ࡱ>  bjbjT~T~ 4v66 ---8e1-Z(% E QjZlZlZlZlZlZlZ\K_lZY!!YYlZ4Z%%%YvjZ%YjZ%% QXVύc-SJVZZ0ZTB_ _XVXV&_~VYY%YYYYYlZlZ#DYYYZYYYY_YYYYYYYYY : National Drug Monograph Desvenlafaxine succinate (Pristiq) September 2010 VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current. Executive Summary: Desvenlafaxine is a serotonin-norepinephrine reuptake inhibitor and an active metabolite of venlafaxine. FDA label indications: Major depressive disorder Pharmacokinetics: Primarily eliminated by the kidney, 45% unchanged. Minimal metabolism by the cytochrome 450 system. Dose: Oral: Initial 50 mg per day; Maximum 100 mg per day. Adjust dose when CrCl <50 mL/min. Efficacy: Desvenlafaxine has demonstrated efficacy superior to placebo in pateints with major depressive disorder although this has not been a consistent finding in all studys with doses ranging from 50 mg to 400 mg per day. There are no relapse prevention trials with the label doses of 50 mg and 100 mg per day. Desvenlafaxine 100 mg and 150 mg per day has demonstrated superior efficacy in treating vasomotor symptoms compared to placebo reducing the frequency and severity of hot flashes. Adverse drug events: Desvenlafaxines adverse event profile is similar to that of other serotonin-norepinephrine reuptake inhibitors with nausea, dry mouth, constipation, fatigue, somnolence, and sweating most commonly reported. Desvenlafaxine can also increase a patients systolic and diastolic blood pressure, pulse rate, and serum lipids. Discontinuation withdrawal symptoms have been reported and a dose taper may be needed to minimize these symptoms. Warnings: Desvenlafaxine has many of the same warnings and precautions as other antidepressants regarding increased suicidal thinking and behavior in children, adolescents, and young adults <24 years; serotonin syndrome; and concurrent use with monoamine oxidase inhibitors. Drug interactions: Interactions involving the cytochrome P450 system, in particular the CYP2D6, are less a concern with desvenlafaxine. Desvenlafaxine is available in 50 mg and 100 mg extended-release tablets at a cost of $2.44 per tablet (day). Introduction Desvenlafaxine is the principle active metabolite of venlafaxine and like its parent is classified as a serotonin-norepinephrine reuptake inhibitor (SNRI). Desvenlafaxine is not the first active metabolite of another antidepressant to be marketed. The secondary amines, nortriptyline and desipramine are the active metabolites of the tertiary amines amitriptyline and impramine, respectively, and offer several advantages related to tolerability compared to their parent compounds. The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy, cost, and other pharmaceutical issues that would be relevant to evaluating desvenlafaxine for possible addition to the VA National Formulary; (2) define its role in therapy relevant to its indication and possible off-label uses; and (3) identify parameters for its rational use in the VA. Pharmacology/Pharmacokinetics1, 2 Desvenlafaxine inhibits the reuptake of serotonin and norepinephrine in the central nervous system. Its affinity for serotonin receptors is less than venlafaxine (Ki = 40.2 and 13.5 nmol/L, respectively), while its affinity for norepinephrine is greater than venlafaxines (Ki = 558.7 and 1,668.0 nmol/L, respectively). In vitro, desvenlafaxine has not demonstrated significant affinity for muscarinic-cholinergic, histamine1, or alpha1-adrenergic receptors. Desvenlafaxine reuptake inhibition of serotonin and norepinephrine is not dose related. Venlafaxines reuptake inhibition of serotonin occurs at all doses, while its inhibition of norepinephrine reuptake is not significant until doses exceed150 225 mg/day. Table 1 displays the affinity constants for select antidepressants. Table 1 Receptor binding affinity constants (Ki, nmol/L) for serotonin and norepinephrine for selected antidepressants AntidepressantNorepinephrineSerotoninDesvenlafaxine558.740.2Duloxetine5.60.8Venlafaxine166813.5Desipramine13.775.5Fluoxetine5991.1Paroxetine45.00.125Citalopram61901.6Sertraline7140.293Ki inhibitory constant; the smaller the constant the greater the affinity/inhibition The pharmacokinetic parameters of desvenlafaxine and venlafaxine are shown in Table 2. Desvenlafaxines bioavailability is less that venlafaxine and both have low protein binding. The cytochrome P450 system has minimal role in desvenlafaxines metabolism as conjugation by UGT (glucuronosyltransferases) isoforms serves its primary metabolic pathway. The CYP 3A4 isozyme contributes to desvenlafaxines metabolism to N, O-didesmethylvenlafaxine and a hydroxylated metabolite. Desvenlafaxine is