Desvenlafaxine

Brand Name:                          Prestiq®

Generic Name:                       Desvenlafaxine

Manufacturer:                       Wyeth Pharmaceuticals

Drug Class:                              Antidepressant; Serotonin/Norepinephrine Reuptake Inhibitor ⁽¹⁾

Uses:                                        Labeled - Major depressive disorder ^(1) (2)

                                                Unlabeled – Menopausal vasomotor symptoms.

Mechanism of Action:           Desvenlafaxine succinate is a potent, selective serotonin and norepinephrine reuptake inhibitor (SNRI) that potentiates these neurotransmitters in the central nervous system. Desvenlafaxine is the major active metabolite of venlafaxine, which is also used to treat major depressive disorders ⁽¹⁾

Pharmacokinetics:

Metabolism:            Desvenlafaxine is primarily metabolized by the liver. Metabolism of desvenlafaxine is primarily via conjugation mediated by UGT isoforms. It also undergoes oxidative metabolism to a minor degree. CYP3A4 mediates the oxidative process, or N-demethylation, of desvenlafaxine. The CYP2D6 metabolic pathway is not involved. ⁽¹⁾

Elimination:             Approximately 45% of desvenlafaxine is excreted unchanged in urine at 72 hours after oral administration. Approximately 19% of the administered dose is excreted as the glucuronide metabolite and < 5% as the oxidative metabolite (N,O-didesmethylvenlafaxine) in urine. ⁽³⁾

Efficacy: ^{(4) (5) (6)}

     Citation:  DeMartinis NA, Yeung PP, Entsuah R, Manley A. 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 May;68(5):677-688.

     Study Design: This was a double-blind, placebo-controlled eight-week study of efficacy and safety of desvenlafaxine.

     Description of the study:  This was an 8-week study that compared DSM-IV defined major depressive disorder patients taking varying doses of desvenlafaxine (100mg/day, 200mg/day, 400mg/day) and placebo therapy. The number of patients in each group ranged from 113-118. The primary outcome measure for this study was change in the 17-item Hamilton Rating Scale for depression from baseline. Other outcome measures included changes in: clinical Global Impressions-Improvement Scale (CGI-I), Montgomery-Asberg Depression Rating Scale, and Clinical Global Impressions-Severity of Illness scale (CGI-S), rates of response and remission, and Visual Analog Scale-Pain Intensity overall score. Statistical significance was not determined of adverse effects. However, the most common were nausea, insomnia, somnolence, dry mouth , dizziness, sweating, nervousness, anorexia, constipation, asthenia, and abnormal ejaculation/orgasm. At 3 weeks, the mean HAM-D score for the 100mg dose was 14.8, significantly lower than the 16.8 with placebo. At 6 weeks, the mean HAM-D score with the 400 mg dose was significantly lower and remained so throughout the final on-therapy visit. The mean change from baseline in HAM-D total score was significantly lower than placebo at the final on-therapy visit in the 100mg and 400mg groups. The 200mg group did not show a significant difference. There were statistically significant increases in both systolic and diastolic BP from baseline in the treatment groups as well as a statistically significant weight loss observed in each of the desvenlafaxine groups.

     Limitations: This was only a 8 week study of desvenlafaxine. This clinical trial and analysis were sponsored by Wyeth — the same company that will be marketing this drug. The authors were also affiliated with the company through either grant support, a member on an advisory board, or employees of the company with stock. This study would only show short term effects of this drug. The authors admit that type II error might have been the reason the 200mg group did not show statistical significance in the primary outcome measure. Also the short duration may have contributed to the lack of statistical evidence that would have showed a dose-related effect. Unblinding was likely in this study because of a significant difference in adverse effects.

     Conclusion: This 8 week study showed that desvenlafaxine was effective in treating MDD. Treatment with the 100 mg dose was better tolerated and the authors stated that the adverse effects were similar to those that were seen with other SNRIs (venlafaxine) . Additional research would be required to show long-term safety and efficacy.

     Citation:  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 Nov;68(11):1663-1672.

     Study Design: This was an 8-week, multicenter, randomized, double-blind, placebo-controlled trial in adult outpatients to evaluate the safety and efficacy of desvenlafaxine.

