Dapoxetine

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Dapoxetine
Dapoxetine-2D-skeletal.png
Systematic (IUPAC) name
(S)-N,N-Dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine
Clinical data
Trade names Kutub, Priligy, Duratia, Pentenal-30, Sustinex, Lejam, Dumax
AHFS/Drugs.com International Drug Names westoxetin 30 mg
Legal status
  • ℞ (Prescription only)
Routes of
administration		 Oral
Pharmacokinetic data
Biological half-life 1.5–1.6 h
Identifiers
CAS Number 119356-77-3
Template:CAS (HCl salt)
ATC code G04BX14 (WHO)
PubChem CID: 71353
IUPHAR/BPS 7901
ChemSpider 64453
UNII GB2433A4M3 YesY
KEGG D03649
ChEMBL CHEMBL2106574
Chemical data
Formula C21H23NO
Molecular mass 305.413 g/mol
  • CN(C)[C@H](C1=CC=CC=C1)CCOC2=CC=CC3=C2C=CC=C3
  • InChI=1S/C21H23NO/c1-22(2)20(18-10-4-3-5-11-18)15-16-23-21-14-8-12-17-9-6-7-13-19(17)21/h3-14,20H,15-16H2,1-2H3/t20-/m0/s1
  • Key:USRHYDPUVLEVMC-FQEVSTJZSA-N

Dapoxetine, marketed as Priligy and Westoxetin, among and other brands, is the first compound developed specially for the treatment of premature ejaculation (PE) in men 18–64 years old.[1][2] Dapoxetine works by inhibiting the serotonin transporter, increasing serotonin's action at the post synaptic cleft, and as a consequence promoting ejaculatory delay.[3] As a member of selective serotonin reuptake inhibitor (SSRI) family, dapoxetine was initially created as an antidepressant. However, unlike other SSRIs, dapoxetine is absorbed and eliminated rapidly in the body. Its fast acting property makes it suitable for the treatment of PE but not as an antidepressant.[4]

Originally created by Eli Lilly pharmaceutical company, dapoxetine was sold to Johnson & Johnson in 2003 and submitted as a New Drug Application to the Food and Drug Administration (FDA) for the treatment of PE in 2004.[5] Dapoxetine has been sold in several European and Asian countries, and lately in Mexico. In the US, dapoxetine has been stuck in phase III development since 2003. However, it is expected to be marketed soon.[3] In 2012, Menarini acquired the rights to commercialise Priligy in Europe, most of Asia, Africa, Latin America and the Middle East.[6]

Therapeutic uses

Premature ejaculation

Randomized, double blind, placebo-controlled trials have confirmed the efficacy of dapoxetine for the treatment of PE.[7] Different dosage has different impacts on different type of PE. Dapoxetine 60 mg significantly improves the mean intravaginal ejaculation latency time (IELT) compared to that of dapoxetine 30 mg in men with lifelong PE, but there is no difference in men with acquired PE.[8] Dapoxetine, given 1–3 hours before sexual episode, prolongs IELT, increases the sense of control and sexual satisfaction in men of 18 to 64 years of age with PE. Since PE is associated with personal distress, interrelationship difficulty, dapoxetine provides help for men with PE to overcome this condition.[9] Because lack of specific approval treatment for PE in the US and some other countries, other SSRIs such as fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram have been used as off label drugs to treat PE. Waldinger's meta analysis shows that the use of these conventional antidepressants increasing IELT from two to ninefold above base line in comparison of three to eightfold when dapoxetine is used.[8] However, these SSRIs must be taken daily in order to achieve meaningful efficacy, and the long half-life increases the risk of the drug accumulation and as a consequence increased of adverse effects such as decreasing sexual libido and causing erectile dysfunction.[10] Dapoxetine, on the other hand, is a fast-acting SSRI. It is rapidly absorbed and eliminated from the body within a few hours. This favorable pharmacokinetics minimizes the risk of the drug's accumulation in the body, and therefore reducing side effects.[4]

Contraindications

A contraindication is a situation in which a drug should not be used, because it may be harmful to the patient.[11] Dapoxetine should not be used in men with moderate to severe hepatic impairment and in those receiving CYP3A4 inhibitors such as ketoconazole, ritonavir, and telithromycine. Dapoxetine can also not be used in patients with heart failure, permanent pacemaker, or other significant ischemic heart disease. Caution is advised in men receiving thioridazine, monoamine oxidase inhibitors, SSRIs, serotonin-norepinephrine reuptake inhibitors, or tricyclic antidepressant. If a patient stops taking one of these drugs, he should wait for 14 days before taking dapoxetine. If a patient stops taking dapoxetine, he should wait for 7 days before receiving these drugs.[3]

