Silodosin

Silodosin
Names
Trade namesUrief, Rapaflo, Silodyx, others
Other namesKAD-3213, KMD-3213
IUPAC name
  • 1-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]indoline-7-carboxamide
Clinical data
Drug classα1-adrenoceptor antagonist[1]
Main usesBenign prostatic hyperplasia (BPH)[1]
Side effectsRetrograde ejaculation, dizziness, low blood pressure with standing, stuffy nose[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • US: B (No risk in non-human studies)
    Routes of
    use    		By mouth
    Typical dose8 mg OD[1]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa609002
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • US: ℞-only
    • EU: Rx-only
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Bioavailability32%
    Protein binding96.6%
    MetabolismLiver glucuronidation (UGT2B7-mediated); also minor CYP3A4 involvement
    Elimination half-life13±8 hours
    Excretion33.5% renal, 54.9% fecal
    Chemical and physical data
    FormulaC25H32F3N3O4
    Molar mass495.543 g·mol−1
    3D model (JSmol)
    SMILES
    • FC(F)(F)COc3ccccc3OCCN[C@H](C)Cc1cc2c(c(c1)C(=O)N)N(CC2)CCCO
    InChI
    • InChI=1S/C25H32F3N3O4/c1-17(30-8-12-34-21-5-2-3-6-22(21)35-16-25(26,27)28)13-18-14-19-7-10-31(9-4-11-32)23(19)20(15-18)24(29)33/h2-3,5-6,14-15,17,30,32H,4,7-13,16H2,1H3,(H2,29,33)/t17-/m1/s1 checkY
    • Key:PNCPYILNMDWPEY-QGZVFWFLSA-N checkY

    Silodosin, sold under the brand name Rapaflo among others, is a medication used to treat benign prostatic hyperplasia (BPH).[1] It may be used together with a 5α-reductase inhibitor.[2] It is taken by mouth.[1]

    Common side effects include retrograde ejaculation, dizziness, low blood pressure with standing, and a stuffy nose.[2] Other side effects may include intraoperative floppy iris syndrome.[1] Use is not recommended in people with significant liver or kidney problems.[2] It is an α1-adrenoceptor antagonist which help muscles in the bladder and prostate relax.[1]

    was approved for medical use in the United States in 2008 and in Europe in 2010.[2][1] In the United States 3 month of treatment costs about 34 USD as of 2021.[3]

    Medical uses

    Silodosin is used for the treatment of BPH in adult men.[4][5]

    Dosage

    The typical dose is 8 mg once per day.[1]

    Contraindications

    According to European labels, silodosin has no contraindications apart from known hypersensitivity.[4][5] Another source names recurring urinary retention, recurring urinary infections, uncontrolled macrohematuria, bladder stones, hydronephrosis, combination with other α1-antagonists or dopamine agonists, and severe renal or hepatic impairment as contraindications.[6]

    Side effects

    The most common adverse effect is loss of seminal emission. This seems to be caused by silodosin's high selectivity for α1A receptors.[4][7]

    Other common adverse effects (in more than 1% of patients) are dizziness, orthostatic hypotension, diarrhoea, and clogged nose. Less common (0.1–1%) are tachycardia (fast heartbeat), dry mouth, nausea, skin reactions, and erectile dysfunction. Hypersensitivity reactions occur in fewer than 0.01% of patients. There have been reports about intraoperative floppy iris syndrome during cataract extractions.[4][5] These side effects are similar to those of other α1 antagonists.

    Interactions

    Combining silodosin with strong inhibitors of the liver enzyme CYP3A4, such as ketoconazole, significantly increases its concentrations in the blood plasma and its AUC. Less potent CYP3A4 inhibitors such as diltiazem have a less pronounced effect on this parameters, which is not considered clinically significant. Inhibitors and inducers of the enzyme UGT2B7, alcohol dehydrogenases, and aldehyde dehydrogenases, as well as the transporter P-glycoprotein (P-gp), may also influence silodosin concentrations in the body. Digoxin, which is transported by P-gp, is not affected by silodosin; this means that silodosin does not significantly inhibit or induce P-gp.[4][5]

    No relevant interactions with antihypertensive drugs or with PDE5 inhibitors have been found in studies; although combination with other α1-antagonists is not well studied.[4][5]

    Pharmacology

    Mechanism of action

    Silodosin has high affinity for the α1A adrenergic receptor in the prostate, the bladder, and the prostatic urethra. By this mechanism it relaxes the smooth muscle in these organs, easing urinary flow and other symptoms of BPH.[8]

