Clinical Therapeutics/Volume 31, Theme Issue, 2009

New Drug

Desvenlafaxine: A New Serotonin-NorepinephrineReuptake Inhibitor for the Treatment of Adults WithMajor Depressive Disorder

Richard Perry, PharroDl-'; and Manouchkathe Cassagnol, PharmD, CGp3,4

lArnold & Marie Schwartz College ofPharmacy and Health Sciences) Long Island University, Brooklyn)New York; 20epartment ofPharmacy, Bellevue Hospital Center, New York) New York; 3College ofPharmacy andAlliedHealth Professions) St.fohn's University, Queens) New York; and "Department ofPharmacy, Long IslandJewish Medical Center, New Hyde Park) New York

ABSTRACTBackground: Desvenlafaxine succinate, a serotonin­

norepinephrine reuptake inhibitor (SNRI), was approvedby the US Food and Drug Administration (FDA) inFebruary 2008 for the treatment of adult patients withmajor depressive disorder (MDD). Desvenlafaxine is thethird SNRI approved by the FDA for this indication.

Objective: This article reviews the available infor­mation for desvenlafaxine, focusing on its pharmaco­dynamics, pharmacokinetics, clinical efficacy, andsafety profile.

Methods: A comprehensive search of MEDLINE(1950-March 2009), International PharmaceuticalAbstracts (1970-March 2009), lSI Web of Knowledge(1996-March 2009), and EMBASE (1974-March2009) was conducted using the terms desvenlafaxine,Ci-desmetbvluenlataxine, and Pristiq. Reference listsof articles were reviewed for other relevant publica­tions. Abstracts of unpublished clinical studies pre­sented at the American Psychiatric Association annualmeetings (2004-2008) were included in the review;also included were data from the FDA and theEuropean Medicines Agency Web sites.

Results: After oral administration, desvenlafaxinereaches Tmax in 7 to 8 hours and is slowly eliminated,with t 1l2 values of 9 to 15 hours. With once-daily dos­ing, steady-state plasma concentrations are achievedwithin 4 to 5 days. Alternate-day dosing should beimplemented in patients with severe renal impair­ment (creatinine clearance, 0:;30 mL/min) and thosewith end-stage renal disease. In patients with moder­ate to severe hepatic impairment, daily doses shouldnot exceed 100 mg. Nine short-term studies of des-

1374

venlataxine have been conducted but only 8 werepublished. These 8 clinical studies evaluated oraldesvenlafaxine 50 to 400 mg/d using randomized con­trolled trials for the treatment of MDD in adult out­patients. Significantly greater efficacy in the reductionof depressive symptoms was found in patients takingdesvenlafaxine 50 mg/d (P < 0.05) compared withplacebo. No additional therapeutic benefits werefound at doses >50 mg/d. Preliminary data supportdesvenlafaxine's efficacy and tolerability in the treat­ment of menopause-associated vasomotor symptoms.Desvenlafaxine was generally well tolerated in clinicaltrials; the most common adverse events were nausea,suicidal ideation, and changes in blood pressure andweight.

Conclusions: Desvenlafaxine 50 mg/d has beenfound to be efficacious and generally well tolerated inshort-term trials for the treatment of adults withMDD. Further studies are needed to determine des­venlafaxines role in the management of MDD andits efficacy compared with other antidepressants. (ClinTher. 2009;31[Theme Issue]:1374-1404) © 2009Excerpta Medica Inc.

Key words: major depressive disorder, desvenlafax­ine, Pristiq, serotonin-norepinephrine reuptake inhibi­tor, vasomotor symptoms.

Accepted for publtcation May 8, 2009dotl 0.1016/J.c1lnthera.2009.07.0120149-2918/$ - see front matter

© 2009 Excerpta Medica Inc. All rights reserved.

Volume 31 Theme Issue

INTRODUCTIONMajor depressive disorder (MDD) is a psychiatric ill­ness that is estimated to affect 151 million peopleworldwide and predicted to be the leading cause ofworldwide disability by 2030.! In the United States, theNational Comorbidity Survey Replication found a life­time prevalence of 16.2%.2 MDD is estimated to resultin 225 million missed workdays and $36.6 billion inproductivity losses per year in the United States.'

As defined by the Diagnostic and Statistical Manualof Mental Disorders. Fourth Edition (DSM-IV),3 indi­viduals with MDD may experience debilitating symp­toms, such as depressed mood, anhedonia, weight andsleep alterations, fatigue, and impaired concentration.Comorbid illnesses, including substance use and anxi­ety disorders, are often seen.? Additionally, MDD is arisk factor for suicide attempts and ideation." If leftuntreated, MDD is associated with social and workimpairment, disability, and reduced quality of life.S,6

The mainstay of the pharmacologic management ofMDD involves the use of antidepressants; the goals oftreatment are to improve mood, functioning, andquality of life. The mechanism by which antidepres­sants have an effect on MDD is unknown; however,they are known to affect neurotransmitters (specifi­cally, serotonin [5-hydroxytryptamine (5-HT)], nor­epinephrine [NE], and dopamine [DA]).

A serotonin-norepinephrine reuptake inhibitor(SNRI), desvenlafaxine succinate," was approved bythe US Food and Drug Administration (FDA) in Feb­ruary 2008 for the treatment of adult patients withMDD.7 Desvenlafaxine is also being investigated forthe treatment of vasomotor symptoms (VMS) associ­ated with menopause.f and clinical trials are underway investigating the possible use of desvenlafaxine forthe treatment of fibrornyalgia and neuropathic pain."Desvenlafaxine is the third SNRI approved by theFDA for the treatment of MDD.

This article reviews the available information fordesvenlafaxine, focusing on its pharmacodynamics,pharmacokinetics, clinical efficacy, and safety profile.

METHODSA comprehensive search of MEDLINE (1950-March2009), International Pharmaceutical Abstracts (1970­March 2009), lSI Web of Knowledge (1996-March

*Trademark: Pnstiq" (Wyeth Pharmaceuticals, Inc., Philadel­phia, Pennsylvania).

2009

R. Perry and M. Cassagnol

2009), and EMBASE (1974-March 2009) was conductedusing the terms desuenlaiaxine, O-desmethylvenlafaxine,and Pristiq (Figure 1). Reference lists of articles werereviewed for other relevant publications. Abstracts ofunpublished clinical studies presented at the AmericanPsychiatric Association annual meetings (2004-2008)and data from the FDA and the European MedicinesAgency Web sites were also included in the review.

CLINICAL PHARMACOLOGYDesvenlafaxine is the O-desmethyl active metabo­lite of venlataxine. Its chemical name is RS-4-[2­dimethylamino-1-( 1-hydroxycyclohexyl)ethyl]phenol,and its empirical formula is C!6H2SN02' The chemicalstructures of desvenlafaxine succinate monohydrate l''

and venlataxine hydrochloride-! are given in Figure 2.

PharmacodynamicsIn the treatment of MDD, the activity of desvenla­

faxine is thought to be mediated by the inhibition ofneuronal reuptake of 5-HT and NE. Preclinical invitro studies found a higher affinity for the human5-HT transporter (hSERT) than for the human NEtransporter (hNET) and weak binding affinity for thehuman DA transrnitter.l- Binding affinity was shownthrough the use of the equilibrium dissociation con­stant (K), which is inversely related to the bindingaffinity. In an in vitro study.l ' desvenlafaxine inhibitedthe binding of [3H]citalopram at hSERT and [3H]nisoxe­tine at hNET, with a K, value of 40.2 ± 1.6 nM and558.4 ± 121.6 nM, respectively. Therefore, desvenla­faxine exhibited a relatively higher binding affinity forthe serotonergic receptor compared with the NEreceptor.

The quantitative measure of the amount of a par­ticular drug or substance that is needed to inhibit agiven biological process by 50% (ICso) is one methodof assessing a compound's effectiveness. Desvenlalax­ines affinity for serotonergic receptors was further dis­played by the relatively higher inhibition of [3H]5-HTcompared with the [3H]NE reuptake suggested bymean ICso values of 47.3 ± 19.4 and 531.3 ± 113 nM,respectively.l- Binding of [3H]WIN 35428, a knownselective DA reuptake inhibitor, to the human DAtransporter (hDAT) was weakly inhibited by desvenla­faxine, with only a 61.6% ± 1.7% inhibition at thehighest concentration tested (100 flM; x, 25 ± 5 flM).Furthermore, these investigators examined the in vivobrain permeability and the effect on neurochemical

1375

Clinical Therapeutics

Pote nti a lly releva nt citat io ns identified (n - 614)EMBASE (251)151Web of Knowledge (203)MEDLlNE (117)Int erna t io na l Pharmaceut ical Abstr act s (2 2)Meeti ng a bs tr acts (2 1)

Cit ation s excluded d ue to lack of relevance (n - 33 1)EMBASE (15 2)151Web of Knowle dge (95) ~MEDLINE (76)Inte rna t io na l Pharmaceuti ca l Abst ract s (8)

Pote nt ially relevant cita tions retri eved and reviewed ( n - 283)151Web of Knowledge ( 108)EM BASE (99)MED LINE (4 1)Meet ing a bstracts (2 1)Inte rna tio na l Pha rm aceuti cal Abst ract s ( 14)

Dup licate citations fo und on sea rches exclude d r-(n - 152)

Pote ntia lly relevant a rticle s retri eved a nd reviewed(n - 13 1)

Cit ation s exclude d ( n - 85)News ar t iclesLetters ~Abstracts of a currently p ublished t ria lReview a rt icles

Y Tr ials incl ude d in t he review (n - 46 ) I

Figure 1. Flow chart of lite rat ure search, identification , and inclusion of trials related to desvenlafaxine.

levels in the brain of male rats. Desvenlafaxine 30 mglkgrapidly penetrated the male rat brain and hypothala­mus and significantly increased NE concentrations(P < 0.011). When given with WAY 100635 (a 5-HT1A

antagonist), it produced a 78 % increase in extracel­lular levels of 5-HT (P = 0.017).

