Canada and Japan) as a once-daily therapy to improve exercise ability in patients with ]. In patients with ], the pulmonary vascular lumen is decreased as a result of vasoconstriction and vascular remodeling, resulting in increased pulmonary artery pressure and pulmonary vascular resistance. Tadalafil is believed to increase pulmonary artery vasodilation, and inhibit vascular remodeling, thus lowering pulmonary arterial pressure and pulmonary vascular resistance. Right heart failure is the principal consequence of pulmonary arterial hypertension. |
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Sildenafil and vardenafil inhibit PDE6, an enzyme found in the eye, more than tadalafil.<ref name="selectivity">{{cite journal | vauthors = Bischoff E | title = Potency, selectivity, and consequences of nonselectivity of PDE inhibition | journal = International Journal of Impotence Research | volume = 16 | issue = Suppl 1 | pages = S11–S14 | date = June 2004 | pmid = 15224129 | doi = 10.1038/sj.ijir.3901208 | doi-access = free }}</ref> Some sildenafil users see a bluish tinge and have a heightened sensitivity to light because of PDE6 inhibition.<ref name="ervin"/> |
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Sildenafil and vardenafil also inhibit ] more than tadalafil.<ref name="selectivity" /> PDE1 is found in the brain, heart, and ].<ref name="selectivity" /> It is thought that the inhibition of PDE1 by sildenafil and vardenafil leads to ], ], and ].<ref name="selectivity" /> |
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On October 6, 2011, the U.S. FDA approved tadalafil to treat the signs and symptoms of benign prostatic hyperplasia (BPH). BPH is a condition in males in which the prostate gland becomes enlarged, obstructing the free flow of urine. Symptoms may include sudden urges to urinate (urgency), difficulty in starting urination (hesitancy), a weak urine stream, and more frequent urination - especially at night. The FDA has also approved tadalafil for treatment of both BPH and erectile dysfunction (ED) where the two conditions co-exist. |
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Tadalafil inhibits PDE11 more than sildenafil or vardenafil.<ref name="selectivity" /> PDE11 is expressed in ], the ], the ], the ], the ], and the ].<ref name="selectivity" /> The effects on the body of inhibiting PDE11 are not known.<ref name="selectivity" /> |
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==Side effects== |
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Tadalafil has been used in approximately 15,000 men participating in clinical trials, and over eight million men worldwide (primarily in the post-approval/post-marketing setting). The most common ]s when using tadalafil are headache, stomach discomfort or pain, indigestion, burping, acid reflux, back pain, muscle aches, ], and stuffy or runny nose. These side effects reflect the ability of PDE5 inhibition to cause vasodilation (cause blood vessels to widen), and usually go away after a few hours. Back pain and muscle aches can occur 12 to 24 hours after taking the drug, and the symptom usually disappears after 48 hours. |
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==Chemistry== |
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In May 2005, the U.S. ] found that tadalafil (along with other PDE5 inhibitors) was associated with vision impairment related to NAION (]) in certain patients taking these drugs in the post-marketing (outside of clinical trials) setting. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION unrelated to PDE5 use, including: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. Given the small number of NAION events with PDE5 use (fewer than one in one million), the large number of users of PDE5 inhibitors (millions) and the fact that this event occurs in a similar population to those who do not take these medicines, the FDA concluded that they were not able to draw a cause and effect relationship, given these patients underlying vascular risk factors or anatomical defects. However, the label of all three PDE5 inhibitors was changed to alert clinicians to a possible association. |
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Tadalafil is an ] ].<ref>{{cite journal | vauthors = Borthwick AD | title = 2,5-Diketopiperazines: synthesis, reactions, medicinal chemistry, and bioactive natural products | journal = Chemical Reviews | volume = 112 | issue = 7 | pages = 3641–3716 | date = July 2012 | pmid = 22575049 | doi = 10.1021/cr200398y }}</ref> It is also a 1,2,3,4-tetrahydro-]. |