    Pharmacokinetics

    The absolute bioavailability after oral intake is 32%. Food has little effect on the AUC. When in the bloodstream, 96,6% of the substance are bound to blood plasma proteins. Its main metabolite is silodosin glucuronide, which inhibits the α1A receptor with 1/8 of the affinity of the parent substance. 91% of the glucuronide are bound to plasma proteins. The enzyme mainly responsible for the formation of the glucuronide is UGT2B7. Other enzymes involved in the metabolism are alcohol dehydrogenases, aldehyde dehydrogenases and CYP3A4.[1][4]

    Silodosin is almost completely excreted in form of its metabolites; 33.5% via the urine and 54.9% via the feces. The biological half-life of silodosin is 11 hours on average, and that of the glucuronide is 18 hours or 24 hours. (Sources are contradictory on this.)[4][5]

    • Silodosin glucuronide
      Silodosin glucuronide
    • KMD-3293, the other main metabolite
      KMD-3293, the other main metabolite

    History

    Silodosin received its first marketing approval in Japan in May 2006, under the brand name Urief, which is jointly marketed by Kissei Pharmaceutical and Daiichi Sankyo.

    Kissei licensed the US, Canadian, and Mexican rights for silodosin to Watson Pharmaceuticals (now Allergan) in 2004. The United States Food and Drug Administration and Health Canada approved silodosin under the brand name Rapaflo on 9 October 2008 and 11 January 2011, respectively.[9][10]

    Society and culture

    Brand names

    Other brand names include Urorec (European Union),[11] Niksol (Croatia), Silorel (Jamaica), Sildoo, Silodal, Silodosia, Silofast (India) Thrupas (South Korea), Flopadex (Egypt), and Urorec (Russia).

    Research

    As α1A adrenoceptor antagonists are being investigated as a means to male birth control due to their ability to inhibit ejaculation but not orgasm, a trial with 15 male volunteers was conducted. While silodosin was completely efficacious in preventing the release of semen in all subjects, 12 out of the 15 patients reported mild discomfort upon orgasm. The men also reported the psychosexual side effect of being strongly dissatisfied by their lack of ejaculation.[7]

    References

    1. 1 2 3 4 5 6 7 8 9 10 "Silodyx EPAR". European Medicines Agency (EMA). 2010-01-10. Archived from the original on 2021-05-16. Retrieved 2021-07-27.
    2. 1 2 3 4 5 "Silodosin Monograph for Professionals". Drugs.com. Archived from the original on 10 August 2020. Retrieved 12 October 2021.
    3. ↑ "Silodosin Prices, Coupons & Savings Tips - GoodRx". GoodRx. Archived from the original on 4 May 2016. Retrieved 12 October 2021.
    4. 1 2 3 4 5 6 7 8 Haberfeld, H, ed. (2019). Austria-Codex (in Deutsch). Vienna: Österreichischer Apothekerverlag. Urorec 4 mg-Hartkapseln.
    5. 1 2 3 4 5 6 "Urorec: EPAR – Product Information" (PDF). European Medicines Agency. 2019-11-21. Archived (PDF) from the original on 2021-08-29. Retrieved 2021-07-27.
    6. ↑ Dinnendahl, V; Fricke, U, eds. (1982). Arzneistoff-Profile (in Deutsch). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
    7. 1 2 Kobayashi K, Masumori N, Kato R, Hisasue S, Furuya R, Tsukamoto T (December 2009). "Orgasm is preserved regardless of ejaculatory dysfunction with selective alpha1A-blocker administration". Int J Impot Res. 21 (5): 306–10. doi:10.1038/ijir.2009.27. PMC 2834370. PMID 19536124.
    8. ↑ FDA Professional Drug Information on Rapaflo. Accessed 2020-01-03.
    9. ↑ "Drugs.com, Watson Announces Silodosin NDA Accepted for Filing by FDA for the Treatment of Benign Prostatic Hyperplasia". Archived from the original on 2018-09-20. Retrieved 2008-02-13.
    10. ↑ Health Canada (4 May 2011). "Summary Basis of Decision - Rapaflo". Drug and Health Products Register. Government of Canada. Archived from the original on 29 August 2021. Retrieved 8 January 2021.
    11. ↑ "Urorec". European Medicines Agency. 2019-11-21. Archived from the original on 2020-12-27. Retrieved 2021-07-27.
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