Results from an in vitro study conducted by Deech­er et al 13 further support these findings.l- Desvenla­faxine 10 pM was submitted to NovaScreen Biosci­ences (Caliper Discovery Alliances & Services, Hanover,Maryland) for evaluation in 63 bioassays, including

1376

receptors, second messengers, and ion channels. Basedon results from a panel of assays, activity was foundonly at the 5-HT and NE monoamine transporters.Additional competitive-binding assays were performedto assess the activity of desvenlafaxine at hSERT,hNET, and hDAT. The affinity was highest for hSERT,with a mean ICso value of 80.6 ± 4 nM; modest activi­ty for hNET was noted, with a mean ICso value of893 ± 194.5 nM. Desvenlafaxine exhibited no signifi­cant affinity for dopaminergic, muscarinic, adrenergic,or serotonergic receptors in this study.l-'

Volume 31 Theme Issue

R. Perry and M. Cassagnol

Figure 2. Chem ical structure of (A) desve nlafax­ine succinate rnonohydrate' " and (B) venla­faxine hydroch loride.!'

PharmacokineticsBehrle et al15 evaluated single oral doses of desven­

lafaxine, administered to 24 healthy male subjects, inan open-label, randomized study. One of 3 doses (100,300, or 600 mg) was given with a medium-fat break­fast. Desvenlafaxine was slowly absorbed, with Tmaxvalues of 7 to 8 hours. Desvenlafaxine also exhibitsslow elimination, with a mean t 1l2 of 9 to 15 hourS.15-17

With once-daily dosing, steady-state plasma concen­trations are achieved within 4 to 5 days.J'' Between­subject variability was low, with the percent coeffi­cient of variations <25% for mean Crnax' t l l2' andAUC. 15 Desvenlafaxine displayed a linear pharrna­cokinetic profile, with Crnax and AUC increasing lin­early over the dose range of 100 to 600 mg. Similarfindings of desvenlafaxines dose-proportional andpredictable changes in its pharrnacokinetic parameters,with both single and steady-state multiple dosing, werereported. 15,16,18 A randomized, placebo-controlled, se­quential, ascending, single-dose study was conductedin 79 healthy male subjects. 16 Oral doses of 150, 225,300, 450, 600, 750, and 900 mg were administeredafter a medium-fat breakfast to cohorts of 10 subjects.Crnax and AUC increased linearly over the dose rangeof 150 to 900 mg. The plasma protein binding of des­venlataxine was ~30% and independent of drug con­centration. The volume of distribution at steady stateafter intravenous administration was 3.4 L/kg, indi­cating distribution into nonvascular compartments. 10

A study conducted by Parker et al 17 investigatedthe absolute bioavailability of desvenlafaxine. Four­teen patients were randomized to receive either singledoses of desvenlafaxine 100 mg (oral tablet) or 50 mgIV (infusion) in each period. The desvenlafaxine intra­venous formulation was found to have a higher meanCrnax (233 ng/mL) than the oral formulation (160 ng/mL).The oral formulation had higher overall exposure(AUCoral' 3996 ng . hlmL; AUCrntravenous' 2443 ng . hlmL);however, elimination t 1l2 values were similar, rangingfrom 14 to 15 hours. The absolute bioavailability ofthe oral formulation was determined to be 80.5%.10,17

The pharrnacokinetic profile of desvenlafaxine whengiven with food was assessed in a randomized, 4-period,4-sequence, inpatient, crossover study evaluating asingle, oral 200-mg dose in 33 healthy male and fe­male subjects.l" Subjects were given desvenlafaxineunder fasting and nonfasting conditions. The medianTmax for desvenlafaxine was ~6 hours in the fastingstate and was increased by ~2 hours when adminis­tered with food. When desvenlafaxine was given with amedium-fat meal, its slow-release profile was not al­teredY Administration with a high-fat meal resultedin a slight increase in Crnax (by ~16%) compared withadministration without food (with food, 90% CI,108-125; fasting, 90% CI,80-125).10,19

Desvenlafaxine is primarily metabolized by glucu­ronidation, mediated by UDP-glucuronosyltransferase

-HCI

(

COOH

• - H20

COOHHO

B

A

A reduction of endogenous estrogen in menopausalwomen is associated with thermoregulatory dysfunctionand the occurrence of hot flushes. The hypothalamus isthe region of the brain involved in thermoregulation.Through its activity in the hypothalamus, at hSERT andhNET, desvenlafaxine may-theoretically-have thepotential to reduce menopausal thermoregulatory dys­function. An in vitro study conducted by Deecher et al14

used tissue samples collected from ovariectomized rats,via microdialysis, from the preoptic area of the hypo­thalamus. Ovariectomy-induced temperature dysfunc­tion, which has been associated with a decrease in 5-HTand NE in the preoptic area of the hypothalamus, mayimprove with the use of desvenlafaxine.

2009 1377

Clinical Therapeutics

enzymes, and to a minor extent by oxidative metabolismvia cytochrome P450 (CYP) isozyme 3A4.20 In contrast,venlataxine is primarily metabolized by CYP2D6, mak­ing it susceptible to CYP2D6 polymorphism, whichmay lead to pharrnacokinetic and interindividual vari­ability in efficacy and/or tolerability. 11 Approximately45% of desvenlafaxine is excreted unchanged in urineat 72 hours after oral administration. 10

SPECIAL POPULATIONSHepatic Impairment

Baird-Bellaire et aIll conducted a study in 24 he­patically impaired patients, evenly distributed amongthe Child-Pugh classes, and 12 matched healthy adults.Subjects received a single, 100-mg oral dose of desven­lafaxine. Blood and urine samples were obtained over96 hours and analyzed. Patients with Child-Pugh cat­egory A, B, or C were considered to have mild, moder­ate, or severe hepatic dysfunction, respectively. Medi­an Tmax of desvenlafaxine ranged from 6 to 9 hoursand was similar for all groups. Mean AUC and t 1l2 ofdesvenlafaxine were similar for patients with mildhepatic impairment and for healthy subjects «5% dif­ference). However, the mean AUC was increased by~31% in patients with moderate hepatic impairmentand by 35% in patients with severe hepatic impair­ment compared with healthy subjects. Systemic clear­ance was decreased by ~20% and 36% in patients withmoderate and severe hepatic impairment, respectively.There was a longer t 1l2 in patients taking desvenlafaxinewith moderate to severe hepatic impairment comparedwith those receiving placebo (hepatically impaired pa­tients, 13-14 hours; healthy subjects, 10 hoursj.I'' Inpatients with mild hepatic impairment, treatment canbe initiated using a 50-mg/d oral dose of desvenlatax­ine; oral doses >50 mg/d may warrant closer monitor­ing for adverse events. This is especially true for thosewith moderate to severe hepatic impairment, in whomthe daily dose should not exceed 100 mg.

Renal ImpairmentThe disposition of desvenlafaxine after administra­

tion of a 100-mg oral dose was studied in patients withmild (creatinine clearance [CrCl], 50-80 mL/min; n =

9), moderate (CrCl, 30-50 mL/min; n = 8), severe(CrCl, 0:;30 mL/min; n = 7), and end-stage renal dis­ease (ESRD) requiring dialysis (n = 9) and in healthy,age-matched control subjects (n = 8). Elimination ofdesvenlafaxine was correlated with CrC!. AUCs in-

1378

creased by ~42%, ~46%, ~108%, and ~116% in thosewith mild, moderate, and severe renal impairment andESRD, respectively, compared with controls. The meanterminal t 1l2 was prolonged from 11.1 hours in controlsubjects to ~13.5, ~15.5, ~17.6, and ~22.8 hours inpatients with mild, moderate, and severe renal impair­ment and ESRD, respectively. 10 In patients with mildto moderate renal impairment, no dose adjustment isnecessary; however, in those with severe renal impair­ment and ESRD, administration of oral desvenlafax­ine 50 mg every other day is recommended.

ElderlyPharrnacokinetic parameters were evaluated in a

study of healthy elderly subjects given doses of 0:;300-mgoral desvenlafaxine. Compared with subjects aged 18to 45 years (n = 16), subjects aged ?75 years (n = 17)exhibited a 32% increase in Crn ax and a 55% increasein AUC. 10 Subjects aged 65 to 75 years (n = 15) had a32 % increase in AUC and no change in Crnax com­pared with subjects aged 18 to 45 years. Althoughthere are no specific dosing recommendations for el­derly patients, close monitoring may be warranteddue to the increases in Crnax '

SexDesvenlafaxine was evaluated for sex differences in

its pharrnacokinetic parameters. Desvenlafaxine had a10% higher AUC and an ~25% higher Crnax in womencompared with age-matched men (no P value reported). 10

These results show that no dose adjustments based onsex are necessary.

PregnancyDesvenlafaxine is currently classified as an FDA

pregnancy category C drug. Moderate teratogeniceffects have been reported with desvenlafaxine inanimal model studies.l'' A review of the literatureidentified no published data regarding the efficacy,safety, or tolerability of desvenlafaxine in pregnant orlactating women. Recently, it was discovered thatneonates exposed to a selective serotonin reuptakeinhibitor (SSRI) or an SNRI late in the third trimesterhave developed complications, including respiratorydistress, prolonged hospitalization, and symptomsresembling serotonin withdrawal syndrome.22 ,23

With these recent warnings, desvenlafaxine shouldonly be used when the potential benefits outweigh therisks.

Volume 31 Theme Issue

DRUG INTERACTIONSThe minor pathway for the metabolism of desvenla­faxine is via CYP3A4. Patat et aF4 studied the effectsof CYP3A4 inhibitors on desvenlafaxine clearance. Apotent CYP3A4 inhibitor, oral ketoconazole (200 mgtwice daily) was administered concomitantly with asingle oral dose of desvenlafaxine 400 mg. The AUCof desvenlafaxine was increased by ~43 % and Crn ax

by ~8%.