Adverse effects

The most common effects when taking dapoxetine are nausea, dizziness, dry mouth, headache, diarrhea, and insomnia.[12][13] Discontinuation due to adverse effects is dose related. According to McMahon in recent study in Asia, the rate of discontinuation is 0.3%, 1.7%, and 5.3% of 1067 studied subjects with placebo, dapoxetine 30 mg, and dapoxetine 60 mg respectively.[14] Unlike other SSRIs used to treat depression, which have been associated with high incidences of sexual dysfunction,[15] dapoxetine is associated with low rates of sexual dysfunction. Taken as needed, dapoxetine has very mild adverse effects on loss of libido (<1%) and ED (<4%).[4]

Overdose

No case of the drug overdose has been reported during clinical trials.[16]

Interactions

Many men that have PE also suffer from erectile dysfunction (ED). Treatment for these patients should consider the drug-drug interaction between dapoxetine and PDE5 inhibitors such as tadalafil (Cialis) or sildenafil (Viagra). In Dresser study (2006), plasma concentration of 24 subjects was obtained. Half of the sample pool were treated with dapoxetine 60 mg + tadalafil 20 mg; the other half were treated with dapoxetine 60 mg + sildenafil 100 mg. These plasma samples were then analyzed using liquid chromatography-tandem mass spectrometry. The results showed that dapoxetine does not alter the pharmacokinetic of tadalafil or sildenafil.[1]

Ethanol doesn't affect the pharmacokinetics of dapoxetine when taking concurrently with dapoxetine.[17]

Mechanism of actions

The mechanism through which dapoxetine affects premature ejaculation is still unclear. However, it is presumed that dapoxetine works by inhibiting serotonin transporter and subsequently increasing serotonin's action at pre and postsynaptic receptors[18] Human ejaculation is regulated by various areas in the central nervous system (CNS).[19] The ejaculatory pathway originates from spinal reflex at the thoracolumbar and lumbosacral level of spinal cord activated by stimuli from male genital. These signals are relayed to the brain stem, which then is influenced by a number of nuclei in the brain such as medial preoptic and paraventricular nulcei.[20] Clement's study performed on anaesthetized male rats showed that acute administration of dapoxetine inhibits ejaculatory expulsion reflex at supraspinal level by modulating activity of lateral paragigantocellular nucleus (LPGi) neurons. These effects cause an increase in pudendal motoneuron reflex discharge (PMRD) latency. However, it is unclear whether dapoxetine acts directly on LPGi or on the descending pathway in which LPGi located.[21]

Pharmacokinetics

Absorption

Dapoxetine is a white powder substance and water- insoluble. Taken 1–3 hours before sexual activity, it is rapidly absorbed in the body. Its maximum plasma concentration (Cm) is reached 1–2 hours after oral administration. The Cm and AUC (Area Under the plasma vs. time Curve) are dose dependent. The Cm and Tm (time needed to obtain the maximum plasma concentration) after single doses of dapoxetine 30 mg and 60 mg are 297 and 498 ng/mL at 1.01 and 1.27 hours respectively. A high fat meal does reduce the Cm slightly, but it is insignificant. In fact, food doesn’t alter dapoxetine pharmacokinetics. Dapoxetine can be taken with or without food.[22]

Distribution

Dapoxetine is absorbed and distributed rapidly in the body. Greater than 99% of dapoxetine is bound to the plasma protein. The mean steady state volume is 162L. Its initial half-life is 1.31hours (30 mg dose) and 1.42 hours (60 mg dose,) and its terminal half life is 18.7 hours (30 mg dose) and 21.9 hours (60 mg dose).[23]

Metabolism

Dapoxetine is metabolized extensively in the liver and kidney by multiple enzymes such as CyP2D6, CyP3A4, and flavin monooxygenase 1 (FMO1). The major product at the end of the metabolic pathway is circulating dapoxetine N- oxide, which is a weak SSRI and contributes no clinical effect. The other products presented less than 3% in the plasma are desmethyldapoxetine and didesmethydapoxetine, which are equipotent to dapoxetine.[24]

Excretion

The metabolites of dapoxetine are eliminated rapidly in the urine with a terminal half-life of 18.7 and 21.9 hours for a single dose of 30 mg and 60 mg respectively.[17]

Safety and tolerability

Cardiovascular safety

The cardiovascular safety profile of dapoxetine has been studied extensively during the drug development. Phase I trials showed that dapoxetine had neither clinical significant electrocardiographic effects nor delayed repolarization effects, with dosing up to 4-fold greater than the maximum recommended dosage which is 60 mg. Phase III studies in men with PE showed a safety and well tolerate profile of dapoxetine with dosing of 30 and 60 mg. There is no cardiovascular adverse had been found.[25]