eliminated by the kidney with ~45% excreted unchanged in 72 hours, ~19% as glucuronide metabolites, and <5% as an oxidative metabolite. Individuals possessing a combination of two null alleles for the CYP2D6 isozyme and classified as poor metabolizers (PM) did not demonstrate any statistical differences in desvenlafaxines pharmacokinetic parameters Cmax, tmax, AUC, oral clearance, or elimination half-life compared to normal extensive metabolizers (EM) after a single oral 100 mg dose of desvenlafaxine. In contrast, PM had mean AUCs and Cmax of venlafaxine that were 149% and 331% greater than in EMs following a single oral 75 mg dose of venlafaxine ER. Correspondingly, the Cmax and AUC for desvenlafaxine after venlafaxine administration were 78% and 73% lower in PMs compared with EMs, respectively. Table 2 Pharmacokinetic parameters of desvenlafaxine and venlafaxine ParameterDesvenlafaxineVenlafaxineBioavailability80.5%92%-100%Protein Binding30%30%Metabolism Conjugation via UGT; CYP3A4 minorCYP2D6, 3A4, 2C9, 2C19 Active metabolite: o-desmethylvenlafaxine (OVD), N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine EliminationRenalRenal: 5% unchanged, 30% OVD, 26% conjugates, 27% inactive metabolitesHalf-life~11 hoursParent 5 hrs, OVD ~11hrs FDA Approved Indication(s) and Off-label Uses1 FDA label indications: Treatment of major depressive disorder. Potential off-label uses: Other antidepressants have label indications for or are used off-label to treat anxiety disorders, bipolar depression, PTSD, chronic pain, and vasomotor symptoms. Results of a search of PubMed and clinical trials.gov found desvenlafaxine has been studied as a treatment for MDD, vasomotor symptoms associated with menopause, fibromyalgia, and diabetic peripheral neuropathy. The findings of the trials in the treatment of fibromyalgia and diabetic peripheral neuropathy have not been published. The findings of the studies of vasomotor symptoms are summarized in the efficacy and adverse events sections of this monograph, although the manufacturer has withdrawn its new drug application for this indication. Current VA National Formulary Alternatives Venlafaxine is an SNRI and on the VANF. Other antidepressants on the VANF include SSRIs (citalopram, fluoxetine, sertraline, paroxetine); TCAs; bupropion; mirtazepine; trazodone; and MAOIs. Only MAOIs are restricted to mental health providers with criteria for use. Dosage and Administration1 The recommended dose of desvenlafaxine is 50 mg taken once daily with or without food. The maximum recommended dose is 100 mg per day. Higher doses up to 400 mg per day have been studied but did not demonstrate additional efficacy and were more likely to result in adverse effects and discontinuation. Desvenlafaxine is only available as an extended-release tablet and must be swallowed whole with fluid and not split, crushed, chewed, or dissolved. As with venlafaxine and certain SSRIs, discontinuation symptoms have been reported with desvenlafaxine. To minimize the risk of these symptoms or their severity, a patients dose should be gradually reduced by decreasing the daily dose by 50 mg (if >50 mg per day) or extending the dosing interval when the dose is 50 mg per day. The manufacturer does not provide specific recommendations as to how often the dose should be decreased. Renal impairment A dose adjustment is not necessary in patients whose creatinine clearance is >50 mL/min. For patients with a CrCl 30-50 mL/min (moderate renal impairment) the recommended daily dose is 50 mg. The recommended daily dose for patients with a CrCl <30 mL/min or end-stage renal disease is 50 mg every other day. Patient undergoing dialysis should not be given supplemental doses. Hepatic impairment The starting dose is 50 mg per day and the maximum recommended dose is 100 mg per day in patients with hepatic impairment. Elderly patients The manufacturer states that dose adjustments solely based on age are not required, but the dose may need to be adjusted based on a patients CrCl. Efficacy4-15 Efficacy Measures Major Depressive Disorder: Primary Measure Hamilton Depression Rating Scale (HAM-D17) an observer rated 17-item scale that assesses mood, sleep, anxiety, suicidality, cognitive and physical retardation, and somatic symptoms. Secondary Measures Response defined as a 50% or greater reduction in HAM-D17 score Remission defined as a HAM-D17 score < 7. HAM-D6 (Bech version: HAM-D items 1, 2, 7, 8,10 & 13) Montgomery Asberg Depression Rating Scale (MADRS) a 10-item scale, 9 of the items are reported by the patient, that assesses tension, sadness, and other symptoms of depression. Clinical Global Impression