Shilling et aFs conducted an in vitro study to deter­mine the inhibitory effects of desvenlafaxine, venla­faxine, duloxetine, paroxetine, sertraline, and bupro­pion on the CYP isozyme system and on P-glycoprotein(Pgp) activities. The inhibitory effects of these agentson CYP1A2, 2A6, 2C19, 2C8, 2C9, 2D6, and 3A4activity were determined in human liver microsomesusing standard and selective probe substrates for theseenzymes. The inhibitory effects of these agents on Pgpactivity were determined in Caco-Z cell monolayersusing digoxin as the Pgp substrate. Desvenlafaxineshowed no inhibition of the CYP enzymes studied(ICsoor K, > 100 flM); venlataxine exhibited minimalinhibition of CYP2D6 (K

j, 93 rM) but no inhibition

of the other CYP enzymes (ICso or K, > 100 flM). InCaco-Z cell monolayers, desvenlafaxine and venlatax­ine showed minimal inhibition (10%-20% of controlactivity) of Pgp-mediated digoxin efflux at the highestconcentration (250 pM). ICso values could not bedefined.

Another study compared the effects of oral desven­lafaxine 100 mg and paroxetirie 20 mg, a knownCYP2D6 inhibitor, on the pharmacokinetics of a singledose of desipramine (a CYP2D6 substrate) in 19 healthysubjects aged 21 to 50 years. 26 Desvenlafaxine hadweak inhibitory effects on the pharmacokinetics ofdesipramine, with an AUC increase of 36% comparedwith an AUC increase with paroxetine of 419%.Therefore, desvenlafaxine exhibits weak inhibition ofthe CYP2D6 isozyme system.

Preskorn et al27 conducted a randomized, single­dose, crossover study to determine the effects of CYP2D6polymorphism (N = 14 [7 extensive metabolizers (EMs),7 poor metabolizers [PMs]) on single oral doses of75-mg/d venlafaxirie extended release (ER) and100-mg/d desvenlafaxine. CYP genotyping was per­formed. After administration of venlataxine ER, meanCrnax (PMs, 98.6 ng/mL; EMs, 39.6 ng/mL) and AUC(PMs, 2548 ng· hlrnL; EMs, 591 ng· hlmL) were signifi­cantly greater in PMs than in EMs (P < 0.001). Dif-

2009

R. Perryand M. Cassagnol

ferences in AUC and Crnax for the EMs and PMs werenot significant in the desvenlafaxine group. Thesefindings indicate that although desvenlafaxine is aweak inhibitor of CYP2D6, it does not affect Pgp.Desvenlafaxine has minimal effects on other CYPisozymes and is not susceptible to CYP2D6 polymor­phic changes. No clinically significant interactionswith potent inhibitors of CYP3A4 were observed, ex­cept when used concomitantly with supratherapeuticdoses of desvenlafaxine.

CLINICAL EFFICACYDesvenlafaxine has been evaluated in various studiesfor the treatment of MDD and VMS associated withmenopause.P'r'" The highlights of those studies arepresented in the following sections.

Short-Term Treatment of Major Depressive DisorderNine short-term studies of desvenlafaxine have

been conducted but only 8 were published. The resultsof these 8 studies evaluating the efficacy of desvenla­faxine are summarized in Table 1.28- 34 These studieswere similarly designed; they are all Phase III, 8-week,randomized, multicenter, double-blind, placebo­controlled, parallel-group trials conducted in adultoutpatients. Eligibility requirements included age::::18 years and a single or recurrent episode of MDDwithout psychotic features, according to DSM-IV cri­teria, with symptoms present for ;:::30 days beforescreening. Required minimum scores at screening andbaseline were 17-item Hamilton Rating Scale for De­pression (HAM-DP) total scores ::::20; HAM-D 17 item1 (depressed mood) scores ::::2; and Clinical GlobalImpressions-Severity (CGI-S) scale scores ::::4 (moder­ately ill).

Trial periods consisted of an initial 6- to 14-dayscreening period, followed by an 8-week treatment pe­riod and then a varying 1- to 2-week period when treat­ment was tapered at the investigators' discretion. Theprimary efficacy measure was the HAM-D!? total score.Secondary efficacy measures used in the clinical trialsincluded the following: Clinical Global Impressions­Improvement (CGI-I) score; Montgomery Asberg De­pression Rating Scale (MADRS) score; CGI-S score;6-item Hamilton Depression Rating Scale (HAM-D6)

score; visual analog scale-pain intensity (VAS-PI)overall and component scores; Covi Anxiety Scale to­tal scores; Sheehan Disability Scale (SDS) scores;World Health Organization 5-item Well-Being Index

1379

..... Q(JJ00 :::l0 ;:;'

~

Ta ble I. Eff icacy of d esvenl afaxine (DVS) in clinica l trials for th e t reatme nt of majo r d ep ressive d iso rd er. I-l::rI'D

P:l"'0

Study No . of Primary Primary Effi ca cy Seconda ry Effica cy Measu res

II'Dc...

Design/ Pa tients Trea t ment Eff icacy Resu lts (Fina l a nd Resu lts (Fina l O n-T he ra py Eva lua tion , ;:;'III

Study Du ra t io n (ITT) Groups Mea sur e Evaluation , LO CF) LO CF [Sig nif ica nt Differen ces Rep orted])

Short-t ermtreatmentLiebowitz MC, R, 447 DVS 50 mg HAM-D17 to tal DVS 50 mg: - 11.5 DVS 50 mg vs PBO: HAM-D6 (P = 0.010 ), MADRSet a l28 DB, FI, (n = 150); DVS sco re, cha nge (P = 0.018); DVS (P = 0.0 22), SDS (P = 0.01 2), W HO-5

PG, PC; 100 mg (n = 147 ); fro m ba se line 100 mg: - 11.0 (P = 0.020), remission rates (P = 0.027)

8 weeks PBO (n = 150) (P = 0.0 65) ; DVS 100 mg vs PBO : HAM-D6 (P = 0.038),

PBO : -9.5 VAS-PI overa ll pain (P = 0.041), VAS-PI back pai n(P = 0.031), VAS-PI a rm, leg , or joint pa in(P = 0.006)

Boyer et MC, R, 483 DVS 50 mg HAM-D17 tota l DVS 50 mg: DVS 50 mg vs PBO : MADRS (P = 0.004), CGI-Sa l29 DB, PG, (n = 164); score, cha nge -13.2 (P = 0.002); (P = 0.00 3), CGI-I (P = 0.00 2), Covi Anxiet y Scale

FI, PC; DVS1 00 mg from base line DVS 100 mg: (P = 0.00 1), SDS (P = 0.003), WHO-5 (P = 0.00 6),

8 wee ks (n = 158); -13.7 (P < 0.001 ); respo nde r rate (P = 0.005)

PBO (n = 161) PBO : - 10.7 DVS 100 mg vs PBO : MAD RS (P < 0.0 01), CGI-S(P < 0.00 1), CGI-I (P < 0.001), Covi Anxiety Sca le(P = 0.004), SDS to ta l (P < 0.00 1), W HO -5(P < 0.00 1), respo nder rate (P = 0.018), remissio nra te (P = 0.003)

Li eb owitz MC, R, 23 4 DVS 100- 200 mg HAM-D17 tota l DVS 100- 200 mg: DVS 100- 20 0 mg vs PBO: MAD RS (P = 0.047) ,

~

Iet a l30 DB, FL, (n = 120); PBO sco re, a t end 14.1 (P = 0.277); VAS-PI ove ra ll pain (P = 0.008), VAS-PI back

i: PG, PC; (n = 114) po int PBO: 15 .1 pai n (P = 0.006), VAS-PI a rm, leg, o r joint pain3 8 weeks (P < 0.001)I'D(JJ.....

I (co nt inue d)-l::rI'D

3I'D

iii"IIIcI'D

N0010

ITa ble I (co ntinued).

St udy No . of Prim ary Prima ry Eff icacy Secon d ary Eff ica cy MeasuresDesign/ Pa t ients Treat me nt Efficacy Resu Its (Final a nd Results (Fina l O n-Th erapy Eva luatio n,

Study Dura tion (ITT ) Groups Mea su re Eva luatio n, LOCF) LOCF [Significant Differen ces Reported])

DeM arti nis MC, R, 461 DVS 100 mg HAM -D17 tota l DVS 10 0 mg: DVS 100 mg vs PBO : CGI-I (P < 0 .001), MADRSet a l31 DB, FI, (n = 114); sco re , change - 10.6 (P < 0.004) ; to tal sco re (P = 0.004), CGI-S (P = 0.002),

PG, PC/ DVS 200 mg fro m ba se line DVS 200 mg : VAS-PI overall pain (P = 0.0 02) , VAS-PI a rm,8 wee ks (n = 116); - 9.63 (P < 0 .077); leg, o r jo int pai n (P < 0.001 ), 505 (P = 0 .003),

DVS 4 00 mg DVS 40 0 mg: WH O-5 (P = 0.004), resp on der ra te (P = 0.017)(n = 113); PBO - 10.74 (P < 0.0 03) ; DVS 200 mg vs PBO: CGI-I (P < 0.047), MADRS(n = 118) PBO : -7.65 total score (P = 0.0 05), 505 (P = 0.042), WH O -5

(P = 0.008)DVS 400 mg vs PBO: CGI-I (P < 0.013), MADRS

tota l sco re (P < 0.001), CGI-S (P < 0.001 ),VAS-PI a rm, leg , or joi nt pa in (P = 0 .019), 50S(P = 0.002), WH O-5 (P < 0.001 ), resp onder rate(P = 0.046), remission ra te (P = 0.035)

Septien - MC, R, 369 DVS 20 0 mg HAM -D17 total DVS 200 mg: DVS 200 mg vs PBO : CGI-I (P < 0.05 ), MADRSVelez et DB, FI, (n = 121); score, change - 12.6 (P = 0 .0 02); (P = 0.0 01) , CGI-S (P = 0.001), VAS-PI overalla l32 PG, PC/ DVS 4 00 mg (n = from ba seline DVS 40 0 mg: pain (P = 0.002), VAS-PI chest pain (P = 0.002),

8 weeks 124); - 12.1 (P = 0 .008); VAS-PI a rm, leg , o r jo int pa in (P < 0 .001 ),PBO (n = 124 ) PBO : - 9.3 respond er rate (P < 0.00 1), remi ssion rat e

(P = 0.017)DVS 4 00 mg vs PBO: CGI-I (P < 0.05), MADRS

(P = 0.005), CGI-S (P = 0 .013), VAS-PI back pa in(P = 0.035 ), VAS-PI chest pa in (P = 0.041),VAS-PI a rm, leg, o r jo int pain (P = 0.009),

(0responder rate (P = 0.005)"'Cl'D

Feige r er MC, R, 23 5 DVS 20 0 - 400 mg HAM -D17 total DVS 200-400 mg: DVS 200-400 mg vs PBO : CGI-I (P = 0.037), ....~a j33 DB, FL, (n = 117); PBO score, change -9 .1 (P = 0.078); MADRS to tal sco re (P = 0.028), CGI-S (P= 0.041), ~

PG, PC; (n = 118) from ba seline PBO : -7.5 HAM-D6 (P = 0.0 06), MADRS response rate :::l0...