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Tadalafil can be synthesized starting from (D)-] methyl ester and ] via a ]. This is followed by condensations with ] and ] to complete the diketopiperazine ring:<ref>{{cite journal | vauthors = Baumann M, Baxendale IR, Ley SV, Nikbin N | title = An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals | journal = Beilstein Journal of Organic Chemistry | volume = 7 | pages = 442–495 | date = May 2011 | pmid = 21647262 | pmc = 3107522 | doi = 10.3762/BJOC.7.57 }}</ref> |
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In October 2007, the FDA announced that the labeling for all PDE5 inhibitors, including tadalafil, requires a more prominent warning of the potential risk of ] as the result of postmarketing reports of deafness associated with use of PDE5 inhibitors.<ref name="FDA PDE5">{{cite web | url= http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109012.htm| title= FDA Announces Revisions to Labels for Cialis, Levitra and Viagra| author= | date= 2007-10-18| publisher= ]| accessdate=2009-09-28 }}</ref> |
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==Drug interactions== |
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Since PDE5 inhibitors such as tadalafil may cause transiently low blood pressure (]), ] (poppers) should not be taken for at least 48 hours after taking the last dose of tadalafil. Using organic nitrites (such as the sex drug ]) within this timeframe may increase the risk of life-threatening hypotension. |
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==History== |
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Since people who have taken tadalafil within the past 48 hours cannot take organic nitrates to relieve angina (such as ] spray), these patients should seek immediate medical attention if they experience ]l chest pain.<ref>{{cite web | url = http://www.rxlist.com/cgi/generic3/cialis_wcp.htm | title = Cialis: Warnings, Precautions, Pregnancy, Nursing, Abuse | publisher = RxList | year = 2007 | accessdate = 2007-04-06}}</ref> In the event of a medical emergency, ]s and medical personnel should be notified of any recent doses of tadalafil. |
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The FDA's approval of sildenafil in 1998<ref>{{cite web| url=http://www.history.com/this-day-in-history/fda-approves-viagra| title=FDA approves Viagra| publisher=History.com| access-date=12 November 2014| archive-date=17 October 2014| archive-url=https://web.archive.org/web/20141017065435/http://www.history.com/this-day-in-history/fda-approves-viagra| url-status=live}}</ref> was a ground-breaking commercial event for the treatment of ED, with sales exceeding ]1 billion. Subsequently, the FDA approved both ]<ref>{{cite web | url = https://www.drugs.com/availability/generic-levitra.html | title = Generic Levitra Availability | publisher = Drugs.com | access-date = 1 June 2015 | archive-date = 29 April 2015 | archive-url = https://web.archive.org/web/20150429055235/http://www.drugs.com/availability/generic-levitra.html | url-status = live }}</ref> and tadalafil in 2003. |
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It initially was developed by the ] company ], and then again developed and marketed worldwide by Lilly ICOS, LLC, the joint venture of ICOS Corporation and ]. Tadalafil was approved in 2009 in the United States for the treatment of pulmonary arterial hypertension<ref>{{cite web| url=https://www.drugs.com/newdrugs/fda-approves-adcirca-tadalafil-pulmonary-arterial-hypertension-1366.html| access-date=13 November 2014| publisher=Drugs.com| title=FDA approves tadalafil for pulmonary arterial hypertension| archive-date=13 November 2014| archive-url=https://web.archive.org/web/20141113171618/http://www.drugs.com/newdrugs/fda-approves-adcirca-tadalafil-pulmonary-arterial-hypertension-1366.html| url-status=live}}</ref> and is under regulatory review in other regions for this condition. In late November 2008, Eli Lilly sold the exclusive rights to commercialize tadalafil for ] in the United States to ] for an upfront payment of $150 million. |