Neurocognitive safety

Studies of SSRIs in patients with major psychiatric disorders prove that SSRIs are potentially associated with certain neurocognitive adverse effects such as anxiety, akathisia, hypomania, changes in mood, or suicidal thought.[26][27] However, there is no study on the effects of SSRIs in men with PE. McMahon’s study in 2012 showed that dapoxetine has no effect on mood and is not associated with anxiety or suicidality.[28]

Withdrawal syndrome

The incidence of antidepressant discontinuation syndrome symptoms in men using dapoxetine to treat premature ejaculation has been described by reviewers as low and/or no different from the incidence of such symptoms in men withdrawn from placebo treatment.[29][29][30] The lack of chronic serotonergic stimulation with on–demand dapoxetine minimizes the potentiation action of serotonin at synaptic cleft, thus decreasing the risk of DESS.[31]

Synthesis

Synthesis of Dapoxetine

Currently very few methods are used to synthesize (S)-dapoxetine. This novel approach consists of only six steps in which three main steps are shown above. The initial reactant is trans-cinnamyl alcohol which is commercial available. Sharpless asymmetric epoxidation and Mitsunobu reaction have been used to produce expected (S)-dapoxetine. The overall yield is 35%. This method is considered a good choice compare to the known methods due to high yield and easily obtainable reactants.[32]

Regulatory history

Dapoxetine was created by Eli Lilly and in phase I clinical trial as an antidepressant. However, It never worked out well as a medication for the treatment of depression and was shelved for a while before subsequently developed to treat PE. In December 2003, Eli Lilly sold patent of dapoxeine to Pharmaceutical Product Development(PPD) for 65 million US dollars in cash. Eli Lilly may also receive royalties payment from PPD if the sale exceeds certain amount. ALZA is the current owner of dapoxetine. However, PPD will receive milestone payment and drug royalties from ALZA. If approved, dapoxetine will be marketed in the US by Ortho McNeil pharmaceutical, Inc. Ortho McNeil as well as Janssen-Ortho Inc, or Janssen-Cilag are all units of Johnson & Johnson. Dapoxetine is currently in phase III clinical trials, pending review by the Federal Drug Administration (FDA).[33]
Dapoxetine has been marketed and approved in more than 50 countries .[34] Dapoxetine has been approved in Italy, Spain, Mexico, South Korea, and New Zealand in 2009 and 2010; marketed in Sweden, Austria, Germany, Finland, Spain, Portugal, and Italy. It has also been approved in France, Malaysia, Philippines, Argentina, and Uruguay.[3]