8 weeks (P = 0.04) s:(co nt inue d)

n~IIIIII.....~(JJ

00 :::l..... Q..

.....

ITable I (co ntinued), Q(JJ

00 :::lN ;:;'

Study No. of Pri ma ry Primary Effi cacy Secondary Efficacy Measures ~

-lDesign/ Patients Treatment Effica cy Resu Its (Final a nd Results (Final On-Th erapy Evaluation , ::rI'D

Study Duration (ITT) Groups Measure Eva luat io n, lOCF) l OCF [Significan t Differen ces Reported]) P:l"'0I'Dc...

Lieberman MC , R, 713 DVS 200-400 mg HAM -D 1? to ta l DVS 200- 400 mg: DVS 200 -400 mg vs PBO : CGI-I (P < 0.001), I ;:;'III

et al34 DB, Fl , (n = 226); VEN score, cha nge - 14.21 (P < 0.001); MADRS (P < 0.001), CGI-S (P < 0.001), HAM-D6PG , PAC; ER 75-150 mg from baseline VEN ER 75-150 mg: (P < 0.001), CoviAnxiety Scal e (P = 0.035 ),8 weeks " (n = 127); VEN - 14,26 (P = 0.001); VAS-PI ove ra ll pain (P = 0.003), VAS-PI ba ck pain

ER 150-225 mg VEN ER 150- (P < 0.001) , VAS-PI che st pain (P = 0.037),

(n = 115); PBO 225 mg: - 14.56 (P VAS-PI arm, leg , o r joint pa in (P = 0.027 )

(n = 245) < 0.001) ; PBO :- 11 .87

l o ng-termtreatment

Rickels MC , R, Not DVS 200-400 Time u ntil No t rep orted Relapses : DVS 200 -400 mg, 24%; PBO ,et al 35 DB, Fl , reported mg ; PBO relapse 42% (P < 0.001 )

PG , PC;6 mo nt hs

Ferguso n MC ,Ol, 99 Not reported HAM -D1? to ta l DVS: -9,92 Not reportedet al36 Fli score, cha nge

12 months from baseline

Gui co - o t, 494t DVS 200-400 mg HAM-D1? to ta l See rex t t Se e t ext!Pabia et 10 months scorea 13?

Ahmed or, 369 t DVS ~20 0 mg Not reported No t rep orted Not reported

~et al38 10 months

i: ITT = intent-to -tr eat population ; LOCF = last-ob servation-carried-forward; MC = multicenter; R = rand omized; DB = doubl e-blind; FI = fixed dos e; PG =3I'D par allel-group; PC ~ placebo-controlled; PBO ~ placebo; HAM-D17 ~ 17-item Ham ilton Rating Sca le for Depr ession ; HAM-D6 ~ 6-item Hamilton Depr ession(JJ Ratin g Scale; MADRS = Mon tgom ery Asberg Depr ession Rating Sca le; SDS = Sheeha n Disability Scale; WHO-S = World Health Organization S-item Well-Being.....-l Index; VAS-PI = visual analog scale- pain inte nsity; CGI-S = Clinical Global Impression s-S everity ; CGI-I = Clinical Glo bal Impressions-Improvement ; FL = flexi-::rI'D ble do se; PAC = placebo- and active-controlled; VEN ER = venlafa xine extended release; O L = op en-lab el.3I'D .. Poo led anal ysis.iii" tTotal number of pati ent s enro lled .IIIc *Discussion in text pro vides a full review.I'D

(WHO-5) scores; remission rates (defined as an HAM-D17score 0:;7); and responder rates (defined as a ::::50% reduc­tion in scores on the HAM-Dp). For analysis, the intent­to-treat population (lIT) was used. The primary endpoint for all efficacy analyses was the final on-therapy(FOT) evaluation, using last-observation-carried­forward data. The trials evaluated oral desvenlafaxineat doses ranging from 50 to 400 mg/d compared withplacebo. Two trials (published as 1 pooled analysis)used oral venlafaxine ER 75 to 150 mg/d and 150 to225 mg/d as a reference treatment.s" Adverse eventsare summarized in Table 11.28-34

The studies conducted by Liebowitz et aF8 andBoyer et aF9 evaluated the efficacy of fixed doses oforal desvenlafaxine 50 and 100 mg/d compared withplacebo. Patients were randomly assigned, on day 1,to receive desvenlafaxine 50 or 100 mg or placebo.Those in the 100-mg group received 50 mg on days 1to 7, which was then increased to 100 mg for the re­mainder of the study period. The study by Liebowitzet al was conducted at multiple centers in the UnitedStates. Patients were randomized to receive desvenla­faxine 50 mg (n = 150), desvenlafaxine 100 mg (n =

147), or placebo (n = 150). The mean age of patientswas 43 years in both desvenlafaxine groups and42 years in the placebo group. The mean baselineHAM-D 17 total score was 23 in all groups, and themean baseline CGI-S score was 4.3 in the desvenlatax­ine 50-mg and placebo groups and 4.4 in the desven­lafaxine 100-mg group.

Patients in the desvenlafaxine 50-mg group had asignificant reduction in their HAM-D 17 total scorescompared with placebo (-11.5 and -9.5, respectively;P = 0.018), with significant reductions starting atweek 4 (P = 0.019).28 Compared with placebo, statis­tical significance was seen in HAM-D6 (P = 0.010),MADRS (P = 0.022), SDS (P = 0.012), and WHO-5(P = 0.020) total scores in the desvenlafaxine 50-mggroup. Remission rates were significantly greater inthe desvenlafaxine 50-mg group versus placebo (34%vs 24%, respectively; P = 0.027). Patients in the des­venlataxine 100-mg group did not achieve statisticalsignificance in the primary efficacy measure comparedwith those in the placebo group, although significancewas observed in HAM-D6 (P = 0.038), VAS-PI overallpain (P = 0.041), VAS-PI back pain (P = 0.031), andVAS-PI arm, leg, or joint pain (P = 0.006). No signifi­cant differences were observed between response rates,Covi Anxiety Scale, CGI-I, and CGI-S scores in either

2009

R. Perry and M. Cassagnol

active-treatment group. Thirty-four patients (23 %)from the desvenlafaxine 50-mg group, 31 patients(21 %) from the desvenlafaxine 100-mg group, and25 patients (17%) from the placebo group withdrewfrom the study. During the double-blind study period,adverse events were reported by 84%, 76%, and 70%of recipients in the desvenlafaxine 50-mg, desvenla­faxine 100-mg, and placebo groups, respectively. Ad­verse events occurring in the desvenlafaxine groups at::::5% incidence and at twice the rate of the placebogroup are shown in Table II. The most common rea­sons for discontinuation were failure to return in thedesvenlafaxine 50-mg group (n = 15 [10%]), adverseevents and failure to return in the desvenlafaxine100-mg group (n = 11 [7%]), and failure to returnand a nonstudy-related request in the placebo group(n = 6 [4%]).

Boyer et aF9 conducted a study of oral desvenla­faxine at multiple centers in Europe and South Africa.Patients were randomized to receive 50 mg/d (n =

164) or 100 mg/d (n = 158) of desvenlafaxine or pla­cebo (n = 161). The mean age of patients in the des­venlataxine 50-mg group was 44 years; the mean ageof patients in the desvenlafaxine 100-mg group and inthe placebo group was 46 years. In all study groups,the mean baseline HAM-D 17 total score was 24 andthe mean baseline CGI-S score was 5.

Significant differences were observed in both active­treatment groups compared with placebo for the meanHAM-D 17 FOT evaluation (desvenlafaxine 50 mg,-13.2 [P = 0.002]; desvenlafaxine 100 mg, -13.7 [P <

0.001]).29 Significant differences began at week 6 inthe desvenlafaxine 50-mg group (P = 0.002) and atweek 4 in the desvenlafaxine 100-mg group (P =

0.014). Significant improvements were seen in the fol­lowing secondary efficacy measures in the desvenlatax­ine 50-mg group compared with the placebo group:MADRS (P = 0.004), CGI-S (P = 0.003), CGI-I (P =

0.002), Covi Anxiety Scale (P = 0.001), SDS (P =

0.003), and WHO-5 (P = 0.006). Responder rateswith desvenlafaxine 50 mg were significantly higherthan with placebo (P = 0.005), although differences inremission rates were not significant.