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Tadalafil was discovered by Glaxo Wellcome (now ]) under a partnership between Glaxo and ICOS to develop new drugs that began in August 1991.<ref name="tadalafil">{{cite journal | vauthors = Daugan A, Grondin P, Ruault C, Le Monnier de Gouville AC, Coste H, Linget JM, Kirilovsky J, Hyafil F, Labaudinière R | title = The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazinopyridoindole-1,4-dione analogues | journal = Journal of Medicinal Chemistry | volume = 46 | issue = 21 | pages = 4533–4542 | date = October 2003 | pmid = 14521415 | doi = 10.1021/jm030056e }}</ref><ref>{{cite news | vauthors = Richards R |title=ICOS At A Crest On Roller Coaster |work=] |page=3B |date=17 September 1991}}</ref> In 1993, the ], biotechnology company ICOS Corporation began studying compound IC351, a ] (PDE5) ]. In 1994, Pfizer scientists discovered that sildenafil, which also inhibits the PDE5 enzyme, caused penile erection in males participating in a clinical study of a heart medicine. Although ICOS scientists were not testing compound IC351 for treating ED, they recognized its potential usefulness for treating that disorder. Soon, in 1994, ] received a patent for compound IC351 (structurally unlike sildenafil and vardenafil), and Phase 1 clinical trials began in 1995. In 1997, the Phase 2 clinical studies were initiated for males experiencing ED, then progressed to the Phase 3 trials that supported the drug's FDA approval. Although Glaxo had an agreement with ICOS to share profits 50/50 for drugs resulting from the partnership, ] let the agreement lapse in 1996 as the drugs developed were not in the company's core markets.<ref name="ervin">{{cite news |vauthors=Ervin K |title=Deep Pockets + Intense Research + Total Control = The Formula -- Bothell Biotech Icos Keeps The Pipeline Full Of Promise |work=] |page=F1 |date=21 June 1998 |access-date=10 January 2009 |url=https://archive.seattletimes.com/archive/19980621/2757327/deep-pockets--intense-research--total-control--the-formula----bothell-biotech-icos-keeps-the-pipeline-full-of-promise |archive-date=24 February 2012 |archive-url=https://web.archive.org/web/20120224150404/http://community.seattletimes.nwsource.com/archive/?date=19980621&slug=2757327 |url-status=live }}</ref> |
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In 1998, ICOS Corporation and Eli Lilly and Company formed the Lilly ICOS, LLC, joint venture company to further develop and commercialize tadalafil as a treatment for ED. Two years later, Lilly ICOS, LLC, filed a new drug application with the FDA for compound IC351 (under the tadalafil generic name, and the Cialis brand name). In May 2002, Lilly ICOS reported to the ] that clinical trial testing demonstrated that tadalafil was effective for up to 36 hours, and one year later, the FDA approved tadalafil. One advantage Cialis has over Viagra and Levitra is its 17.5-hour ] (thus Cialis is advertised to work for up to 36 hours,<ref>{{cite web | url = https://www.drugs.com/tadalafil.html | title = Tadalafil | publisher = Drugs.com | access-date = 23 February 2018 | archive-date = 16 December 2017 | archive-url = https://web.archive.org/web/20171216183027/https://www.drugs.com/Tadalafil.html | url-status = live }}</ref> after which time there remains approximately 25% of the absorbed dose in the body) when compared to the four-hour half-life of sildenafil (Viagra). |
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In 2007, Eli Lilly and Company bought the ICOS Corporation for $2.3 billion. As a result, Eli Lilly owned Cialis and then closed the ICOS operations, ending the joint venture and firing most of ICOS's approximately 500 employees, except for 127 employees of the ICOS biologics facility, which subsequently was bought by CMC Biopharmaceuticals A/S (CMC). |
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Persons surnamed "Cialis" objected to Eli Lilly and Company's so naming the drug, but the company has maintained that the drug's trade name is unrelated to the surname.<ref>{{cite news | url = http://observer.guardian.co.uk/sex/story/0,12550,887478,00.html | title = Drugs giant says its new pill will pack more punch than rival Viagra | vauthors = Revill J | date = 2 February 2003 | access-date = 6 April 2007 | work = ] | archive-date = 3 April 2007 | archive-url = https://web.archive.org/web/20070403082632/http://observer.guardian.co.uk/sex/story/0,12550,887478,00.html | url-status = live }}</ref> |