     Description of the study: This was a multicenter phase 3 trial. Patients were randomized into three groups: placebo, 100mg/day desvenlafaxine or 200mg/day desvenlafaxine. Two-hundred forty-seven patients were randomized to a treatment group. The groups were run in a parallel design. Patients randomized to the 200mg group were on 100 mg/day for the first 14 days of treatment. The primary efficacy measure was the HAM-D score. Secondary outcome measures included the CGI-I scale, CGI-S,Montgomery-Asberg Depression Rating Scale, Covi Anxiety Scale, Sheehan Disability Scale, World Health Organization 5-item Well Being Index, and Visual Analog Scale for Pain Intensity scores. These scores were compared to baseline from readings/values obtained at days 14, 28, and 56. The intent-to-treat data handling method was used for the primary outcome measure comparing HAM-D score from baseline to final endpoint. Any dropouts were subject to the modified last point carried forward data handling method which they used. The results of the study showed the HAM-D total score in the desvenlafaxine group to be 14.1 and the placebo group to be 15.1. This difference was not statistically significant (p=.277). The only point at which there was a significant difference in favor of desvenlafaxine was at week 6. The most common adverse effects that were reported were nausea, dry mouth, constipation, anorexia, somnolence, and nervousness. The incidence of nausea was 30% in the desvenlafaxine group and 9% in the placebo group. Statistically significant increases in blood pressure were seen along with weight loss in the desvenlafaxine groups.

Limitations: This clinical trial and analysis were sponsored by Wyeth — the same company that will be marketing this drug. The authors were also affiliated with the company through either grant support, a member on an advisory board, or employees of the company. Unblinding was likely in this study because of a significant difference in adverse effects. Since this study used an intent-to-treat analysis, the fact that roughly 25% of the study groups dropped out of the study, this most likely skewed the results to show less effectiveness.

Conclusion: The results of this study do not serve to back up results of the previous phase 3 trial. These results were not shown to be significant in the primary outcome measure or in many of the secondary outcome measures. This may have been due to the lower mean baseline HAM-D score of 23.7 seen in this study. Lower starting scores have been associated with a lower frequency of significant results. Of note is the fact that no patient reported a severe side effect during the study. This study should be looked at in the context of the other studies on the safety and efficacy. While the safety profile is consistent with other studies, the efficacy portion was lacking and may have been due to the lower baseline HAM-D scores.

Citation:       Speroff L, Gass M, Constantine G, Olivier S. Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms. Obstetrics & Gynecology. 2008 Jan;111(1):77-87.

Study Design: This was a randomized, double-blind, placebo-controlled study.

Description of the study: This study enrolled 707 healthy, postmenopausal women that experienced 50 or more moderate to severe hot flushes per week. These participants were randomly assigned to one of five groups — 50, 100, 150, 200mg of desvenlafaxine or placebo. The duration of the study was 52 weeks. The primary outcome measures were change from baseline in average daily number of moderate to severe hot flushes and in daily hot flush severity score at weeks 4 and 12. A moderate hot flush was described as a warm sensation with sweating that does not disrupt activity. Any warm sensation that did not result in sweating was classified as mild. Of the 707, 620 women with an average of 11 qualifying hot flushes per day at baseline completed at least one on-therapy evaluation. Of those 620, 368 completed the entire 52-week study. The data handling method used during this study was intent-to-treat. Desvenlafaxine groups had significantly more discontinuations than the placebo groups had. Reductions from baseline to week 12 were 55%, 64%, 60%, and 60% for the 50-, 100-, 150-, and 200-mg groups. The reduction in the placebo group was 51%. The 100mg group produced the most significant result, showing the greatest decrease from baseline in the average daily number of moderate-to-severe hot flushes at both weeks 4 and 12 (-6.62 compared with -5.22 hot flushes; p=.013 and -7.23 compared with -5.50 hot flushes; p=.005). There was no significant difference from placebo for the 50 and 200 mg doses at either time point.  Patients did discontinue due to adverse events significantly more than placebo in the 150 and 200 mg groups. Adverse reactions with an incidence of 10% or more included: asthenia, dry mouth, nausea, dizziness, insomnia, and somnolence. Nausea was the most common of those in the desvenlafaxine groups.