Significant improvements were observed in the fol­lowing secondary efficacy measures in the desvenla­faxine 100-mg group compared with placebo: MADRS(P < 0.001), CGI-S (P < 0.001), CGI-I (P < 0.001),Covi Anxiety Scale (P = 0.004), SDS (P < 0.001),WHO-5 (P < 0.001), responder rates (P = 0.018), and

1383

Clinical Therapeutics

Table II. Adverse events occurring at ~5% incidence and at twice the rate of the placebo group in short-te rmtrials eva luating desven lafaxine (DVS) in the treatment of major depressive disorder. Values are givenas no . (%) of patients in the safety population.

Stu dy Adverse Event Incidence

Liebowitz et a l28 DVS 50 mg DVS 100 mg Placebo(n = 151) (n = 148) (n = 152)

Dizziness 25 (17) 10 (7) 6 (4)Dry mou th 15 (10) 23 (16) 6 (4)Co nstipat ion 14 (9) 16 (11) 5 (3)Inso mn ia 14 (9) 15 (10) 4 (3)Decreased appetite 8 (5) 15 (10) 7 (5)Hyperhidrosis 10 (7) 14 (10) 4 (3)Fatig ue 9 (6) 10 (7) 5 (3)Abdominal pa in 9 (6) 5 (3) 4 (3)Anxiety 5 (3) 7 (5) 1 « 1)Blurred vision 7 (5) 5 (3) 2 (1)

Boyer et a l29 DVS 50 mg DVS 100 mg Pla cebo(n = 166) (n = 158) (n = 161)

Nau sea 44 (27) 48 (30) 17 (11)Dizziness 17 (10) 11 (7) 6 (4)Insom nia 13 (8) 14 (9) 7 (4)Co nstipation 13 (8) 8 (5) 7 (4)Fat igue 12 (7) 11 (7) 5 (3)Anxiety 4 (2) 9 (6) 5 (3)Decrea sed a ppet ite 8 (5) 7 (4) 1 « 1)

Liebowitz et a l30 DVS 100-200 mg Place bo(n = 121) (n = 117)

Abdom ina l pa in* 7 (6) 7 (6)Asth enia* 13 (11) 8 (7)Back pa in* 4 (3) 7 (6)Flu syndro me* 6 (5) 8 (7)Head ache" 37 (31) 36 (31)Infect io n* 10 (8) 7 (6)Pain* 7 (6) 9 (8)Ano rexia 16 (13) 7 (6)Con st ipat io n 20 (17) 7 (6)Diarrhea* 14 (12) 8 (7)Dry mou th 31 (26) 14 (12)Dys pepsia* 9 (7) 5 (4)Nau sea 36 (30) 10 (9)Vo mit ing 8 (7) 2 (2)Art hra lgia 8 (7) 4 (3)Myalgia* 4 (3) 7 (6)Ab no rmal dreams" 6 (5) 6 (5)

(co ntinued)

1384 Volume 31 Theme Issue

R. Perry and M. Cassagnol

Tabl e II (continued ).

Study Adverse Event Inciden ce

Li eb owi tz et a l30 Anxiety" 6 (5) 6 (5)(cont) Dizziness* 19 (16) 14 (12)

Hostility* 4 (3) 6 (5)Insomnia* 21 (17) 13 (11)Nervou sn ess 13 (11) 5 (4)Somnolen ce 14 (12) 7 (6)Trem or 8 (7) 0URT infection 2 (2) 7 (6)Yawning 8 (7) 0Sweati ng 9 (7) 4 (3)Abn ormal sexua l

function 3 (3) 2 (2)

DeMartinis et al3' DVS 100 mg DVS 200 mg DVS 400 mg Pla cebo(n = 118) (n = 116) (n = 116) (n = 120)

Nausea 41 (35 ) 36 (31) 47 (41) 10 (8)Insomnia 26 (22) 21 (18) 35 (30 ) 10 (8)Somnolen ce 24 (20) 25 (22) 30 (26) 10 (8)Dry mouth 20 (17) 22 (19) 29 (25 ) 12 (10)Sweating 12 (10) 19 (16) 24 (21) 4 (3)Dizziness 20 (17) 18 (16) 22 (19) 7 (6)Nervousn ess 6 (5) 10 (9) 17 (15) 5 (4)Anorexia 14 (12) 14 (12) 16 (14) 3 (3)Con stipati on 14 (12) 10 (9) 16 (14) 3 (3)Abnormal ejac ulatio n/

o rga sm 2 (2) 7 (6) 13 (11 ) 1 « 1)Asth enia 8 (7) 13 (11 ) 12 (10) 6 (5)lmpoten ce! 3 (7) 3 (7 ) 5 (9) 1 (3)Anorgasm ia 4 (3) 3 (3) 9 (8) 0Tremor 5 (4) 11 (9) 9 (8) 1 « 1)Vo mit ing 6 (5) 8 (7 ) 8 (7) 4 (3)Abnormal vision 6 (5) 7 (6) 8 (7 ) 2 (2)Mydrias is 3 (3) 2 (2) 8 (7 ) 1 « 1)Abn ormal dr eams 7 (6) 7 (6) 8 (7) 4 (3)Tachycardia 4 (3) 3 (3) 6 (5) 2 (2)Vasodila t io n 2 (2) 6 (5) 5 (4) 0Taste pervers io n 1 « 1) 1 « 1) 6 (5) 2 (2)Yawning 3 (3) 6 (5) 2 (2) 0

Septi en -Velez et a l32 DVS 200 mg DVS 400 mg Pla ceb o(n = 123) (n = 125) (n = 125)

Abdomina l pain 7 (6) 10 (8) 5 (4)Asth enia 14 (11 ) 20 (16) 4 (3)Anorexia 15 (12) 12 (10) 0Constipation 18 (15) 18 (14) 7 (6)Dry mouth 27 (22) 29 (23) 11 (9)

(co nt inued)

2009 1385

Clinical Therapeutics

Table II (continu ed ).

Study Adver se Event Incid en ce

Sep tien-Velez et aP2 Nausea 57 (46) 63 (50) 14 (11 )(cont) Vomiting 9 (7) 15 (12) 0

Anxiety 6 (5) 8 (6) 4 (3)Dizzin ess 19 (15) 17 (14) 8 (6)Som nol en ce 12 (10) 7 (6) 2 (2)Trem or 10 (8) 13 (10) 0Vertigo 13 (11 ) 9 (7) 3 (2)Sweati ng 34 (28) 36 (29) 9 (7 )Abnormal vision 7 (6) 2 (2) 0Mydri asis 16 (13) 9 (7) 0lrnpoten ce! 2 (5) 7 (15) 2 (5)Abnormal ejaculatio n/

o rgas rnt 3 (8) 1 (2) 0Dysuria! 2 (5) 4 (9) 0Urinary frequen cy! 3 (8) 0 1 (3)Imp aired urin a tion! 2 (5) 2 (4) 0

Feiger et aP3 DVS 200-400 mg Pla cebo(n = 117) (n = 118)

Nausea 42 (36) 11 (9)Dr y mo ut h 36 (31) 12 (10)Hyperh idrosis 23 (20) 4 (3)Insomnia 19 (16) 7 (6)Somnolen ce 18 (15) 6 (5)Decrea sed a p pet ite 18 (15) 0Tremor 13 (11) 3 (3)Blurred vision 12 (10) 2 (2)Yawning 11 (9) 0Sed a tion 10 (9) 0Vo mit ing 10 (9) 4 (3)Mydri asi s 10 (9) 0Middle insomnia 9 (8) 1 « 1)Initial insomnia 7 (6) 4 (3)Erecti le dysfunctions 7 (1 6) 0Constipation 7 (6) 3 (3)Feeling jittery 6 (5) 0Dysp epsia 6 (5) 0

Li eb erm an et aP4 DVS 200- VEN ER VEN ER400 mg 50-225 mg 75-15 0 mg Pla ceb o(n = 231) (n = 117) (n = 127) (n = 245)

Nausea 87 (38) 34 (29) 27 (21) 30 (12)Somno len ce 31 (13) 22 (19) 12 (9) 16 (7)

(co nt inue d)

1386 Volume 31 Theme Issue

R. Perry and M. Cassagnol

Tabl e II (co nti nued).

Study Adverse Event Incidenc e

Lieb erman et aj34 Dry mouth 47 (20) 30 (26) 17 (13) 10 (4)(cont) Sweating 45 (20) 21 (18) 12 (9) 10 (4)

Asthenia 21 (9) 7 (6) 10(8) 10 (4)Constipation 32 (14) 9 (8) 6 (5) 7 (3)Abnormal vision 13 (6) 5 (4) 3 (2) 3 (1)Anorexia 23 (10) 18 (15) 6 (5) 3 (1)Vomiting 17 (7) 3 (3) 3 (2) 2 «1)Tachycardia 13 (6) 5 (4) 0 2 «1 )impotence] 7 (9) 4 (11) 2 (6) 1 (1)

URT - upp er respiratory tract; VEN ER - venlafaxine extended relea se.* Advers e events that did not occur at twice th e rate of pla cebo.t Incid ence in men reported : DVS 100 mg, n = 42 ; DVS 200 mg, n = 45 ; DVS400 mg, n = 53; and placebo, n = 40.t Incid ence in men reported : DVS 200 mg, n = 38 ; DVS 400 mg, n = 47; and pla cebo, n = 40 .§ Incid ence in men reported : DVS 200-400 mg, n - 45 ; and pla cebo, n - 37.

II Incidence in men reported : DVS 200-400 mg, n = 75; VEN ER 75-150 mg, n = 35; VEN ER 150-225 mg, n = 36; andplacebo, n = 85.

remission rates (P = 0.003).29 VAS-PI scores were notreported. During the double-blind study period, ad­verse events were reported by 78%, 77%, and 62% ofrecipients in the desvenlafaxine SO-mg, desvenlafaxine100-mg, and placebo groups, respectively. Adverseevents occurring in the desvenlafaxine groups at ::::S%incidence and at twice the rate of the placebo groupare shown in Table II. Seventeen patients (10%) fromthe desvenlafaxine SO-mg group, 20 (13 %) from thedesvenlafaxine 100-mg group, and 13 (8%) from theplacebo group withdrew from the study. The mostcommon reason for discontinuation in the desvenla­faxine SO- and 100-mg groups was adverse events(n = 8 [S%] and n = 11 [7%], respectively). In theplacebo group, adverse events (n = S [3%]) and unsat­isfactory clinical response (n = S [3%]) were the mostcommon reasons for withdrawal.