Improvement/Severity (CGI-I/S) a single item, clinician-related question used to assess response to treatment. Scored from 1 7 with higher scores signifying disease worsening. Visual Analog Scale Pain Intensity (VAS-PI) Covi Anxiety Scale score Summary of efficacy findings Major Depressive Disorder: Pivotal trials4-6 Two studies were presented to the FDA as the pivotal evidence of desvenlafaxines efficacy. Both trials (#332 and #333) were identically designed Phase 3, multi-center, double-blind, parallel-group and 8-weeks in duration comparing fixed doses of desvenlafaxine 50 mg and 100 mg per day to placebo in adults. Pertinent inclusion criteria were a diagnosis of MDD without psychotic features by DSM-IV criteria, depression symptoms for at least 30 days, HAM-D17 score > 20 (with depressed mood > 2), and CGI-S score > 4 (moderately ill). Pertinent exclusion criteria were a significant risk of suicide; frequent suicidal thoughts or suicide being considered regardless of the existence of a plan or intent; a history within the previous 12 months of substance use disorder or dependence, other Axis I diagnosis, or anxiety symptoms that were greater than depressive symptoms on standardized scales. The mean change from baseline of the HAM-D17 score at the final on-therapy evaluation was the primary measure of efficacy. Secondary measures were as identified above. A total of 451 and 485 subjects were enrolled in the two trials, respectively. Between 80% and 90% of each treatment group completed the trials. The FDA results of the final on-therapy changes in HAM-D17 scores are shown in Table 3. Table 3 FDA Primary Analysis: Least-squares mean (LSM) change from baseline in HAM-D17 scores Study #332 (N = 447)Study #333 (N = 483)PlaceboDSV 50DSV 100PlaceboDSV 50DSV 100n150150147161164158LSM-9.6-11.5-11.0-10.8-13.2-13.7p-value0.020.090.004<0.001DSV = desvenlafaxine A sensitivity analysis using a mixed model repeated approach measures (MMRM) conducted separately by the manufacturer and FDA found the 50 mg and 100 mg doses to be significantly superior to placebo in both studies. Effect sizes from the MMRM analysis for the 50 mg and 100 mg doses in the 332 trial were -2.54 and -2.02, and -2.88 and 3.42 in the 333 trial, respectively. The response rates per the HAM-D17, MADRS, and CGI-I did not differ among the treatment groups in the 332 trial. A significantly greater proportion of those assigned to desvenlafaxine 50 mg achieved remission compared to placebo, 34% vs. 24%; p=.027, respectively. The remission rate with desvenlafaxine 100 mg was 31%. The response rates at the end of the 333 trial were 65% for desvenlafaxine 50 mg and 63% for desvenlafaxine 100 mg both significantly greater than the 50% achieved with placebo. A significantly greater proportion of the groups assigned to desvenlafaxine 100 mg achieved remission compared to placebo, 45% and 29%, respectively. The remission rate in the 50 mg group was 37%. Analysis of key secondary efficacy variable The mean change in CGI-I scores did not differ significantly between desvenlafaxine 50 mg or 100 mg groups and placebo in the 332 trial but did for both doses in the 333 trial. In the 332 trial 48% of patients assigned to placebo and 55% of those on active drug were very much or much improved after 8-weeks. In the 333 trial these values were 73% for active drug and 53% for placebo. The results of other secondary efficacy variables while not provided in the FDA Medical Review were included in their respective publications. Findings were mixed in the 332 trial with the desvenlafaxine 50 mg group differing from placebo in adjusted mean change from baseline in the HAM-D6, MADRS, the WHO 5-item Well Being Index and the total Sheehan Disability Scale and individual domain of work, social life and leisure activities, and family life and home responsibilities. Significant differences were found between desvenlafaxine 100 mg and placebo in the HAM-D6 and VAS-PI overall pain scores. Neither dose of desvenlafaxine significantly improved CGI-S or Covi Anxiety Scale scores. In the 333 trial subjects assigned to desvenlafaxine were noted to have significantly greater improvements from baseline in the MADRS total, CGI-S, and COVI Anxiety Index by week 8. Both desvenlafaxine treatment groups showed significant improvement in the total Sheehan Disability Scale and individual domain of work, leisure activities, family and social lives, home responsibilities, and work and social disability. Overall well being on the WHO 5-item Well Being Index improved significantly in both treatment groups. Other Placebo-Controlled Clinical Trials in MDD7-9 Published findings from