Desvenlafaxine

Desvenlafaxine (brand name: 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 (sold under the brand names Effexor and Efexor). It is being targeted as the first non-hormonal based treatment for menopause.

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.

The FDA approved the drug for antidepressant use in February 2008, and was to be available in US pharmacies in May 2008.

Canada
On February 4, 2009, Health Canada approved use of desvenlafaxine for treatment of depression in Canada. 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. 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, 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." Furthermore, "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 this application was for "Pristiq".

The Committee for Medicinal Products for Human Use found, 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.

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.

Pharmacology
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 times more potent at inhibiting serotonin uptake than norepinephrine uptake. When most normal metabolizers take venlafaxine - 70% of the benefit comes from venlafaxine being metabolized into desvenlafaxine so the effects are very similar. Desvenlafaxine is related to the atypical opioids Tramadol(Ultram) and Tapentadol(Nucynta).

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. Suicidal ideation was monitored and was determined to be significant in 1-2 patients in each study. 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. These side-effect patterns are consistent with those of other SNRIs venlafaxine (Effexor) and duloxetine (Cymbalta, Yentreve). Relative rates are not available, as there were no head-to-head studies.

Wyeth Pharmaceuticals also reports the following as potential side effects: headache, sweating, diarrhea, hypertension, abnormal bleeding and/or bruising, glaucoma, 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 problems or cardiovascular diseases should always make sure that their doctor is aware of prior heart or blood pressure conditions. Blood pressure should be regularly checked in those taking Pristiq.

Although Pristiq did not increase mental or physical impairment in individuals consuming normal amounts of alcohol in a clinical study, it is generally a good idea to avoid alcohol consumption while taking Pristiq.

Pristiq has also been implicated with higher rates of discontinuation syndrome than are seen with other SSRI and SNRI antidepressant medications due to its relatively 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. Discontinuation symptoms can include dizziness, nausea, headache, irritability, insomnia, anxiety, fatigue, diarrhea, abnormal dreams, hyperhydrosis and paresthesia (described as "electric shock" sensations).

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-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of PRISTIQ® or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. PRISTIQ is not approved for use in pediatric patients.

Internal validity
In published phase 3 trials, desvenlafaxine was compared only to placebo. In these trials, primary endpoints were powered to measure a reduction in depression (HAM-D17) scores  and not the standard response measure of ≥50% reduction in depression scores.

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. 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. 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. This statement on ethnic backgrounds is solely based on an interpretation of the medication's package insert.