Another trial by Liebowitz et a130 was conducted atmultiple sites in the United States with patients whowere randomized to 2 study groups: adjustable-dosedesvenlafaxine 100 or 200 mg/d by mouth (n = 120) orplacebo (n = 114). Desvenlafaxine 100 mg/d was givenfor the first 2 weeks and then increased to 200 mg/d.Doses could be reduced to 100 mg/d if there weresafety or tolerability concerns. At the end of the 8-weekperiod, patients had the option of enrolling in a long-

2009

term, open-label extension study. Mean ages in thedesvenlafaxine and placebo groups were 41.9 and39.3 years, respectively. Both groups had mean baselineHAM-D 17 total scores of 23.7 and CGI-S scores of 4.4.After the 2-week titration period, mean daily doses inthe ITT population ranged from 179 to 19S.3 mg.

At end point, there was no statistically significantdifference in the adjusted mean HAM-D 17 total scorebetween groups.s" HAM-D 17 was significantly greaterat week 1 for the placebo group (P = 0.021) and atweek 6 for the desvenlafaxine group (P = 0.042). Sig­nificant improvements were seen in the desvenlafaxinegroup compared with the placebo group on the fol­lowing secondary efficacy measures: MADRS (P =

0.047), VAS-PI overall pain (P = 0.008), VAS-PI backpain (P = 0.006), and VAS-PI arm, leg, or joint pain(P < 0.001). During the double-blind study period,there was a significant difference in the amount ofreported adverse events (desvenlafaxine group, 93 %;placebo group, 79% [P < 0.01]). Adverse events oc­curring at ::::S% incidence and at twice the rate of theplacebo group are shown in Table II. Thirty patientsin the desvenlafaxine group and 21 patients in theplacebo group discontinued the study. Adverse eventswere the most common reason for discontinuation inthe desvenlafaxine group (n = 13 [11 %]) and failure

1387

Clinical Therapeutics

to return was the most common reason in the placebogroup (n = 10 [9%]).

DeMartinis et a13 1 conducted a study of oral, fixed­dose treatment regimens at multiple centers in the UnitedStates; patients were randomized to the followinggroups: oral desvenlafaxine 100 mg (n = 114),200 mg(n = 116), or 400 mg (n = 113) or to placebo (n =

118). Patients in the 200-mg group had their dosetitrated as follows: 100 mg on days 1 to 3 and 200 mgon day 4. Patients in the 400-mg group had their dosetitrated as follows: 100 mg, days 1 to 3; 200 mg, days4 to 7; and 400 mg, day 8. No titration occurred inthe desvenlafaxine 100-mg group. Those who com­pleted the study were given the option of enrolling in along-term, open-label extension study. The mean base­line age in all groups ranged from 39.0 to 40.7 years.HAM-D 17 total scores ranged from 22.9 to 23.2 andCGI-S scores from 4.3 to 4.4. No significant differ­ence was found between groups in baseline character­istics or demographics.

At end point, those patients who received desvenla­faxine 100 and 400 mg had significantly greater de­creases in HAM-D 17 scores compared with those whoreceived placebo (100 mg: -10.6, P < 0.004; 400 mg:-10.74, P < 0.003; placebo, -7.6S).31 Desvenlafaxine200 mg was not significantly different than placebo(-9.63). The following secondary efficacy measureshad significant improvements in the desvenlafaxine100-mg group compared with placebo: CGI-I (P <

0.001), MADRS total score (P = 0.004), CGI-S(P = 0.002), VAS-PI overall pain (P = 0.002), VAS-PIarm, leg, or joint pain (P < 0.001), SDS (P = 0.003),and WHO-S (P = 0.004). Changes in the followingsecondary efficacy measures were significant in thedesvenlafaxine 200-mg group compared with placebo:CGI-I (P < 0.047), MADRS total score (P = O.OOS),SDS (P = 0.042), and WHO-S (P = 0.008). Changes inthe following secondary efficacy measures were signifi­cant in the desvenlafaxine 400-mg group comparedwith placebo: CGI-I (P < 0.013), MADRS total score(P < 0.001), CGI-S (P < 0.001), VAS-PI arm, leg, orjoint pain (P = 0.019), SDS (P = 0.002), and WHO-S(P < 0.001). Significant response rates were observedin the desvenlafaxine 100-mg (P = 0.017) and 400-mg(P = 0.046) groups compared with placebo. Remis­sion rates in only the desvenlafaxine 400-mg groupachieved significance (P = 0.03S) compared with pla­cebo. During the double-blind study period, adverseevents were reported by 90%, 93%, 87%, and 84%

1388

of recipients in the desvenlafaxine 100-, 200-, and400-mg groups and the placebo group respectively.Adverse events occurring in the desvenlafaxine groupat ::::S% incidence and at twice the rate of the placebogroup are shown in Table II. Twenty-seven patients(24%) in the desvenlafaxine 100-mg group, 26 (22%)in the desvenlafaxine 200-mg group, 3S (31 %) in thedesvenlafaxine 400-mg group, and 22 (19 %) in theplacebo group discontinued the study. The most com­mon reasons for discontinuation were adverse eventsin the desvenlafaxine groups and failure to return inthe placebo group.

In the study by Septien-Velez et al,32 oral, fixeddoses of desvenlafaxine 200 mg (n = 121) and 400 mg(n = 124) were compared with placebo (n = 124) atmultiple sites in Europe and South Africa. All patientsin the desvenlafaxine groups received 200 mg on thefirst study day, and those in the 400-mg group hadtheir dose titrated to 400 mg on day 8. The mean ageof patients in the desvenlafaxine 200- and 400-mggroups was 4S.4 and 43.4 years, respectively; meanage in the placebo group was 46.7 years. The meanbaseline HAM-D 17 total scores of patients in the des­venlataxine 200 mg, desvenlafaxine 400 mg, and pla­cebo groups were 24.8, 2S .2, and 2S .3, respectively.The mean baseline CGI-S score was 4.9 for all studygroups. SDS and WHO-S assessments were not con­ducted. Additionally, those individuals who completedthe study were given the option to begin desvenlatax­ine treatment in a long-term, open-label, extensionstudy.

At the FOT evaluation, the HAM-D 17 total scorechange from baseline was significantly greater in boththe desvenlafaxine 200-mg (-12.6; P = 0.002) and400-mg (-12.1; P = 0.008) groups compared with theplacebo group (-9.3).32 Total scores in both active­treatment groups were significantly different thanplacebo beginning at week 4 (desvenlafaxine 200 mg,P:S; 0.004; desvenlafaxine 400 mg, P :s; 0.049). Scoreson the following secondary efficacy measures in thedesvenlafaxine 200-mg group were significant com­pared with placebo: CGI-I (P < O.OS), MADRS (P =

0.001), CGI-S (P = 0.001), VAS-PI overall pain (P =

0.002), VAS-PI chest pain (P = 0.002), and VAS-PIarm, leg, or joint pain (P < 0.001). Scores on the fol­lowing secondary efficacy measures in the desvenla­faxine 400-mg group were significant compared withthe placebo group: CGI-I (P < O.OS), MADRS (P =

O.OOS), CGI-S (P = 0.013), VAS-PI back pain (P =

Volume 31 Theme Issue

0.035), VAS-PI chest pain (P = 0.041), and VAS-PIarm, leg, or joint pain (P = 0.009). Compared withplacebo, a significantly greater responder rate wasseen in both the desvenlafaxine 200-mg (P < 0.001)and 400-mg (P = 0.005) groups. Remission rates weresignificantly higher in the desvenlafaxine 200-mggroup compared with placebo (P = 0.017). No signifi­cant difference in remission rates was seen betweenthe desvenlafaxine 400-mg group and the placebogroup. During the double-blind study period, adverseevents were reported by 85% and 90% of patients inthe desvenlafaxine 200- and 400-mg groups, respec­tively; 70% of individuals in the placebo group re­ported adverse events. Adverse events occurring in thedesvenlafaxine groups at ::::5% incidence and at twicethe rate of the placebo group are shown in Table II.The trial was completed by 73% of the desvenlafaxine200-mg group, 73% of the desvenlafaxine 400-mggroup, and 78% of the placebo group. The most com­mon reasons for discontinuation were adverse events inthe desvenlafaxine 200-mg (n = 25 [21%]) and 400-mg(n = 26 [21 %]) groups and unsatisfactory response inthe placebo group (n = 15 [12%]).

Feiger et a133 conducted a Phase III, 8-week, ran­domized, double-blind, placebo-controlled, parallel­group, flexible-dose study that evaluated oral desven­lafaxine 200 to 400 mg (n = 117) versus placebo (n =

118) at multiple sites in the United States. Patientsreceived 200 mg of the study medication daily for thefirst 14 days of the trial, which was to be decreased to100 mg/d if there was a problem with tolerance. Pa­tients then received up to 400 mg/d of the study medi­cation; dosing was based on tolerance of adverseevents. Patients who completed the study had the op­tion of enrolling in a long-term trial. Mean ages in thedesvenlafaxine and placebo groups were 37.5 and38.7 years, respectively. The mean baseline HAM-D 17total scores in the desvenlafaxine and placebo groupswere 23.3 and 23.1, respectively. Both groups hadbaseline CGI-S scores of 4.3. After the 2-week titra­tion period, mean daily doses in the ITT populationranged from 324 to 373 mg.