three other double-blind, randomized, placebo-controlled, parallel-group design 8-week trials were reviewed. These trials were conducted in the U.S. or Europe and South Africa and employed desvenlafaxine doses of 100, 200, and 400 mg per day. The findings from these trials were mixed. In a forced-dose titration trial to 200 mg/day, desvenlafaxine did not demonstrate significantly greater efficacy that placebo. Another trial comparing doses of 100 mg, 200 mg and 400 mg to placebo reported all three doses significantly improved HAM-D17 and CGI-I scores compared to placebo. In the third trial, desvenlafaxine 200 mg and 400 mg per day was significantly better than placebo based on changes in HAM-D17 and CGI-I scores. In the later two trials, patients taking active drug were 1.7 to 2.4 times more probable to achieve remission (although 100 mg and 200 mg group contained unity in their 95% confidence intervals in one trial). In the FDAs review it concluded that a dose-response effect was not demonstrated and that higher doses offered no additional efficacy. Active Controlled Trials in MDD10, 11 A third 8-week, multi-center, randomized, double-blind, placebo-controlled, fixed dose trial compared desvenlafaxine 50 mg and 100 mg, duloxetine 60 mg per day to placebo. Duloxetine was included as an active control and the study was not powered for comparisons between desvenlafaxine and duloxetine. The study design, inclusion and exclusion criteria, and outcome variables were identical to those in Studies 332 and 333. A total of 638 patients enrolled and 615 were included in the intention to treat (ITT) analysis. The study did not meet its primary efficacy end point of identifying a significant change from baseline for HAM-D17 total score. Paired analyses of the differences in adjusted means found desvenlafaxine 100 mg (1.8, 95% CI: 0.2 3.4, p=0.028) and duloxetine (1.7, 95% CI: 0 3.4, p=0.047) to differ from placebo. No difference was found between desvenlafaxine 50 mg and placebo. Similar overall and pair wise findings were reported for secondary variables CGI-I, MADRS, CGI-S, and HAM-D6. Response and remission rates did not differ between the four treatment arms ranging between 38% to 49% and 20% to 29%, respectively. These same investigators pooled the ITT populations of this trial with the 332 and 333 trials. Both doses of desvenlafaxine resulted in significantly greater improvements in the difference in adjusted mean change in the HAM-D17 compared to placebo: desvenlafaxine 50 mg 1.8 (95% CI: 0.9-2.8, p<.001) and 100 mg 2.1 (1.2-3.1, p<.001). Similarly, both doses of desvenlafaxine resulted in significant improvement in secondary efficacy variables. The pooled results of two 8-week, double-blind, multi-center, placebo-controlled, flexible-dose, venlafaxine-active control trials have also been published. The outcome measures used were the same as those in studies 332 and 333. The target dose of desvenlafaxine was 200 mg per day with an investigators option to increase it to 400 mg per day. The dose of venlafaxine ER was 75mg or 150 mg per day in one trial and 150 mg or 225 mg per day in the other; the results of these two groups were not pooled given the different doses. A total of 738 patients enrolled in the two studies (desvenlafaxine n=226, venlafaxine ER 75-150 mg n=127, venlafaxine ER 150-225 mg n=121, and placebo n=250); 713 were used in the ITT analysis. After 8-weeks, the adjusted mean difference from baseline versus placebo for desvenlafaxine was -2.34, p<.001; venlafaxine ER 57-150 mg -2.40, p=.001; and venlafaxine ER 150-225 mg -2.69, p<.001. Desvenlafaxine and both venlafaxine doses were significantly superior to placebo in the majority of secondary outcome measures including the MADRS, CGI-S, HAM-D6, and VAS-PI overall pain. Desvenlafaxine did not differ from placebo in response or remission rates. Both doses of venlafaxine ER had significantly greater response rates than placebo and a significantly greater proportion in the venlafaxine 150-225 mg group achieve remission compared to placebo. Relapse Prevention12 A double-blind , randomized, placebo-controlled, phase III trial conducted in Europe, the U.S., and Taiwan measured relapse rates over 6 months after 12-weeks of open-label treatment with desvenlafaxine 200 mg or 400 mg per day. Patients demonstrating clinical improvement (HAM-D17 score < 11) at the end of the open-label trial were eligible to be randomized to placebo or to continue their current dose of desvenlafaxine. Time to relapse was the studys primary efficacy endpoint with relapse defined as a HAM-D17 score > 16 or a CGI-Improvement score > 6 at any office