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] Desvenlafaxine From Wikipedia, the free encyclopedia Jump to: navigation, search Desvenlafaxine Systematic (IUPAC) name 4-[2-dimethylamino-1-(1-hydroxycyclohexyl) ethyl]phenol Clinical data AHFS/Drugs.com monograph MedlinePlus a608022 Licence data US FDA:link Pregnancy cat. C (US) Legal status ?-only (US) Routes Oral Pharmacokinetic data Bioavailability 80% Protein binding Low (30%) Metabolism CYP3A4, (CYP2D6 is not involved) Half-life 11 h Excretion 45% excreted unchanged in urine Identifiers CAS number 93413-62-8 Yes ATC code N06AX23 PubChem CID 125017 DrugBank DB06700 ChemSpider 111300 Yes UNII NG99554ANW Yes KEGG D07793 Yes ChEMBL CHEMBL1118 Yes Chemical data Formula C16H25NO2 Mol. mass 263.38 g/mol SMILES[show] InChI[show] Yes (what is this?) (verify) Desvenlafaxine (brand name: Pristiq), also known as O-desmethylvenlafaxine, is a n antidepressant of the serotonin-norepinephrine reuptake inhibitor class develo ped and marketed by Wyeth (now part of Pfizer). Desvenlafaxine is a synthetic fo rm of the major active metabolite of venlafaxine (sold under the brand names Eff exor and Efexor). It is being targeted as the first non-hormonal based treatment for menopause.[1] Contents 1 Approval status 1.1 United States 1.2 Canada 1.3 European Union 2 Pharmacology 3 Side effects 4 Clinical efficacy 4.1 Internal validity 4.2 External validity 5 References 6 External links Approval status

United States Wyeth announced on 23 January 2007 that it received an "approvable" letter from the Food and Drug Administration for desvenlafaxine. Final approval to sell the drug was contingent on a number of things, including: a satisfactory FDA inspection of Wyeth's Guayama, Puerto Rico facility, wher e the drug is to be manufactured; several postmarketing surveillance commitments, and follow-up studies on low -dose use, relapse, and use in children; clarity by Wyeth around the company's product education plan for physicians and patients; approval of desvenlafaxine's proprietary name, Pristiq.[2] The FDA approved the drug for antidepressant use in February 2008, and was to be available in US pharmacies in May 2008.[3] Canada On February 4, 2009, Health Canada approved use of desvenlafaxine for treatment of depression in Canada.[4] Pristiq is now available in Canadian pharmacies. European Union In the European Union desvenlafaxine succinate has not been approved for any ind ication. In 2008, Wyeth withdrew its application for Ellefore, the product under review for treatment of major depressive disorder. The reasons given by Wyeth, and comments regarding the findings of the reviewing agency are provided in a "q uestion and answer" format document.[5] The European Medicines Agency explained that the [Committee for Medicinal Products for Human Use] had some concerns and w as of the provisional opinion that Ellefore could not have been approved for the treatment of major depressive disorder [and] overall, the effectiveness of Elle fore had not been shown convincingly. In relation to its parent substance, venla faxine, desvenlafaxine seemed to be less effective with no advantages in terms o f safety and tolerability. Id. The Withdrawal Assessment Report,[5] which summarizes the data submitted by the applicant and the opinion of the reviewing agency further noted, at page 19, tha t It is curious that the results of all flexible dose studies show a small and non-significant difference from placebo. One would expect the flexible dose stu dies to produce more positive results, because doses are suited to individual ne eds rather than being forced, as they are, in the fixed dose studies. Furthermor e, flexible dose study mirror to a greater extent the clinical situation. The ap plicant attributes the failure of the flexible dose studies to the high proporti on of failed studies that is usually seen in depression studies but does not add ress the systematic nature of the difference in study results between the fixed and the flexible dose studies.Id. The Benefit Risk Assessment section of the Withdrawal Assessment Report begins a t p. 26 by noting that "Desvenlafaxine is the main metabolite of venlafaxine. As venlafaxine is alr eady approved for the treatment of [Major Depressive Disorder] and as venlafaxin e is almost entirely transformed into desvenlafaxine, it would be expected that efficacy and safety of desvenlafaxine in the treatment of MDD would be very simi lar to that of venlafaxine. Id." Furthermore,