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In October 2011, the US FDA approved tadalafil<ref>{{Cite web|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm274642.htm|title=FDA approves Cialis to treat benign prostatic hyperplasia|date=6 October 2011|publisher=U.S. ] (FDA) |archive-url=https://web.archive.org/web/20170118091151/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm274642.htm|archive-date=18 January 2017|url-status=dead}}</ref> to treat the signs and symptoms of benign prostatic hyperplasia. Benign prostatic hyperplasia is a condition in which the prostate gland becomes enlarged, obstructing the free flow of urine. Symptoms may include sudden urges to urinate (urgency), difficulty in starting urination (hesitancy), a weak urine stream, and more frequent urination — especially at night. The FDA has also approved tadalafil for the treatment of both benign prostatic hyperplasia and erectile dysfunction where the two conditions co-exist. |
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==Society and culture== |
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===Marketing=== |
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In the United States, the FDA relaxed rules on prescription drug marketing in 1997, allowing advertisements targeted directly to consumers.<ref name="wink wink">{{cite news |vauthors=Elliott S |title=For Impotence Drugs, Less Wink-Wink |work=] |page=C2 |date=10 January 2006 |access-date=22 April 2018 |url=https://www.nytimes.com/2006/01/10/business/media/for-impotence-drugs-less-winkwink.html |archive-date=22 April 2018 |archive-url=https://web.archive.org/web/20180422205230/https://www.nytimes.com/2006/01/10/business/media/for-impotence-drugs-less-winkwink.html |url-status=live }}</ref> Lilly-ICOS hired the Grey Worldwide Agency in New York, part of the ], to run the Cialis advertising campaign.<ref name="elliott">{{cite news |vauthors=Elliott S |title=Viagra and the Battle of the Awkward Ads |work=] |page=1 |department=Business Day |date=25 April 2004 |access-date=22 April 2018 |url=https://www.nytimes.com/2004/04/25/business/viagra-and-the-battle-of-the-awkward-ads.html |archive-date=22 April 2018 |archive-url=https://web.archive.org/web/20180422203623/https://www.nytimes.com/2004/04/25/business/viagra-and-the-battle-of-the-awkward-ads.html |url-status=live }}</ref> Marketing for Cialis has taken advantage of its greater duration compared to its competitors in advertisements for the drug; Stuart Elliot of '']'' opined: "The continuous presence of females in Cialis ads is a subtle signal that the drug makes it easier for them to set the pace with males, in contrast to the primarily male-driven imagery for Levitra and Viagra."<ref name="elliott" /> Iconic themes in Cialis ads include couples side by side in matching bathtubs and the slogan "When the moment is right, will you be ready?"<ref name="elliott" /> Cialis ads were unique among the ED drugs in mentioning specifics of the drug.<ref name="mccarthy">{{cite news|url=https://www.theglobeandmail.com/report-on-business/first-they-tried-to-play-it-safe/article1115524/|title=First they tried to play it safe; Ads for erectile dysfunction drug Cialis bared all - including a scary potential side effect. It was risky but it has paid off|vauthors=McCarthy S|date=5 March 2005|work=]|page=B4|access-date=12 June 2017|archive-date=14 December 2019|archive-url=https://web.archive.org/web/20191214162205/https://www.theglobeandmail.com/report-on-business/first-they-tried-to-play-it-safe/article1115524/|url-status=live}}</ref> As a result, Cialis ads were also the first to describe the side effects in an advertisement, as the FDA requires advertisements with specifics to mention side effects. One of the first Cialis ads aired at the 2004 ].<ref name="mccarthy" /> Just weeks before the Super Bowl, the FDA required more possible side effects to be listed in the advertisement, including ].<ref name="mccarthy" /> Although many parents objected to the Cialis ad being aired during the Super Bowl, ]'s halftime "]" overshadowed Cialis.<ref name="mccarthy" /> In January 2006, the Cialis ads were tweaked, adding a doctor on screen to describe side effects and only running ads where more than 90 percent of the audience are adults, effectively ending Super Bowl ads.<ref name="wink wink" /> In 2004, Lilly-ICOS, Pfizer, and GlaxoSmithKline spent a combined $373.1 million to advertise Cialis, Viagra, and Levitra respectively.<ref name="mccarthy" /> Cialis has sponsored many sporting events, including the ] and the ], once being title sponsor of the PGA Tour ] tournament.<ref name="loyd">{{cite news | vauthors = Loyd L |title=Two Pills Look to Topple Viagra's Reign in Market; Levitra Expects Approval Next Month, Cialis Later This Year |work=] |page=E01 |date=6 July 2003}}</ref> |
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=== Economics === |