visit. The HAM-D17, HAM-D6, CGI-I, CGI-Severity and Covi Anxiety Scale scores were used as secondary efficacy measures. Of the 594 patients enrolled in the open-label trial, 63% were randomized: 185 to placebo and 190 to desvenlafaxine. Patients continuing on desvenlafaxine had a significantly longer time to relapse compared to placebo. After 6 months 42% in the placebo arm had relapsed compared to 24% assigned to desvenlafaxine, p< .001. The hazard ratio for relapse (desvenlafaxine vs. placebo) was 0.45 (95% CI 0.31 0.66, p<.0001). At the end of the open-label trial ~70% of patients randomized had achieved remission; at the end of 6 months 69% of the desvenlafaxine and 44% on placebo were in remission, p< .001. Compared to placebo, patients randomized to desvenlafaxine demonstrated significant differences (improvement) on all secondary outcome measures at the studys end. The FDA considered the findings of this maintenance trial clinically irrelevant since the doses used in the study were greater than what is recommended. Menopausal Vasomotor Symptoms (off-label use)13, 14 Desvenlafaxines efficacy and safety for the treatment of vasomotor symptoms was assessed in a multi-center, randomized, double-blind, placebo-controlled trial. Desvenlafaxine doses of 50, 100, 150, and 200 mg taken for up to 52 weeks. Primary outcome measures, change from baseline in average daily number of moderate-to-severe hot flushes and in daily hot flush severity score, were measured after 4 and 12 weeks of treatment. Over 600 women participated in the study. After 12-weeks only the 100 mg desvenlafaxine dose significantly reduced the mean daily number of hot flushes more than placebo, 64% and 51%, respectively. The average daily severity of hot flushes was also reduced by 100 mg desvenlafaxine compared with placebo at week 12 (50% vs. 29%, NNT = 4.7). A significantly greater proportion of the 100- and 200-mg desvenlafaxine groups achieved a >75% reduction in the number of hot flushes compared with placebo after 12-weeks: 100 mg 49.7%, NNT = 4.7 (95% CI 3.0 13.2); 200 mg 45.0%, NNT=6.1(95% CI 3.4 39.8). All doses of desvenlafaxine were associated with a significantly shorter time to a 50% reduction in hot flushes (<1 week) compared with placebo (3-4 weeks). The average number of nighttime awakenings due to hot flushes was significantly reduced with desvenlafaxine100, 150 and 200 mg than with placebo. Subjects assigned to desvenlafaxine reported significantly more adverse events in the first week of treatment than those assigned to placebo. A second multi-center, placebo-controlled trial randomized 567 postmenopausal women to desvenlafaxine 100 mg or 150 mg per day, or to placebo for 26-weeks. Both desvenlafaxine groups reported significantly greater reductions in hot flashes (60% and 66%) than placebo (47%) after 12-weeks. Only the 150 mg dose remained significant after 26-weeks, however, the study was not powered beyond 12-weeks. Study discontinuation was significantly greater in the first week in both desvenlafaxine groups than with placebo. Discontinuation symptoms after the last dose of study medication were more common in the desvenlafaxine 100 mg and 150 mg subjects (51.1% and 55.9%, respectively) than in those whod taken placebo, 28.3%. The dose was not tapered at the end of the study. Adverse Events (Safety Data) Deaths and Other Serious Adverse Events4 No deaths were reported in the clinical trials attributable to desvenlafaxine were reported. Few serious adverse events were reported in the 332 and 333 trials: desvenlafaxine 11 events in 9 subjects (1.4%) and placebo 2 events in 2 subjects (0.6%). Serious adverse events reported with desvenlafaxine were: lower limb thrombosis, migraine, depression, suicide ideation, elevated transaminase, hypotension, and lumbar disc herniation. In the placebo group serious adverse events reported were intestinal obstruction, and womb infection. . Common Adverse Events4 Desvenlafaxines common adverse events are shown in Tables 4, 5 and 6. Table 4 Common adverse events reported in studies #332 and #333 (pooled) as percent Placebo n=313DSV 50 mg n=317DSV 100 mg n=306DSV total n=623Cardiovascular Hypertension Palpitation 1% 1 3% 1 3% 2 3% 2Gastoinstestinal Nausea Dry mouth Diarrhea Constipation Anorexia Abdom. Pain Dyspepsia Vomiting 11 7 9 4 3 7 3 4 22 12 11 9 6 8 3 3 23 16 6 8 8 7 3 3 22 14 9 8 7 7 3 3Nervous system Insomnia Dizziness Headache Asthenia Somnolence Anxiety Nervousness Abnml. Dreams Dec. Libido Vertigo Hostility Tremor Paresthesia 5 4 17 4 5 2 1 3 3 0.3 2 2 2 12 13 20 8 6 3 2 4 2 2 2 2 2 11 7 22 9 9 7 3 3 3 2 3 3 3 11 10 21 8 7 5 3 4 3 2 2 2 2Other Systems