"Efficacy of desvenlafaxine would be expected based on the fact that venlafa xine is an antidepressant with established efficacy and the fact that desvenlafa xine is the active metabolite of venlafaxine. However the efficacy results are f ar from impressive. The evidence with respect to long-term efficacy is considere d lacking. The dose used in the randomised withdrawal study does not support lon g-term efficacy in the doses that are indicated in the SPC (50 mg). In addition, the definition of relapse that was used in the long-term study allows for relap ses that might be due to deteriorations that are not related to depression. Ther efore, the data of the long-term study need to be re-analysed with an acceptable definition of relapse."Id. Similarly, a parallel application for approval of another desvenalfaxine succina te product as a treatment for vasomotor symptoms associated with menopause ("hot flashes") was withdrawn by Wyeth under similar circumstances in 2008. The propo sed product contained the same active compound at the same dose as "Ellefore" bu t this application was for "Pristiq". The Committee for Medicinal Products for Human Use found,[6] that "meaningful benefit of Pristiqs had not been demonstrated, when considered a longside the safety of the medicine in postmenopausal women, including side effe cts after stopping treatment." Complete reporting from the European Medicines Agency regarding the withdrawal o f Wyeth's application for Ellefore, including multiple language versions of the Q and A document, is freely available for public review.[7] Complete reporting from the European Medicines Agency regarding the withdrawal o f Wyeth's application for Pristiqs, including the Withdrawal Assessment Report a s well as multiple language versions of the Q and A document, is also freely ava ilable for public review.[8] Pharmacology Desvenlafaxine is a synthetic form of the isolated major active metabolite of ve nlafaxine, and is categorized as a serotonin-norepinephrine reuptake inhibitor ( SNRI). It works by blocking the transporter "reuptake" proteins for key neurotra nsmitters affecting mood, thereby leaving more active neurotransmitters in the s ynapse. The neurotransmitters affected are serotonin (5-hydroxytryptamine) and n orepinephrine (noradrenaline). It is approximately 10 times more potent at inhib iting serotonin uptake than norepinephrine uptake.[9] When most normal metaboliz ers take venlafaxine - 70% of the benefit comes from venlafaxine being metaboliz ed into desvenlafaxine so the effects are very similar.Citation needed Side effects Side-effect profiles were consistent for all three studies evaluated, with nause a being the most profound and prevalent. Although rates varied substantially fro m study to study, nausea was consistently the most common complaint (30-50% vs p lacebo 9-11%) and the most common reason for discontinuation.[10][11][12] Suicid al ideation was monitored and was determined to be significant in 1-2 patients i n each study.[10][11][12] The most commonly observed adverse reactions in Pristi q-treated MDD patients in short-term fixed-dose studies (incidence = 5% and at l east twice the rate of placebo in the 50 or 100 mg dose groups) were nausea, diz ziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, p riapism, night terrors, anxiety, and delayed ejaculation.[13] These side-effect patterns are consistent with those of other SNRIs venlafaxine (Effexor) and dulo xetine (Cymbalta, Yentreve).[14][15] Relative rates are not available, as there were no head-to-head studies. Wyeth Pharmaceuticals also reports the following as potential side effects:[13]

headache, sweating, diarrhea, hypertension, abnormal bleeding and/or bruising, g laucoma, increased cholesterol and triglyceride levels, low sodium levels in the blood, and seizures. Increases in blood pressure along with small increases in heart rate were noted in clinical trials of Pristiq, so patients with pre-existing blood pressure prob lems or cardiovascular diseases should always make sure that their doctor is awa re of prior heart or blood pressure conditions. Blood pressure should be regular ly checked in those taking Pristiq.[16] Although Pristiq did not increase mental or physical impairment in individuals c onsuming normal amounts of alcohol in a clinical study, it is generally a good i dea to avoid alcohol consumption while taking Pristiq.[17] Pristiq has also been implicated with higher rates of SSRI discontinuation syndr ome than are seen with other SSRI and SNRI antidepressant medications due to its relatively short half-life. Discontinuation syndrome side effects can be so sev ere as to be described as "intolerable" by former users, with some individuals u nable to cease use due to extremely long-term withdrawal symptoms following cess ation of use.[18] Discontinuation symptoms can include dizziness, nausea, headac he, irritability, insomnia, anxiety, fatigue, diarrhea, abnormal dreams, hyperhy drosis and paresthesia (described as "electric shock" sensations).[19] This drug carries the following FDA Black Box Label: WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-t erm studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of PRISTIQ or any other antidepressant in a child, ado lescent, or young adult must balance this risk with the clinical need. Short-ter m studies did not show an increase in the risk of suicidality with antidepressan ts compared to placebo in adults beyond age 24; there was a reduction in risk wi th antidepressants compared to placebo in adults aged 65 and older. Depression a nd certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant t herapy should be monitored appropriately and observed closely for clinical worse ning, suicidality, or unusual changes in behavior. Families and caregivers shoul d be advised of the need for close observation and communication with the prescr iber. PRISTIQ is not approved for use in pediatric patients.[20] Clinical efficacy Pristiq 50 mg tablets (US) Internal validity In published phase 3 trials, desvenlafaxine was compared only to placebo. In the se trials, primary endpoints were powered to measure a reduction in depression ( HAM-D17) scores[10][11][12] and not the standard response measure of =50% reduct ion in depression scores.[21] Response scores were secondary measures which the studies may or may not have be en powered to address. These trials showed dose-erratic reductions in HAM-D17 sc ores, reductions which undermined the results. Response rates varied from 43-60% , lower than most current antidepressants, which have a 60-70% response rate.[21 ] Remission rates of 23-37% for desvenlafaxine are also lower than those of othe r antidepressants, which have rates of 30-40%. Of course, generalizations of thi s nature cannot be made without careful statistical testing, and such testing wa s beyond the scope of this project. Treatment duration for the three reviewed trials seemed inadequate, given the st