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Tadalafil is metabolized predominantly by the hepatic CYP3A4 enzyme system. The presence of other drugs which induce this system can shorten tadalafil half-life and reduce serum levels, and hence efficacy, of the drug. |
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In Australia, tadalafil is subsidized through the Repatriation Pharmaceutical Benefits Scheme (RPBS) for patients with a specific accepted war- or service-related disability.<ref>{{Cite web|title=Tadalafil|url=https://www.pbs.gov.au/medicine/item/4597Y|publisher=Pharmaceutical Benefits Scheme|access-date=19 August 2020|archive-date=24 January 2021|archive-url=https://web.archive.org/web/20210124182520/https://www.pbs.gov.au/medicine/item/4597Y|url-status=live}}</ref> |
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In the US, a generic version of tadalafil is available.<ref>{{cite web |title=Generic Cialis |url=https://www.goodrx.com/cialis?form=tablet&dosage=20mg}}</ref> While some health insurance providers cover at least part of the cost (typically limiting the number of doses covered per month), many providers, including those operating under Medicare Part D, do not cover the cost of medications prescribed for erectile dysfunction.<ref>{{cite news |vauthors=Parker-Pope T |title=The Cost of Treating Erectile Dysfunction|url=http://well.blogs.nytimes.com/2009/08/28/the-cost-of-treating-erectile-dysfunction/|access-date=20 December 2016|work=]|date=28 August 2009|archive-date=10 September 2015|archive-url=https://web.archive.org/web/20150910151315/http://well.blogs.nytimes.com/2009/08/28/the-cost-of-treating-erectile-dysfunction/|url-status=live}}</ref><ref>{{cite news |title=Coverage Summary -- Impotence Treatment |url=https://www.unitedhealthcareonline.com/ccmcontent/ProviderII/UHC/en-US/Assets/ProviderStaticFiles/ProviderStaticFilesPdf/Tools%20and%20Resources/Policies%20and%20Protocols/UnitedHealthcare%20Medicare%20Coverage/Impotence_Treatment_UHCMA_CS.pdf|access-date=20 December 2016|publisher=United Health Care|date=16 August 2016|archive-date=29 August 2021|archive-url=https://web.archive.org/web/20210829075116/https://www.uhcprovider.com/?rfid=UHCOContRD|url-status=dead}}</ref> |
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==Selectivity compared with other PDE5 inhibitors== |
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Tadalafil, sildenafil, and vardenafil all act by inhibiting the PDE5 enzyme. These drugs also inhibit other PDE enzymes. Sildenafil and vardenafil inhibit PDE6, an enzyme found in the eye, more than tadalafil.<ref name="selectivity">{{cite journal |last=Bischoff |first=E |date=June 2004 |title=Potency, selectivity, and consequences of nonselectivity of PDE inhibition |journal= |volume=16 |pages=S11–4 |pmid=15224129 |doi=10.1038/sj.ijir.3901208 |url=http://www.nature.com/ijir/journal/v16/n1s/full/3901208a.html |accessdate=January 19, 2009}}</ref> Some sildenafil users see a bluish tinge and have a heightened sensitivity to light because of PDE6 inhibition.<ref name="ervin"/> Sildenafil and vardenafil also inhibit ] more than tadalafil.<ref name="selectivity" /> PDE1 is found in the brain, heart, and ].<ref name="selectivity" /> It is thought that the inhibition of PDE1 by sildenafil and vardenafil leads to ], ], and ].<ref name="selectivity" /> Tadalafil inhibits PDE11 more than sildenafil or vardenafil.<ref name="selectivity" /> PDE11 is expressed in ], the ], the ], the ], the ], and the ].<ref name="selectivity" /> The effects on the body of inhibiting PDE11 are not known.<ref name="selectivity" /> |
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In the UK, a generic version of tadalafil became available in November 2017, reducing its price per pill, and is available through the ].{{citation needed|date=August 2020}} In China, CMOAPI is the largest manufacturer of Tadalafil powder.<ref>{{Cite web|title=Tadalafil powder & Intermediate|url=https://www.cmoapi.com/our-products/tadalafil/|access-date=7 September 2021|website=cmoapi.com|archive-date=9 November 2021|archive-url=https://web.archive.org/web/20211109005826/https://www.cmoapi.com/our-products/tadalafil/|url-status=live}}</ref> |
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==Marketing== |