Sweating Abnl. Vision (mydriasis/blurred) Abnl. Ejaculation/orgasm Impotence (men) 5 1 0 0 10 3 1 3 11 3 3 5 10 3 2 1 Table 5 ADE comparison of placebo, desvenlafaxine and active-control duloxetine (%) [*95%CI] Adverse EventPlacebo n=161DSV 50 mg n=148DSV 100 mg n=150Duloxetine 60 mg n=157Nausea14 (9%)33 (22%)35 (23%)[17-31%]49 (31%) [24-39%]Insomnia5 (3)16 (11)21 (14) [9-21]29 (19) [13-25]Decreased appetite5 (3)14 (10)14 (9) [5-15]29 (19) [13-25]Fatigue6 (4)12 (8)15 (10) [6-16]19 (12) [7-18]Somnolence4 (3)9 (6)17 (11) [7-18]23 (15) [10-21]Constipation4 (3)9 (6)10 (7) [3-12]17 (11) [6-17]Hyperhidrosis3 (2)7 (5)9 (6) [3-11]16 (10) [6-16]*95% confidence intervals were calculated to determine if there was overlap between the ADEs for the higher dose of desvenlafaxine and duloxetine. Table 6 ADE comparison of placebo, desvenlafaxine and active-control venlafaxine ER [*95%CI] Adverse Event Placebo n=245 DSV 200-400 mg n=231Venlafaxine ER 75-150 mg n=127Venlafaxine ER 150-225 mg n=117Nausea30 (12%)87 (38%) [31-44%]27 (21%)34 (29%) [21-38%]Somnolence16 (7)31 (13) [9-19]12 (9)22 (19) [12-27]Dry mouth10 (4)47 (20) [15-26]17 (13)30 (26) [18-35]Sweating10 (4)45 (20) [15-25]12 (9)21 (18) [1-26]*95% confidence intervals were calculated to determine if there was overlap between the ADEs for desvenlafaxine and the higher dose of venlafaxine. Other Adverse Events1, 4 Changes in cholesterol, triglycerides, blood pressure, pulse rate, and weight reported in clinical trials are shown in Table 7. No specific monitoring recommendations are provided by the manufacturer. Table 7 Incidence (%) of lipid abnormalities, proteinuria and mean changes in vital signs PlaceboDSV 50 mgDSV 100 mgTotal cholesterol > 261 mg/dl or increase > 50 mg/dl 2 3 4LDL cholesterol > 190 mg/dl or increase > 50 mg/dl 0 1 0Triglycerides, fasting > 327 mg/dl321Proteinuria468Supine SBP, mm Hg Supine DBP, mm Hg-1.4 -0.6 1.2 0.7 2.0 0.8Supine pulse, bpm-0.3 1.3 1.3Weight, kg 0.0-0.4-0.6 ECG findings No important or clinically significant ECG findings were reported in the 332 and 333 studies. Effect on liver function tests Potentially clinically significant elevations (>3 times the upper limit of normal) in AST occurred in 0.6%, 0.4%, and 0 subjects assigned to placebo, desvenlafaxine 50 mg and 100 mg, respectively. Elevated serum ALT concentrations occurred 0.4%, 1.5%, and 0.3% in the placebo, desvenlafaxine 50 mg and 100 mg groups, respectively. No cases met the criteria of Hys rule and no cases resulted in serious adverse events. Taper/posttherapy-emergent adverse events15 Taper/posttherapy-emergent adverse events were those not present during the last 7 days of treatment. In the clinical trials for MDD when desvenlafaxine was to be discontinued the dose was to be tapered over 1 to 2 weeks. The taper was accomplished by lowering the dose and/or extending the dosing interval, e.g., every other day. Subjects receiving desvenlafaxine 50 or 100 mg per day either had their desvenlafaxine abruptly stopped or reduced to 50 mg for 1week prior to discontinuation. Higher doses were reduced by 50% weekly until the daily dose was 100 mg which was then discontinued after 1 week. A pooled analysis of nine 8-week trials found discontinuation symptoms to be significantly more common in those assigned to desvenlafaxine 50 to 400 mg per day (39%) than placebo (26.8%). Common discontinuation symptoms (vs. placebo) were dizziness 8.9% (1.9%), headache 5.8% (5.5%), irritability 3.5% (1.4%), insomnia 3.2% (2.2%), diarrhea 3.1% (2.2%), abnormal dreams 2.6% (0.5%) and hyperhidrosis 2.2% (1.4%). In the maintenance MDD trial, taper/posttherapy-emergent adverse events were reported by 31% (open-label phase) and 53% (double-blind phase) of those who received desvenlafaxine compared to 28% taking placebo. Taper/posttherapy-emergent adverse events following treatment with desvenlafaxine included dizziness (22%), nausea (14%), headache (12%), irritability (10%), diarrhea (7%), insomnia (7%), anxiety (6%), fatigue (5%), abnormal dreams (5%) and hyperhidrosis (5%). Patients who received placebo reported headache (7%), insomnia (6%), and nausea (5%) following its discontinuation. Discontinuation-emergent signs and symptoms scores were significantly greater 3-weeks after the end of the double-bind treatment phase for those who had taken the 400 mg dose compared to those who had taken placebo. No difference was reported in the 200 mg treatment group. The treatment trial for menopausal vasomotor symptoms did not include a dose taper at the cessation of treatment. Discontinuation symptoms were reported by 31% in the placebo group and 48% of those who received