Limitations: This study had conflicts-of-interest because the authors were associated with the company that is manufacturing desvenlafaxine – Wyeth Pharmaceuticals. This study also showed no clinically significant results as there was a great benefit (51%) seen in the placebo group alone. Lack of other studies to confirm the results that they showed.

Conclusion: This study does not confirm a need for desvenlafaxine to be a drug of choice over conventional hormonal treatments for hot flushes. The authors even state themselves that hormone therapy is the most effective therapy. The 100mg dose did show some efficacy, however other studies would need to be conducted to confirm this. Also, methods would need to be developed to better control tolerability of the drug, considering there was a very high dropout rate.

Contraindications: Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any excipients in the Pristiq formulation. ⁽³⁾ Concomitant use of monoamine oxidase inhibitors (MAOI) (MAOI use within the preceding 14 days before desvenlafaxine initiation or within 7 days after desvenlafaxine discontinuation); risk of potentially life-threatening serotonin syndrome. ⁽¹⁾ Finally the use of desvenlafaxine in children is contraindicated. ⁽²⁾

Precautions: ^(1) (2)

• Children, adolescents, and young adults up to age 24 years; suicidal ideation and behavior has been reported, particularly during the first few months of therapy or following changes in dosage
• Clinical worsening, suicidality, unusual changes in behavior has been reported in patients of all ages, especially during therapy initiation
• Abrupt withdrawal; serious discontinuation symptoms have been reported with abrupt desvenlafaxine withdrawal; monitoring recommended; reduce dose gradually if possible.
• Bipolar disorder; increased risk of precipitation of a mixed/manic episode; rule out disorder prior to initiating therapy.
• Cardiovascular, cerebrovascular, or lipid metabolism disorders, preexisting; increases in blood pressure and heart rate have been reported and may cause exacerbation of these underlying conditions
• Cholesterol and triglyceride elevations have been reported during controlled studies; consider serum lipid monitoring.
• Concomitant use of drugs that affect coagulation (e.g., NSAIDs, aspirin, warfarin); risk of bleeding, including life-threatening hemorrhage.
• Concomitant use of drugs containing desvenlafaxine or venlafaxine.
• Concomitant use of serotonergic drugs (SSRIs, serotonin-norepinephrine reuptake inhibitors, triptans); risk of serotonin syndrome; monitoring recommended if concurrent use is clinically warranted.
• Concomitant use with serotonin precursors, (e.g., tryptophan supplements); risk of serotonin syndrome, concurrent use not recommended.
• Glaucoma, narrow-angle (angle-closure glaucoma) or raised intraocular pressure, history of or at risk for; increased risk of mydriasis.
• Hypertension, uncontrolled; may exacerbate condition; regular monitoring recommended
• Hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) has occurred, greater risk in patients who are volume-depleted, elderly, or receiving concurrent diuretic therapy; discontinue if symptomatic hyponatremia occurs.
• Interstitial lung disease and eosinophilic pneumonia have been rarely reported
• Hepatic impairment, including cirrhosis; decreased venlafaxine clearance; lower dose may be required
• Mania, history of; risk of activation of mania/hypomania
• Medical diseases or conditions that could affect metabolism or hemodynamic responses (e.g., myocardial infarction, unstable heart disease)
• Renal impairment, moderate or severe or end-stage renal disease; decreased desvenlafaxine clearance; lower dose is required
• Seizures, history of; seizures have been reported in pre-marketing clinical trials involving desvenlafaxine
• Pregnancy category: C. Alternate agents should be used when available. Desvenlafaxine should only be used when benefits clearly outweigh the risks.

Adverse effects: ^(2) (1)