At end point, no significant difference was found be­tween treatment groups in the reduction of HAM-D 17total scores from baseline.U The desvenlafaxine grouphad significantly greater improvements in the follow­ing secondary efficacy measures at end point: CGI-I(P = 0.037), MADRS total score (P = 0.028), CGI-S(P = 0.041), HAM-D6 (P = 0.006), and MADRS re-

2009

R. Perry and M. Cassagnol

sponse rate (P = 0.04). During the double-blind studyperiod, adverse events were reported by 96% of pa­tients in the desvenlafaxine group and by 86% ofthose in the placebo group. Adverse events occurringin the desvenlafaxine group at ::::5% incidence andat twice the rate of the placebo group are shown inTable II. Twenty-nine patients in the desvenlafaxinegroup and 15 in the placebo group discontinued thestudy. A significantly greater number of patients in thedesvenlafaxine group (n = 15) discontinued treatmentdue to adverse events compared with the placebo group(n = 4) (P = 0.008).

Lieberman et a134 conducted a pooled analysis of2 similarly designed, Phase III, double-blind, multi­center, placebo- and active-controlled, parallel-group,flexible-dose trials of oral desvenlafaxine in adult out­patients with a primary diagnosis of MDD. The in­cluded studies were reported to be underpowered andhave a high placebo response rate. One study wasconducted in Europe and the other was conducted inthe United States. Included patients met the DSM-IVcriteria for a single or recurrent episode of MDD,without psychotic features. Eligible patients were re­quired to have baseline and initial screening scores asfollows: HAM-D 17 total score ::::22; HAM-D 17 item 1(depressed mood) score ::::2; CGI-S scale score z-l (mod­erately ill); and a Raskin Depression Rating Scale scoregreater than the Covi Anxiety Scale score. Patientswere assigned to either the desvenlafaxine, venlatax­ine ER (active control), or placebo groups; they re­ceived 8 weeks of active treatment followed by a taperperiod, based on final dose. Dosing schedules variedbetween the 2 studies. Both trials targeted 200 mg/din the desvenlafaxine group, but only the US studystarted patients on 100 mg/d, then titrated their doseto 200 mg/d on day 5. On study day 28, both studiesallowed for an increase to 400 mg/d or a decrease to200 mg/d, based on investigator judgment. Venlafax­ine ER was initiated at 75 mg/d in both trials. The UStrial had a dose increase to 150 mg/d on day 5 and to225 mg/d after day 28. The European trial had anoptional increase to 150 mg/d after day 28. The differ­ent venlataxine ER dosing data were not pooled butwere listed as 2 distinct groups: the European study(75-150 mg/d) and the US study (150-225 mg/d). Theprimary and secondary efficacy measures were similarto previous studies. All efficacy measures used theITT population (N = 713), with 226, 127, 115, and245 patients in the desvenlafaxine, venlataxine ER 75

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Clinical Therapeutics

to 150 mg/d, venlataxine ER 150 to 225 mg/d, andplacebo groups, respectively. Baseline mean age (years)and total scores on the HAM-D 17 and CGI-S weresimilar among groups (desvenlafaxine: 43, 25.4, and4.6, respectively; venlataxine ER 75-150 mg/d, 46,25.8, and 4.8, respectively; venlataxine ER 150­225 mg/d, 42, 25.1 and 4.3, respectively; and placebo,42,25.5 and 4.6, respectively).

At week 8, using the mixed-effect model for re­peated measures analysis, a significant decrease in themean HAM-D 17 total scores from baseline was ob­served in the desvenlafaxine (-14.21; P < 0.001),venlafaxine ER 75- to 150-mg/d (-14.26; P = 0.001),and venlafaxine ER 150- to 225-mg/d (-14.56; P <

0.001) groups compared with the placebo group(-11.87).34 Significant differences were observed start­ing at week 3 for the desvenlafaxine group (P = 0.022),week 6 for the venlataxine ER 75- to 150-mg/d group(P = 0.002), and week 2 for the venlataxine ER 150­to 225-mg/d group (P = 0.002). Scores on secondaryefficacy measures that achieved significance in thedesvenlafaxine group compared with the placebo groupcomprised the following: CGI-I (P < 0.001), MADRS(P < 0.001), CGI-S (P < 0.001), HAM-D6 (P < 0.001),Covi Anxiety Scale (P = 0.035), VAS-PI overall pain(P = 0.003), VAS-PI back pain (P < 0.001), VAS-PIchest pain (P = 0.037), and VAS-PI arm, leg, or jointpain (P = 0.027). Responder and remission rates be­tween the desvenlafaxine and placebo groups werenot statistically significant. Adverse events occurringin the desvenlafaxine groups at ::::5% incidence andat twice the rate of the placebo group are shown inTable II. The analysis was not designed for direct com­parison between the 3 active-treatment groups. There­fore, a conclusion cannot be drawn regarding the ef­ficacy of desvenlafaxine versus venlataxine.

Efficacy and tolerability of the FDA-approved oraldaily dose of desvenlafaxine 50 mg in the treatment ofadults with MDD was reported in the trials conductedby Liebowitz et a128 and Boyer et a129 in comparisonwith placebo and desvenlafaxine 100 mg. The othershort-term trials reported inconsistent benefits whenusing doses >50 mg.

Long-Term Treatment ofMajor Depressive Disorder

Desvenlafaxines efficacy in the long-term treat­ment of MDD is supported by preliminary data fromthe abstracts of 4 studies presented at scientific meet-

1390

ings. Rickels et a135 conducted a 6-month, Phase III,multicenter, randomized, flexible-dose, parallel-group,placebo-controlled, double-blind trial with a primaryefficacy end point of time until relapse in adult outpa­tients who had previously responded to treatment in a12-week, open-label, flexible-dose trial of oral desven­lafaxine 200 to 400 mg/d. Relapse was defined by::::1 of the following criteria: HAM-D 17 score ::::16 atany visit; CGI-I score ::::6 at any visit; or discontinua­tion due to unsatisfactory response. Although the pri­mary end point was not reported, the desvenlafaxinegroup had significantly fewer relapses than the place­bo group (24% vs 42%, respectively; P < 0.001). Atend point, the HAM-D 17 total score in the desvenla­faxine group was improved compared with placebo(P values not reported). In the desvenlafaxine group, themost frequently reported adverse events included nau­sea, dizziness, asthenia, abnormal dreams, headache, andsweating (incidence not reported).

The long-term efficacy of desvenlafaxine was also as­sessed as a secondary end point in a 12-month, Phase III,multicenter, open-label, flexible-dose study that en­rolled adult outpatients (N = 99) with MDD and amean HAM-D 17 total score of 21.15 at baseline.s"Change in baseline on the HAM-D 17 total score wasthe primary efficacy end point. The mean daily dosewas >300 mg by mouth; a majority of patients report­edly received 400 mg. At final observation, the meanchange in total HAM-D 17 score was -9.92 (clinicalsignificance not reported). Nausea and headache werereported during the study (Table II).

Long-term efficacy and efficacy after a switch todesvenlafaxine were assessed in a 10-month extensionstudy of outpatients with MDD from 2 previous8-week, randomized, double-blind studies.F Patientswere switched to open-label oral desvenlafaxine 200to 400 mg/d from the previous short-term study ofvenlataxine ER (n = 175), desvenlafaxine (n = 143), orplacebo (n = 176). The HAM-D 17 was the primaryscale used to assess efficacy. Response rate, describedas a CGI-I score of 2 or a 50% reduction in HAM-D 17or MADRS scores, was also assessed. At the end of thedouble-blind period, patients were classified as respond­ers (n = 360) or nonresponders (n = 134). ResponderHAM-D 17 scores were not reported. HAM-D 17 meanscores for nonresponders at double-blind baseline forgroups initially receiving venlataxine ER, desvenlafax­ine, and placebo were 26.5, 25.2, and 25.2, respec­tively; open-label baseline scores were 21.8,20.5, and

Volume 31 Theme Issue

21.3, respectively; and end point FOT scores were14.5, 12.7, and 10.5, respectively. Response rates us­ing the HAM-D 17 definition were 53%, 48%, and67% for the nonresponder group initially receivingvenlataxine ER, desvenlafaxine, and placebo, respec­tively; the rates for the responder group were 87%,83%, and 84%, respectively. Although rates of spe­cific adverse events were not reported, discontinua­tion rates were 16%, 11%, and 23 % for those initiallyreceiving venlafaxine ER, desvenlafaxine, and place­bo, respectively (P values not reported).

A 10-month, open-label, extension study for par­ticipants enrolled in 2 prior double-blind, 8-weekoutpatient studies (previously randomized to receiveoral desvenlafaxine, venlataxine ER, or placebo) wasconducted.i" The primary objective was to assess tol­erability of desvenlafaxine 200 mg/d after a switchfrom venlataxine ER (n = 183) compared with thoseswitched from placebo (n = 186). Only rates of nauseaduring the first month and discontinuation due toadverse events during the first week after the switch todesvenlafaxine were reported. A significant differencein the rates of nausea between groups was observedduring the first 2 weeks after the switch to desvenla­faxine (week 1: placebo to desvenlafaxine, 35%; ven­lafaxine ER to desvenlafaxine, 4% [P < 0.001]; week 2:placebo to desvenlafaxine, 3%; venlataxine ER todesvenlafaxine, 0% [P = 0.03]). By weeks 3 and 4,nausea rates for both groups were 2%. Nine percentof patients switched from placebo to desvenlafaxine,and 1% in the venlataxine ER to desvenlafaxinegroup discontinued treatment during the first week dueto adverse events (P values not reported).

Because results regarding the long-term efficacy ofdesvenlafaxine are available only in abstract form,this aspect of the drug cannot be fully evaluated. Thedata have provided some preliminary evidence thatdesvenlafaxine may be efficacious in preventing MDDrelapse and that patients switched to desvenlafaxineafter being treated with venlataxine ER may have adecreased risk of initially developing nausea. Becausethe data are limited, however, a final conclusion can­not be made.