desvenlafaxine. Dose did not influence the frequency of discontinuation symptoms. There was a direct relationship with the duration of therapy and the incidence of discontinuation symptoms. Nausea, dizziness, and headache were the most commonly reported complaints following discontinuation. Tolerability Sixteen percent of subjects assigned to placebo withdrew from Study 332, compared to 23% and 21% of participants assigned to desvenlafaxine 50 mg and 100 mg. Eight percent of subjects assigned to placebo withdrew from Study 333, compared to 10% and 13% taking desvenlafaxine 50 mg and 100 mg, respectively. Overall, withdrawals due to adverse events were low, 3%-7%, and were more common with desvenlafaxine 100 mg (7%) than with placebo or desvenlafaxine 50 mg (3%-5%). Discontinuation due to adverse effects was more likely in the first week of treatment with desvenlafaxine than placebo. Contraindications1 Hypersensitivity to desvenlafaxine, venlafaxine or any excipients in desvenlafaxine formulation. Concomitant use with an MAOI or having taken an MAOI in the past 14 days. Warnings and Precautions1 Boxed Warning: Increased risk of suicide thinking and behavior in children, adolescents, and young adults (18 24 years) taking antidepressants for MDD and/or other psychiatric disorders. Worsening of depression, emergence of suicidal thoughts and/or behavior. Development of serotonin syndrome during treatment with desvenlafaxine alone or in combination with other serotinergic drugs such as other antidepressants and the triptans, Sustained increase in diastolic blood pressure was noted in clinical trials. Abnormal bleeding. Concurrent use with other drugs that affect clotting or increase the risk bleeding, e.g., NSAIDS, should be used with caution and patients informed of the increased risk and how to respond. Narrow-angle glaucoma: mydriasis has been reported with desvenlafaxine. Activation of mania or hypomania. Cardiovascular or cerebrovascular disease. Due the potential increase in blood pressure, elevation in serum cholesterol and/or triglycerides. Clinical trials excluded persons with recent history of myocardial infarction, unstable heart disease, or uncontrolled hypertension. Discontinuation symptoms after stopping desvenlafaxine either abruptly or during dose reduction have been reported. Renal impairment, moderate, severe or ESRD, requires a dose reduction (See Dosing). Use in Pregnancy Pregnancy Category C. Third trimester exposure of SSRIs and SNRIs have resulted in prolonged hospitalization, respiratory support, and tube feeding for the neonate. While a risk: benefits decision, the manufacturer suggests considering tapering desvenlafaxine in the third trimester. Use in Breast Feeding Desvenlafaxine is excreted into human milk. Sentinel Events No data available. Look-alike / Sound-alike (LA / SA) Error Risk Potential As part of a JCAHO standard, LASA names are assessed during the formulary selection of drugs. Based on clinical judgment and an evaluation of LASA information from four data sources (Lexi-Comp, USP Online LASA Finder, First Databank, and ISMP Confused Drug Name List), the following drug names may cause LASA confusion: LA/SA for generic name desvenlafaxine: venlafaxine, desipramine, desloratidine LA/SA for trade name Pristiq: None identified Drug Interactions Drug-Drug Interactions As with all antidepressants concomittant use with a monoamine oxidase inhibitor or sibutramine is to be avoided. Concurrent use with NSAIDs may increase the risk of gastrointestinal bleeding or bleeding in general. Prolonged bleeding times may occur when used with anticoagulants such as warfarin. Patients should be advised to avoid alcohol consumption while taking desvenlafaxine. Concomitant use with potent CYP3A4 may increase desvenlafaxines concentrations. Following a single 400 mg dose of desvenlafaxine after ketoconazole 200 mg twice a day increased desvenlafaxine AUC 43% and Cmax 8%. Drugs which inhibit other CYP isozymes are not expected to significantly alter devenlafaxines pharmacokinetics. Desvenlafaxines inhibitory effects on drugs metabolized by CYP2D6 are thought to be minimal based on pharmacokinetic drug interaction trials with desipramine. Drug-Lab Interactions No drug-lab interactions have been identified. Acquisition Costs Table 8 Acquisition costs of desvenlafaxine and venlafaxine DrugDoseCost/Day/patient ($)Cost/Year/patient ($)Desvenlafaxine SA50 mg QD2.44890.60Desvenlafaxine SA100 mg QD2.44890.60Venlafaxine IR75 mg BID0.40/0.67146.00/244.55Venlafaxine SA150 225 mg1.79/1.95 - 3.57653.35/711.11 1303.05Duloxetine 60 mg2.65967.25Prices as of August 11, 2010 and may not reflect all