The Full Wiki

Desvenlafaxine: Wikis


Note: Many of our articles have direct quotes from sources you can cite, within the Wikipedia article! This article doesn't yet, but we're working on it! See more info or our list of citable articles.


From Wikipedia, the free encyclopedia

Systematic (IUPAC) name
CAS number 93413-62-8
ATC code N06AX23
PubChem 125017
Chemical data
Formula C16H25NO2 
Mol. mass 263.375 g/mol
Pharmacokinetic data
Bioavailability 80%
Protein binding Low (30%)
Metabolism CYP3A4, (CYP2D6 is not involved)
Half life 11 h
Excretion 45% excreted unchanged in urine
Therapeutic considerations
Licence data

US FDA:link

Pregnancy cat. C(US)
Legal status -only (US)
Routes Oral

Desvenlafaxine (Pristiq), also known as O-desmethylvenlafaxine, is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class developed and marketed by Wyeth (now part of Pfizer). Desvenlafaxine is a synthetic form of the major active metabolite of venlafaxine (Effexor, Efexor). It is being targeted as the first non-hormonal based treatment for menopause.[1]


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, where the drug is to be manufactured;
  • several post-marketing commitments;
  • 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]


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 indication. 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 "question and answer" format document.[5] The European Medicines Agency explained that

the [Committee for Medicinal Products for Human Use] had some concerns and was of the provisional opinion that Ellefore could not have been approved for the treatment of major depressive disorder [and] overall, the effectiveness of Ellefore had not been shown convincingly. In relation to its parent substance, venlafaxine, desvenlafaxine seemed to be less effective with no advantages in terms of safety and tolerability. Id.

The Withdrawal Assessment Report[6], which summarizes the data submitted by the applicant and the opinion of the reviewing agency further noted, at page 19, that

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 studies to produce more positive results, because doses are suited to individual needs rather than being forced, as they are, in the fixed dose studies. Furthermore, flexible dose study mirror to a greater extent the clinical situation. The applicant attributes the failure of the flexible dose studies to the high proportion of failed studies that is usually seen in depression studies but does not address 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 at p. 26 by noting that

"Desvenlafaxine is the main metabolite of venlafaxine. As venlafaxine is already approved for the treatment of [Major Depressive Disorder] and as venlafaxine is almost entirely transformed into desvenlafaxine, it would be expected that efficacy and safety of desvenlafaxine in the treatment of MDD would be very similar to that of venlafaxine. Id."


"Efficacy of desvenlafaxine would be expected based on the fact that venlafaxine is an antidepressant with established efficacy and the fact that desvenlafaxine is the active metabolite of venlafaxine. However the efficacy results are far from impressive. The evidence with respect to long-term efficacy is considered lacking. The dose used in the randomised withdrawal study does not support long-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 relapses that might be due to deteriorations that are not related to depression. Therefore, 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 succinate product as a treatment for vasomotor symptoms associated with menopause ("hot flashes") was withdrawn by Wyeth under similar circumstances in 2008. The proposed product contained the same active compound at the same dose as "Ellefore" but was this application was for "Pristiqs".

The Committee for Medicinal Products for Human Use found[7], that

"meaningful benefit of Pristiqs had not been demonstrated, when considered alongside the safety of the medicine in postmenopausal women, including side effects after stopping treatment."

Complete reporting from the European Medicines Agency regarding the withdrawal of Wyeth's application for Ellefore, including multiple language versions of the Q and A document, is freely available for public review. [8]

Complete reporting from the European Medicines Agency regarding the withdrawal of Wyeth's application for Pristiqs, including the Withdrawal Assessment Report as well as multiple language versions of the Q and A document, is also freely available for public review. [9]


Desvenlafaxine is a synthetic form of the isolated major active metabolite of venlafaxine, and is categorized as a serotonin-norepinephrine reuptake inhibitor (SNRI). It works by blocking the transporter "reuptake" proteins for key neurotransmitters affecting mood, thereby leaving more active neurotransmitters in the synapse. The neurotransmitters affected are serotonin (5-hydroxytryptamine) and norepinephrine (noradrenaline). It is approximately 10-fold more potent at inhibiting serotonin uptake than norepinephrine uptake. [10] When most normal metabolizers take venlafaxine - 70% of the benefit comes from venlafaxine being metabolized into desvenlafaxine so the effects are very similar.[11]

Side effects

Side-effect profiles were consistent for all three studies evaluated, with nausea being the most profound and prevalent. Although rates varied substantially from study to study, nausea was consistently the most common complaint (30-50% vs placebo 9-11%) and the most common reason for discontinuation.[12][13][14] Suicidal ideation was monitored and was determined to be significant in 1-2 patients in each study.[12][13][14] The most commonly observed adverse reactions in Pristiq-treated MDD patients in short-term fixed-dose studies (incidence >= 5% and at least twice the rate of placebo in the 50 or 100 mg dose groups) were nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, priapism, night terrors, anxiety, and delayed ejaculation.[15] These side-effect patterns are consistent with those of other SNRIs venlafaxine (Effexor) and duloxetine (Cymbalta, Yentreve).[16][17] Relative rates are not available, as there were no head-to-head studies.

