Desvenlafaxine
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Desvenlafaxine
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| Systematic (IUPAC) name | |
| 4-[2-dimethylamino-1-(1-hydroxycyclohexyl) ethyl]phenol |
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| Identifiers | |
| CAS number | |
| ATC code | N06 |
| PubChem | |
| Chemical data | |
| Formula | C16H25NO2 |
| Mol. mass | 263.375 g/mol |
| Synonyms | O-desmethylvenlafaxine Norvenlafaxine |
| Pharmacokinetic data | |
| Bioavailability | C |
| Protein binding | high >90% |
| Metabolism | CYP1A2 and CYP 2D6 |
| Half life | 12 hours |
| Excretion | ? |
| Therapeutic considerations | |
| Licence data |
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| Pregnancy cat. |
? |
| Legal status | |
| Routes | Oral |
Desvenlafaxine succinate, marketed under the name Pristiq, is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class from Wyeth. It is a metabolite of venlafaxine (Effexor). Pristiq is also being targeted as the first non-hormonal based treatment for menopause.[1]
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[edit] Approval status
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 will be available in US pharmacies in May 2008.[3]
[edit] Executive Summary
Desvenlafaxine succinate extended release tablets, (hereafter referred to as desvenlafaxine), is a norepinephrine/serotonin reuptake inhibitor. Desvenlafaxine is a synthetic form of a known active metabolite of venlafaxine.
[edit] Current Standard of Therapy
For Major Depressive Disorder (MDD), there is no single, gold standard treatment modality. The approach to treatment depends on patient preference, compliance, and practitioner assessment. For mild to severe depression without psychoses or suicidal ideation, psychotherapy, medications, or both are first line treatments. The specific pharmacotherapy choice depends on patient’s past experience, acceptance, and specific complaints (insomnia, somnolence, pain, etc.).5 Some common first line pharmacological agents include SSRI, TCAs, DNRTI, SNRI.5
Objective assessment of patient’s initial status and progress involved one of several surveys including AMSIT Mental Status Exam, Hamilton Depression Scale (HAM-D17), and a Depression Inventory. Adequate response to therapy is defined as a >=50% reduction in Depression scores. Stages of Major Depressive Episode Treatment include Acute (12wks), Continuation (4-9 months) and Maintenance Phases. Typical therapy lasts not only for the acute phase, but is maintained for an additional 16-36 weeks during the continuation phase. Only after the continuation phase is the discontinuation of therapy considered. 5,6
[edit] 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 discontinuation2,3,4. Suicidal ideation was monitored and was determined to be significant in 1-2 patients in each study2,3,4. Other common side effects were dry mouth, sweating, dizziness, fatigue, constipation, anorexia, and sexual dysfunction. These side effect patterns are consistent with other SNRIs venlafaxine and cymbalta.7,8 Relative rates are not available, as there were no head to head studies.
[edit] Clinical Efficacy
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) scores2,3,4, not the standard response measure of >=50% reduction in depression scores6.
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, which undermined the results. Response rates varied from 43-60%, which is lower than most current antidepressants, which have a 60-70% response rate.6 Remission rates of 23-37% for desvenlafaxine are also lower than other antidepressant rates of 30-40%. Of course, generalizations of this nature cannot be made without careful statistical testing, which was beyond the scope of this project.
Treatment duration for the three reviewed trials seemed inadequate, given the staging of MDD. MDD acute phase lasts 12 weeks, while all three reviewed studies only treated patients for 8 weeks.5,6 Although it may not be practical or required to continue therapy for an entire year during a study, it is difficult to determine if desvenlafaxine is an appropriate therapy without these data.
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 dose2. 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.1
[edit] References
1 Desvenlafaxine package insert. Philadelphia, PA; Wyeth; 2/2008
2 DeMartinis NA, Yeung PP, Entsuah R, Manley AL.A double-blind, placebo-controlled study of the efficacy and safety of desvenlafaxine succinate in the treatment of major depressive disorder. J Clin Psychiatry. 2007;68(5):677-88.
3 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. 2007;68(11):1663-72
4 Septien-Velez L, Pitrosky B, Padmanabhan SK, Germain JM, Tourian KA. A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in the treatment of major depressive disorder. Int Clin Psychopharmacol. 2007;22(6):338-47
5 Karasu, TB, Gelenberg, A, Meriam, A, Wang, P. Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Second Edition.. American Psychiatric Association. Retrieved from http://www.psychiatryonline.com/content.aspx?aid=48690 on 04/22/08
6 Applied Therapeutics: The Clinical Use of Drugs 8th ed. Koda-Kimble, MA, Young, LY, Kradjan, WA, Guglielmo, BJ, Alldredge, BK, Corelli, RL. Lippincott Williams & Wilkins 2005
7 Effexor XR package insert. Philadelphia, PA; Wyeth, 2/2008
8 Cymbalta package insert. Indianapolis, IN; Eli Lilly 12/2007
9 Comparison of commonly used antidepressants. Pharmacist’s Letter/Prescriber’s Letter 2008;24(5):240509. Retrieved from http://www.pharmacistsletter.com/(S(ok22th45y25x0145y35kdi31))/pl/detaildocuments/240509.pdf?cs=STUDENT&s=PL on 04/24/2008
- ^ (July 24,2007). "Wyeth Receives Approvable Letter From FDA for PRISTIQ for the Treatment of Vasomotor Symptoms Associated With Menopause". Press release.
- ^ (January 23, 2007). "Wyeth Receives Approvable Letter From FDA For Pristiq (Desvenlafaxine Succinate) For The Treatment Of Major Depressive Disorder". Press release. Retrieved on 2007-04-04.
- ^ Wyeth (February 29, 2008). "FDA Approves Pristiq". Press release. Retrieved on 2008-02-29.
[edit] External links
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