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In the United States, the FDA relaxed rules on prescription drug marketing in 1997, allowing advertisements targeted directly to consumers.<ref name="wink wink">{{cite news |first=Stuart |last=Elliott |title=For Impotence Drugs, Less Wink-Wink |work=] |page=C2 |date=January 10, 2006 |accessdate=January 15, 2009 |url=http://www.nytimes.com/2006/01/10/business/media/10adco.html}}</ref> Lilly-ICOS hired the Grey Worldwide Agency in New York, part of the ], to run the Cialis advertising campaign.<ref name="elliott">{{cite news |first=Stuart |last=Elliott |title=Viagra and the Battle of the Awkward Ads |work=] |page=1 |date=April 25, 2004 |accessdate=January 15, 2009 |url=http://query.nytimes.com/gst/fullpage.html?sec=health&res=9D0CE2DB123AF936A15757C0A9629C8B63}}</ref> Marketers for Cialis has taken advantage of its greater duration compared to its competitors in advertisements for the drug; Stuart Elliot of ''The New York Times'' opined: "The continuous presence of women in Cialis ads is a subtle signal that the drug makes it easier for them to set the pace with their men, in contrast to the primarily male-driven imagery for Levitra and Viagra."<ref name="elliott" /> Iconic themes in Cialis ads include couples in bathtubs and the slogan "When the moment is right, will you be ready?"<ref name="elliott" /> Cialis ads were unique among the ED drugs in mentioning specifics of the drug.<ref name="mccarthy">{{cite news |first=Shawn |last=McCarthy |title=First they tried to play it safe; Ads for erectile dysfunction drug Cialis bared all - including a scary potential side effect. It was risky but it has paid off |work=] |page=B4 |date=March 5, 2005}}</ref> As a result, Cialis ads were also the first to describe the side effects in an advertisement, as the FDA requires advertisements with specifics to mention side effects. One of the first Cialis ads aired at the 2004 ].<ref name="mccarthy" /> Just weeks before the Super Bowl, the FDA required more possible side effects to be listed in the advertisement, including ].<ref name="mccarthy" /> Although many parents objected to the Cialis ad being aired during the Super Bowl, ]'s halftime "]" overshadowed Cialis.<ref name="mccarthy" /> In January 2006, the Cialis ads were tweaked, adding a doctor on screen to describe side effects and only running ads where more than 90 percent of the audience are adults, effectively ending Super Bowl ads.<ref name="wink wink" /> In 2004, Lilly-ICOS, Pfizer, and GlaxoSmithKline spent a combined $373.1 million to advertise Cialis, Viagra, and Levitra respectively.<ref name="mccarthy" /> Cialis has sponsored many ] events, including the ] and the ], once being title sponsor of the PGA Tour ] tournament.<ref name="loyd">{{cite news |first=Linda |last=Loyd |title=Two Pills Look to Topple Viagra's Reign in Market; Levitra Expects Approval Next Month, Cialis Later This Year |work=] |page=E01 |date=July 6, 2003}}</ref> |
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==Synthesis== |
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The undesired trans β-carboline can be equilibrated to give the cis isomer by treatment with aqueous HCl at 60°C for 36 hours.<ref> |
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{{Patent|EP|1546149}}</ref><ref>{{US patent|5859006}} </ref><ref>{{US patent|6025494}} </ref><ref>{{US Patent|6,911,542}}</ref><ref> |
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{{Cite doi|10.1016/S0960-894X(03)00159-8}} |
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</ref><ref>Drugs of the Future, 2001, 26, 15-19.</ref> |
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==References== |
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== Research == |
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Tadalafil is being studied for treating ].<ref>{{cite journal | vauthors = Spirito L, Manfredi C, La Rocca R, Napolitano L, Di Girolamo A, Capece M, Trama F, Sciorio C, Sokolakis I, Creta M, Arcaniolo D | title = Daily low-dose tadalafil may reduce the penile curvature progression rate in patients with acute Peyronie's disease: a retrospective comparative analysis | journal = International Journal of Impotence Research | date = December 2022 | volume = 36 | issue = 2 | pages = 129–134 | pmid = 36513814 | doi = 10.1038/s41443-022-00651-8 | s2cid = 254674530 }}</ref><ref>{{cite journal | vauthors = Park HJ, Park SW, Kim TN |title=PD21-09 Daily Tadalafil Therapy: A New Treatment Option for Peyronie's Disease? |journal=Journal of Urology |date=2019 |volume=201 |issue=Supplement 4 |doi=10.1097/01.JU.0000555753.36349.5d|s2cid=149818851 |doi-access=free }}</ref> |
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