aging of Major Depressive Disorder (MDD). MDD acute phase lasts 12 weeks, while all three reviewed studies treated patients for only 8 weeks.[21][22] Although i t may not be practical or required to conduct a study of continuing therapy for an entire year, without the data that would result it is difficult to determine whether or not desvenlafaxine is an appropriate therapy. External validity There may be some differences in efficacy across ethnic backgrounds. One study, with three different dose strengths, showed efficacy in the 100 mg and 400 mg do ses, but no efficacy in the 200 mg dose. This group had a notably higher proport ion of blacks and Hispanics than the other two active groups. The only other stu dy which listed ethnic distributions had a notably higher proportion of blacks a nd Hispanics in the placebo group vs. the active group. Although kinetic studies have indicated there are no known active metabolites for desvenlafaxine, the po ssibility of ethnic variations in response cannot be ruled out.[23] This stateme nt on ethnic backgrounds is solely based on an interpretation of the medication' s package insert. References ^ "Wyeth Receives Approvable Letter From FDA for PRISTIQ for the Treatment o f Vasomotor Symptoms Associated With Menopause" (Press release). Wyeth. 2007-0724. Retrieved 2007-07-31. ^ "Wyeth Receives Approvable Letter From FDA For Pristiq (Desvenlafaxine Suc cinate) For The Treatment Of Major Depressive Disorder" (Press release). 2007-01 -23. Retrieved 2007-04-04. ^ "FDA Approves Pristiq" (Press release). Wyeth. 2008-02-29. Retrieved 200802-29. ^ Health Canada Notice of Compliance - Pristiq. February 4, 2009, retrieved on March 9, 2009. ^ a b http://www.ema.europa.eu/humandocs/PDFs/EPAR/ellefore/H-932-WQ&A-en.pd f ^ http://www.ema.europa.eu/humandocs/PDFs/EPAR/pristiqs/12542108en.pdf ^ http://www.ema.europa.eu/humandocs/Humans/EPAR/ellefore/elleforeW.htm ^ http://www.ema.europa.eu/humandocs/Humans/EPAR/pristiqs/pristiqsW.htm ^ http://jpet.aspetjournals.org/cgi/content/full/318/2/657 ^ a b c DeMartinis, NA; Yeung, PP; Entsuah, R; Manley, AL (2007). "A doubleblind, placebo-controlled study of the efficacy and safety of desvenlafaxine suc cinate in the treatment of major depressive disorder". J Clin Psychiatry 68 (5): 677 88. doi:10.4088/JCP.v68n0504. PMID 17503976. ^ a b c Liebowitz, MR; Yeung, PP; Entsuah, R.. "A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in adult outpatients with m ajor depressive disorder". J Clin Psychiatry 68 (11): 1663 72. doi:10.4088/JCP.v68 n1105. PMID 18052559. ^ a b c Septien-Velez, L; Pitrosky, B; Padmanabhan, SK; Germain, JM; Tourian , KA (2007). "A randomized, double-blind, placebo-controlled trial of desvenlafa xine succinate in the treatment of major depressive disorder". Int Clin Psychoph armacol 22 (6): 338 47. doi:10.1097/YIC.0b013e3281e2c84b. PMID 17917552. ^ a b Pristiq Package Insert ^ Effexor XR package insert. Philadelphia, PA; Wyeth, 2/2008 ^ Cymbalta package insert. Indianapolis, IN; Eli Lilly 12/2007 ^ Prisiq extended release package insert. Wyeth Pharmaceuticals ^ Pristiq extended release package insert. Wyeth Pharmaceuticals ^ http://www.crazymeds.us/effexor.html ^ Effexor XR package insert. Wyeth Pharmaceuticals ^ http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021992s021lbl.pdf ^ a b c Koda-Kimble, Mary Anne; Young, Lloyd Lee; Kradjan Wayne A, Guglielmo , B. Joseph; Alldredge, Brian K. (June 2004). Applied Therapeutics: The Clinical Use of Drugs. Lippincott Williams & Wilkins. ISBN 978-0-7817-4845-2. ^ Karasu, TB; Gelenberg, A; Meriam, A; Wang, P. "Practice Guideline for the Treatment of Patients With Major Depressive Disorder Second Edition". Practice G

uideline for the Treatment of Patients With Major Depressive Disorder, Second Ed ition. American Psychiatric Association. doi:10.1176/appi.books.9780890423363.48 690. ISBN 0-89042-336-9. Retrieved 2008-04-22. ^ Desvenlafaxine package insert. Philadelphia, PA; Wyeth; 2/2008 External links Pfizer's Pristiq site for U.S. residents [show] v t e Antidepressants (N06A) [show] v t e Serotonergics View page ratings Rate this page What's this? Trustworthy Objective Complete Well-written I am highly knowledgeable about this topic (optional) Categories: Alcohols Phenethylamines Phenols Serotonin-norepinephrine reuptake inhibitors Navigation menu Create account Log in Article Talk Read Edit View history Main page Contents Featured content Current events Random article Donate to Wikipedia Interaction

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