See also

References

  1. ↑ 1.0 1.1 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ 3.0 3.1 3.2 3.3 Government, A. ( 2010). Australian Public Assessment Report for Dapoxetine (D. o. H. a. A. T. G. Administration, Trans.).
  4. ↑ 4.0 4.1 4.2 Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ http://www.menarini.com/news/News-Archive/20122/Morrisville-N.C.-and-Florence-Italy-May-14-2012-NEWS-RELEASE
  7. ↑ McMahon, C. G., McMahon, C. N., & Leow, L. J. (2006). New agents in the treatment of premature ejaculation. Neuropsychiatr Dis Treat, 2(4), 489-503.
  8. ↑ 8.0 8.1 Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Shabsigh, R., Broderick, G. A., Miloslavsky, M., & Bull, S. (2006). Dapoxetine has long-term efficacy in the treatment of premature ejaculation. Journal of Urology, 175(4), 297-298.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Contraindications. (2012) Retrieved 11/27, 2012, from http://www.drugs.com/enc/contraindications.html
  12. ↑ Buvat, J., Tesfaye, F., Rothman, M., Rivas, D. A., & Giuliano, F. (2009). Dapoxetine for the Treatment of Premature Ejaculation: Results from a Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial in 22 Countries. European Urology, 55(4), 957-968. doi: Doi 10.1016/J.Eururo.2009.01.025
  13. ↑ (French) (2013) « Éjaculation précoce : pas de dapoxétine » http://www.prescrire.org/fr/3/31/48533/0/NewsDetails.aspx
  14. ↑ McMahon, C. G., Kim, S. W., Park, N. C., Chang, C. P., Rivas, D., Tesfaye, F., . . . Aquilina, J. W. (2010). Treatment of Premature Ejaculation in the Asia-Pacific Region: Results from a Phase III Double-blind, Parallel-group Study of Dapoxetinejsm_1560256..268. J Sex Med, 7, 12.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Jhanjee, A., Kumar, P., Bhatia, M. S., & Srivastava, S. (2011). Dapoxetine-A Novel Drug for Premature Ejaculation. Delhi Psychiatry Journal, 14(1), 5.
  17. ↑ 17.0 17.1 Modi, N. B., Dresser, M., Desai, D., & Jazrawi, R. P. (2005). Dapoxetine for the treatment of premature ejaculation: Lack of interaction with ethanol. Journal of Urology, 173(4), 239-239.
  18. ↑ Gengo, P. J., View, M., Giuliano, F., McKenna, K. E., Chester, A., Lovenberg, T., . . . Gupta, S. K. (2005). Monoaminergic transporter binding and inhibition profile of dapoxetine, a medication for the treatment of premature ejaculation. Journal of Urology, 173(4), 239-239.
  19. ↑ Goldstein, I. (2003, 11/17/12). The Central Mechanisms of Sexual Function Retrieved 11/11/12, 2012, from http://www.bumc.bu.edu/sexualmedicine/publications/the-central-mechanisms-of-sexual-function/
  20. ↑ Giuliano, F., & Clement, P. (2005). Physiology of ejaculation: emphasis on serotonergic control. [Review]. Eur Urol, 48(3), 408-417. doi:10.1016/j.eururo.2005.05.017
  21. ↑ Clement, P., Bernabe, J., Gengo, P., Denys, P., Laurin, M., Alexandre, L., & Giuliano, F. (2007). Supraspinal site of action for the inhibition of ejaculatory reflex by dapoxetine. European Urology, 51(3), 825-832. doi: Doi 10.1016/J.Eururo.2006.10.011
  22. ↑ McMahon, C. G., Althof, S. E., Kaufman, J. M., Buvat, J., Levine, S. B., Aquilina, J. W., . . . Porst, H. (2011). Efficacy and safety of dapoxetine for the treatment of premature ejaculation: integrated analysis of results from five phase 3 trials. [Meta-Analysis Research Support, Non-U.S. Gov't]. J Sex Med, 8(2), 524-539. doi:10.1111/j.1743-6109.2010.02097.x PMID 21059176
  23. ↑ Dapoxetine: a guide to its use in premature ejaculation (D. T. Perspective, Trans.). (2011) (Vol. 27, pp. 1-4).
  24. ↑ Dresser, M., Lindert, K., Lin, D., Gidwani, S., Gupta, S. K., & Modi, N. B. (2004). Pharmacokinetics of single and multiple escalating doses of dapoxetine in healthy volunteers. Clinical Pharmacology & Therapeutics, 75(2), P32-P32. doi: Doi 10.1016/J.Clpt.2003.11.123
  25. ↑ Kowey, P. R., Mudumbi, R. V., Aquilina, J. W., & DiBattiste, P. M. (2011). Cardiovascular safety profile of dapoxetine during the premarketing evaluation. [Research Support, Non-U.S. Gov't]. Drugs R D, 11(1), 1-11. doi:10.2165/11587660-000000000-00000
  26. ↑ Khan, A., Khan, S., Kolts, R., & Brown, W. A. (2003). Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: Analysis of FDA reports. American Journal of Psychiatry, 160(4), 790-792. doi: Doi 10.1176/Appi.Ajp.160.4.790
  27. ↑ Tamam, L., & Ozpoyraz, N. (2002). Selective serotonin reuptake inhibitor discontinuation syndrome: A review. Advances in Therapy, 19(1), 17-26. doi: Doi 10.1007/Bf02850015
  28. ↑ McMahon, C. G. (2012). Dapoxetine: a new option in the medical management of premature ejaculation. Ther Adv Urol, 4(5), 233-251. doi:10.1177/1756287212453866
  29. ↑ 29.0 29.1 Lua error in package.lua at line 80: module 'strict' not found.
  30. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  31. ↑ Waldinger, M. D. (2007). Premature ejaculation — Definition and drug treatment. Drugs, 67(4), 547-568. doi: Doi 10.2165/00003495-200767040-00005.
  32. ↑ Venkatesan, K., & Srinivasan, K. V. (2008). A stereoselective synthesis of (S)-dapoxetine starting from trans-cinnamyl alcohol. arkivoc, 16, 9.
  33. ↑ Dapoxetine: LY 210448. (2005). [Review]. Drugs R D, 6(5), 307-311.
  34. ↑ Priligy® for Premature Ejaculation: Partnership with Menarini. (2012) Retrieved 11/17, 2012, from http://www.furiex.com/pipeline/marketed-products/priligy/
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