Wyeth Pharmaceuticals also reports the following as potential side effects:[18] headache, sweating, diarrhea, hypertension, abnormal bleeding and/or bruising, glaucoma, increased cholesterol and triglyceride levels, low sodium levels in the blood, and seizures. Pristiq has also been implicated with higher rates of discontinuation syndrome than are seen with other SSRI and SNRI antidepressant medications due to its short half-life. Discontinuation syndrome side effects can be so severe as to be described as "intolerable" by former users, with some individuals unable to cease use due to extremely long-term withdrawal symptoms following cessation of use.[19]

Clinical efficacy

Pristiq tablets

Internal validity

In published phase III Trials, desvenlafaxine was compared only to placebo. In these trials, primary endpoints were powered to measure a reduction in depression (HAM-D17) scores[12][13][14] and not the standard response measure of ≥50% reduction in depression scores.[20]

Response scores were secondary measures which the studies may or may not have been powered to address. These trials showed dose-erratic reductions in HAM-D17 scores, reductions which undermined the results. Response rates varied from 43-60%, lower than most current antidepressants, which have a 60-70% response rate.[20] Remission rates of 23-37% for desvenlafaxine are also lower than those of other antidepressants, which have rates of 30-40%. Of course, generalizations of this nature cannot be made without careful statistical testing, and such testing was beyond the scope of this project.

Treatment duration for the three reviewed trials seemed inadequate, given the staging of Major Depressive Disorder (MDD). MDD acute phase lasts 12 weeks, while all three reviewed studies treated patients for only 8 weeks.[20][21] Although it 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 100mg and 400mg doses, but no efficacy in the 200mg dose. This group had a notably higher proportion of blacks and Hispanics than the other two active groups. The only other study which listed ethnic distributions had a notably higher proportion of blacks and Hispanics in the placebo group vs. the active group. Although kinetic studies have indicated there are no known active metabolites for desvenlafaxine, the possibility of ethnic variations in response cannot be ruled out.[22]


  1. ^ Wyeth (2007-07-24). "Wyeth Receives Approvable Letter From FDA for PRISTIQ for the Treatment of Vasomotor Symptoms Associated With Menopause". Press release. Retrieved 2007-07-31. 
  2. ^ "Wyeth Receives Approvable Letter From FDA For Pristiq (Desvenlafaxine Succinate) For The Treatment Of Major Depressive Disorder". Press release. 2007-01-23. Retrieved 2007-04-04. 
  3. ^ Wyeth (2008-02-29). "FDA Approves Pristiq". Press release. Retrieved 2008-02-29. 
  4. ^ Health Canada Notice of Compliance - Pristiq. February 4, 2009, retrieved on March 9, 2009.
  5. ^
  6. ^
  7. ^
  8. ^
  9. ^
  10. ^
  11. ^
  12. ^ a b c DeMartinis, NA; Yeung, PP; Entsuah, R; Manley, AL (2007). "A double-blind, placebo-controlled study of the efficacy and safety of desvenlafaxine succinate in the treatment of major depressive disorder". J Clin Psychiatry 68 (5): 677–88. 
  13. ^ a b c Liebowitz, MR; Yeung, PP; Entsuah, R.. "A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in adult outpatients with major depressive disorder". J Clin Psychiatry 68 (11): 1663–72. 
  14. ^ a b c Septien-Velez, L; Pitrosky, B; Padmanabhan, SK; Germain, JM; Tourian, KA (2007). "A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in the treatment of major depressive disorder". Int Clin Psychopharmacol 22 (6): 338–47. doi:10.1097/YIC.0b013e3281e2c84b. 
  15. ^ Pristiq Package Insert
  16. ^ Effexor XR package insert. Philadelphia, PA; Wyeth, 2/2008
  17. ^ Cymbalta package insert. Indianapolis, IN; Eli Lilly 12/2007
  18. ^ Pristiq Package Insert
  19. ^
  20. ^ 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 978-0781748452. 
  21. ^ Karasu, TB; Gelenberg, A; Meriam, A; Wang, P. Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Second Edition. 1. American Psychiatric Association. doi:10.1176/appi.books.9780890423363.48690. Retrieved 2008-04-22. 
  22. ^ Desvenlafaxine package insert. Philadelphia, PA; Wyeth; 2/2008

External links

Got something to say? Make a comment.
Your name
Your email address