discounts. Ranges reflect generic and brand prices for venlafaxine. Prices are not updated after the monograph is posted. Pharmacoeconomic Analysis No pharmacoeconomic studies were identified. Conclusions Desvenlafaxine, the third SNRI to be marketed, has demonstrated superior efficacy when compared to placebo as a treatment for major depressive disorder. However, said superiority has not been consistently demonstrated in all outcome measures and clinical trials. There are no long term trials assessing relapse prevention of major depressive disorder for the approved 50 mg and 100 mg per day dose, hence there are no long term tolerability data either. Desvenlafaxine 100 mg significantly reduced the frequency and severity of hot flashes in two clinical trials. Desvenlafaxines advantages as an antidepressant are that a patient can be started on a therapeutic dose. It can be used in patients for whom venlafaxine or duloxetine might be appropriate without concern of CPY450 drug-drug interactions, i.e., presence of 2D6 inhibitors, or who are known to have poor metabolizer CYP2D6 status. Desvenlafaxines disadvantages or limitations include its moderate efficacy compared to placebo, a safety and tolerability profile analogous to other SNRIs and SSRIs, the possibility of discontinuation symptoms requiring a dosage taper, and the lack of an alternative formulation such as a liquid for patients who cannot swallow the extended-release tablet intact. References: Pristq (desvenlafaxine) package insert. Wyeth Pharmaceuticals. February 2008. Sopko MA, Ehret MJ, Grgas M. Desvenlafaxine: Another Me Too drug? Ann Pharmacother 2008;42: 1439-46. Preskorn S, Patroneva A, Silman H, et al. Comparison of the pharmacokinetics of venlafaxine extended-release and desvenlafaxine in extensive and poor cytochrome P450 2D6 metabolizers. J Clin Psychopharmacol 2009; 29:39-43. Centers for Drug Evaluation and Research Medical Review, Application 21-992 desvenlafaxine succinate sustained release oral tablets, February 5, 2008. Accessed at www.fda.gov, May 6, 2010. Liebowitz MR, Manley AL, Padmanabhan SK, et al. Efficacy, safety, and tolerability of desvenlafaxine 50 mg/day and 100 mg/day in outpatients with major depressive disorder. Curr Med Res Opin 2008;24: 1877-90. Boyer P, Montgomery S, Lepola U, et al. Efficacy, safety, and tolerability of fixed-dose desvenlafaxine 50 and 100 mg/day for major depressive disorder in a placebo-controlled trial. Int Clin Psychopharmacol 2008; 23: 243-53 Septien-Velez L, Pitrosky B, Padmanabhan SK, et al. A randomized, double-blind, placebo-controlled trial of desvenlafaxine succinate in the treatment of major depressive disorder. Int Clin Psychopharmacol 2007;22: 338-47. Liebowitz MR, Young 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: 1663-72. DeMartinis NA, Yeung PP, Entsuah, et 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; 68:677-88. Lieberman DZ, Montgomery SA, Tourian KA, et al. A pooled analysis of two placebo-controlled trials of desvenlafaxine in major depressive disorder. In Clin Psychopharmacol 2008;23: 188-97. Tourian KA, Padmanabhan SK, Groak J, et al. Desvenlafaxine 50 and 100 mg/d in the treatment of major depressive disorder: an 8-week, Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial and post hoc pooled analysis of three studies. Clin Ther 2009;31: 1405-23. Rickels K, Montgomery SA, Tourian KA, et al. Desvenlafaxine for the prevention of relapse in major depressive disorder. J Clin Psychopharmacol 2010;30:18-24. Speroff L, Gass M, Constantine G, et al. Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms. Obstet Gynecol 2008;111: 77-87. Archer DF, Dupont CM, Constantine GD, et al. Desvenlafaxine for the treatment of vasomotor symptoms associated with menopause: a double-blind, randomized, placebo-controlled trial of efficacy and safety. Am J Obstet Gynecol 2009;200: 238.e1-238.e10. Montgomery SA, Fava M, Padmanabhan SK, et al. Discontinuation symptoms and taper/poststudy-emergent adverse events with desvenlafaxine treatment for major depressive disorder. Int Clin Pscychopharmacol 2009; 24:296-305. Prepared September, 2010 Contact person: Todd Semla, MS, Pharm.D., BCPS     Desvenlafaxine DRAFTUpdated version may be found at  HYPERLINK "http://www.pbm.va.gov" www.pbm.va.gov or vaww.pbm.va.gov PAGE 1Portions of these documents or records, or information contained herein, which resulted from Pharmacy Benefits Management Drug Usage Evaluation and Utilization Review activities, may be considered confidential and privileged under the provisions of 38 U.S.C. 5705 and its implementing regulations. 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