• Most common (10% and twice that of placebo in phase III trials): most considered moderate to mild in severity.
• abdominal pain
• asthenia
• anorexia
• constipation (9-14%)
• xerostomiam(11-25%)
• nausea/vomiting (22-41%) – greatest during the first week of treatment and then subsided.
• Dizziness (13-16%)
• Insomnia (9-15%)
• nervousness
• somnolence (drowsiness) (4-12%)
• sweating
• tremor
• vertigo
• ejaculation dysfunction
• diaphoresis – 10-21%
• headache (20-29%)
• Others:
• Cardiac
• Increased blood pressure was reported, thus it is recommended that pre-existing hypertension be corrected before starting this drug.
• Orthostatic hypotension (<2%), Tachycardia (<2%), Palpitations (1-3%), Increased LDL level (1-2%), Increased serum cholesterol (3-10%), Increased serum triglycerides (1-6%)
• GI
• Weight loss (1-2%)
• Hypersensitivity (<2%)
• Ophthalmic
• Blurred vision (3-4%), Mydraisis (2-6%)
• Psychological
• Anxiety (3-5%), Dream disorder (2-4%), Feeling nervous (2%), Irritability (2%), Mania (0.1%)
• Genitourinary
• Abnormal ejaculation (0-5%), Absence of ejaculation (0-2%), Erectile dysfunction (3-11%), Late ejaculation (1-7%), Orgasm incapacity (0-8%), Reduced libido (3-6%), Delay when starting to pass urine (<2%)
• Miscellaneous
• Yawning (1-4%), Fatigue (7-11%), Shivering (<4%)

Drug Interactions ⁽²⁾

• Other SNRIs: potential for additive adverse effects
• SSRIs: potential for additive adverse effects including the potential for serotonin syndrome
• Other CNS agents: information is not available on the safety of this combination
• Possible pharmacodynamics interaction with: melatonin, kava kava, Piper methysticum  or valerian, Valeriana officinalis
• Tramadol : possible increase risk of seizures and serotonin syndrome
• Pentazocine, tryptophan, methylphenidate, metoclopramide, dexmethylphenidate : increase risk of serotonin syndrome

Dosage and Administration: ⁽³⁾

            Major Depressive Disorder

            Recommended dose: 50 mg once daily, with or without food. It should be administered at about the same time each day. The tablet should be taken whole and not chewed or crushed. When discontinuing therapy, the dose should be tapered.

            Extended treatment has not been studied and the maintenance dose of 50mg should be periodically reevaluated by the physician.

Discontinuing: If discontinuing desvenlafaxine, the manufacturer recommends giving a dose of 50mg less frequently to titrate the patient off of the medication.

Max dose: Studies were conducted with dosages of 50-400mg/day, however no added benefit was seen at doses higher than 50mg/day and there was an increase in adverse effects at higher dosages.

            Pregnancy

            When treating pregnant women in the third trimester the physician may consider tapering the desvenlafaxine.

            Renal impairment

            Severe renal impairment: (CrCl <30) : 50mg given every other day.

            Hepatic impairment

            No dosage adjustment is necessary, however dosages >100mg/day are not recommended.

Lactation: (1) Desvenlafaxine is excreted in human milk. Infant risk cannot be ruled out.

Conclusion: All of the studies that have been conducted with desvenlafaxine have been against a placebo control. To determine real world benefit of this medication, a comparable study between desvenlafaxine and venlafaxine should be conducted. Without proof of added benefit of desvenlafaxine over venlafaxine, through a cost/benefit analysis, it is difficult to say that this drug should replace venlafaxine in treatment decisions.

References:

1. Desvenlafaxine. Greenwood Village, Colorado : s.n., Mar 31, 2008. DRUGDEX Drug Point System.

2. Desvenlafaxine. Clinical Pharmacology. [Online] March 4, 2008. [Cited: March 31, 2008.] www.clinicalpharmacology.com.

3. Wyeth Pharmaceuticals. Prestiq Product Information. [Online] February 2008. [Cited: March 31, 2008.] http://www.wyeth.com/content/ShowLabeling.asp?id=497.

4. A double-blind, placebo-controlled study of the efficacy and safety of desvenlafaxine succinate in the treatment of major depressive disorder. DeMartinis NA, Yeung PP, Entsuah R, Manley A. 5, 2007, J Clin Psychiatry, Vol. 68, pp. 677-688.

5. A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in adult outpatients with major depressive disorder. Liebowitz MR, Yeung PP, Entsuah R. 11, Nov 2007, J Clin Psychiatry, Vol. 68, pp. 1663-1672.

6. Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms. Speroff L, Gass M, Constantine G, Olivier S. 1, Jan 2008, Obstetrics & Gynecology, Vol. 111, pp. 77-87.

Prepared by: Richard Campbell, Doctor of Pharmacy Candidate