Vasomotor Symptoms AssociatedWith Menopause

The manufacturer has submitted a separate NewDrug Application for desvenlafaxine to the FDA re­garding the treatment of menopause-associated VMS.45

2009

R. Perryand M. Cassagnol

Specific VMS symptoms targeted for treatment in­clude hot flushes, night sweats, and associated sleepdisruptions.F'<'" Although desvenlafaxine has not beenapproved for these indications, there are several stud­ies evaluating its efficacy for VMS associated withmenopause (Table III).3 9,42,43 Results of secondary end­point evaluations are summarized in Table IV,3 9,42,43

and adverse events are summarized in Table V.3 9,42,43

Speroff et a139 conducted a 52-week, randomized,double-blind, fixed-dose, placebo-controlled trial atmultiple centers in the United States to assess the ef­ficacy of desvenlafaxine in the treatment of hot flushesin postmenopausal women. To be eligible for enrollment,patients had to experience >7 self-reported moderate tosevere hot flushes per day or ::::50 per week. Patientswere randomized in a 2:2:2:2:1 fashion to oral des­venlataxine 50 mg (n = 141),100 mg (n = 145),150 mg(n = 137), or 200 mg (n = 120) or to placebo (n = 77).The study design did not call for dosage titration.Patients recorded frequency and severity of hot flushesand nighttime awakenings due to hot flushes. Severitywas defined as follows: (1) mild, fleeting warm sensa­tion with no perspiration that does not disrupt activi­ty; (2) moderate, warm sensation with sweating thatdoes not disrupt activity; or (3) severe, hot sensationwith sweating that disrupts activity. Although the triallasted for 52 weeks, efficacy evaluations were con­ducted only at weeks 4 and 12.

The primary efficacy measures were the changefrom baseline to week 12 in the mean daily number ofmoderate to severe hot flushes and the mean dailyseverity score of hot flushes compared with placebo.v?Secondary efficacy evaluations included the meanchange from baseline in the daily number of mild,moderate, and severe hot flushes; the mean changefrom baseline in the daily number of nighttime awaken­ings due to hot flushes; the proportion of womenachieving ::::75% reduction from baseline in the meandaily number of hot flushes (50% reductions werealso evaluated but results were not provided); and themedian time to 50% reduction in number of hotflushes for 3 consecutive days (defined as onset of ac­tion). Patients' mean age was 53.47 years. Baselinemean daily number of moderate to severe hot flusheswas 10.9, and the mean number of nighttime awaken­ings was 3.7.

At week 4, only patients in the desvenlafaxine100-mg group had a significantly greater decrease frombaseline in the mean daily number of moderate to se-

1391

Tabl e III. Efficacy of desven lafaxine (DVS) in clinica l t rials for the t reatment ofvasomotor symptoms assoc iate d wit h menopa use......(JJ10N

~i:3I'D(JJ.....-l::rI'D

3I'D

Study

Speroff et al39

Archer et a l42

Archer et a l43

Study Design/Dura tion

MC , R, DB, FI,PC/52 weeks

MC, R, DB, FI,PC/ 12 wee ks

MC , R, DB, FI,PCj 26 weeks

No. ofPatients

(ITT)

620

436

484

Trea tm ent Groups

DVS 50 mg (n = 141);DVS 100 mg (n = 145);DVS 150 mg (n = 137 );DVS 200 mg (n = 120);PBO (n = 77)

DVS 100 mg (n = 143) ;DVS 150 mg (n = 143);PBO (n = 150 )

DVS 100 mg (n = 162);DVS 150 mg (n = 144);PBO (n = 178)

Primary Effica cy Measures a ndResul ts (Fina l Evalu at ion , LO CF)

Chan ge from baseline to week 12 in t he mean daily number of mod erat e tosevere HFs

DVS 50 mg: -6.10 (P = 0.326)DVS 10 0 mg : -7.23 (P = 0.005 )DVS 150 mg : -6 .94 (P = 0.02 0)DVS 20 0 mg: - 6 .46 (P = 0.130)PBO: - 5.50

Chan ge fro m baseline to wee k 12 in t he mean daily severity score of HFsDVS 50 mg: - 0.43 (P = 0.754)DVS 10 0 mg : - 0.80 (P = 0.0 02)DVS 150 mg : - 0 .59 (P = 0.23 5)DVS 20 0 mg: -0.74 (P = 0.013)PBO: - 0.47

Cha nge from baseline to wee k 12 in t he mean daily nu mb er of mod erate tosevere HFs

DVS 10 0 mg : -7.1 (P = 0 .005)DVS 150 mg: - 7.0 (P = 0.012)PBO: - 5.8

Chan ge from baseline to wee k 12 in t he mean daily severity sco re ofmoderate to severe HFs

DVS 10 0 mg : -0.65 (P < 0.001 )DVS 150 mg: - 0 .66 (P < 0.001)PBO: - 0.33

Chan ge fro m baseline to wee k 12 in t he mean daily nu mb er of mod erat e tosevere HFs

DVS 10 0 mg: -6.3 (P = 0.002)DVS 150 mg: -7.0 (P < 0.00 1)PBO: - 4. 9

Chan ge fro m baseline to wee k 12 in t he mean daily severity score ofmoderate to severe HFs

DVS 100 mg: -0.54 (P = 0.002)DVS 150 mg: - 0 .71 (P < 0.001 )PBO: - 0.28

Q:::l;:;.~

-l::rI'D

P:l"'0I'Dc...;:;.III

IIIIIIcI'D

ITT ~ intent-to-treat popu lation; LOCF ~ last-observation-carried-forward; MC ~ multicenter; R ~ randomized; DB ~ doub le-blind, FI ~ fixed dose; PC - placebo­controlled; PBO ~ placebo; HFs ~ hot flushes.

R. Perry and M. Cassagnol

Tabl e IV. Res ults of secondary efficacy measures at end po int (week 12) in clinical trials eval uating desvenla­fa xine (DVS) for t he treatment of vasomotor symptoms associated with menopause.

Study

Speroff et a J39

Archer et a l42

2009

Secondary Efficacy Measures

No. of mild, moderate, and severe HFs(mea n cha nge from baseline)

DVS 50 mgDVS 100 mgDVS 150 mgDVS 200 mgPlacebo

No. of nighttime awakenings (mea n changefrom baseline)

DVS 50 mgDVS 100 mgDVS 150 mgDVS 200 mgPlacebo

75% Responder ra te (~ 75% reduct io n fro mbaseline in mean da ily number of HFs)

DVS 50 mgDVS 100 mgDVS 150 mgDVS 200 mgPlacebo

Time to onset of action , d (me dian time to50% redu ctio n in number of HFs fo r3 co nsecut ive days)

DVS 50 mgDVS 100 mgDVS 150 mgDVS 200 mgPlacebo

Weekly weighted severit y sco re (mean sco recha nge from baseline)

DVS 100 mgDVS 150 mgPlacebo

No. o f mild, moderate, a nd severe HFs(mean change from baseline)

DVS 100 mgDVS 150 mgPlacebo

Results by TreatmentGroup (ITT Po pula t io n,Final Eva luation , LOCF)

- 6.47-7.44-7.40- 6.79-5.88

- 2.30- 2.77- 2.69-2 .68- 2.21

33.3%50 .0%40 .9%45 .0%28.6%

12.07.06.05.0

24.0

-143.5-139.7-123.3

-7.7-7.2- 6.1

P vsPlacebo

0.3650.0160.0200.175

0.6720.0130.0340.043

0.4730.0030.0780.022

0.0270.001

<0.00 1<0.001

0.0060.025

0.0030.036

(continued )

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Clinical Therapeutics

Tabl e IV (co nt inued) .

Results by TreatmentGroup (ITT Popu lati on , Pvs

Study Secondary Eff icacy Measures Fina l Eva lua t io n, LO CF) Pla ceb o

Arch er et a l42 No. of nightti me awakenings (mean cha nge(co nt) from base line)

DVS 100 mg -2 .0 0.00 3DVS 150 mg - 1.8 0.048Placeb o - 1.4

Med ian t ime to ~50% reducti on in numbe r ofHFs, d

DVS 100 mg 7.0 <0.001DVS 150 mg 8 .0 <0.001Placeb o 25 .0

~50% Resp onder rate (~5 0% redu ction ofmoderate to severe HFs)

DVS 100 mg 74 .8% <0.001DVS 150 mg 77.6% <0.001Placebo 51.3%

~75% Respo nd er ra te (~75% reducti o n ofmod erate to severe HFs)

DVS 100 mg 49.7% <0.001DVS 150 mg 53.2% <0.001Placeb o 29.3%

Archer et a l43 Weekly weighted severit y score (mea n scorecha nge from baseline to week 12)

DVS 100 mgDVS 150 mgPlaceb o

No. of mild , moderate, a nd severe HFs(mean change from baseline to week 12)

DVS 100 mgDVS 150 mgPlaceb o

No. of nighttime awa kenings (mean cha ngefrom baseline to week 12)

DVS 100 mgDVS 150 mgPlaceb o

Median tim e to ~50% reduction in no. of HFs, dDVS 100 mgDVS 150 mgPlaceb o

- 122. 2- 135.5

- 98 .8

- 7.3- 7.7- 5 .6

- 2.0- 2.4

1.6

7.07.0

28 .0

0.002<0.001

0.003<0.001

0.0 26<0.001<0.001

<0.001<0.001

(co nt inued)

1394 Volume 31 Theme Issue

R. Perry and M. Cassagnol

Table IV (continued) .

Stud y

Archer et a l43

(cant)

Secondar y Efficacy Measures

;::50% Respond er rate (:e: 50% reduction ofmod erat e to severe HFs)

DVS100mgDVS 150 mgPlacebo

;::75% Respond er rat e (:e:75% red uction ofmod erat e to severe HFs)

DVS100mgDVS 150 mgPlacebo

Results by TreatmentGroup (ITT Populat ion,Fina l Evaluation, LOCF)

67.9%75.0%47.8%

41.4%45 .1 %26.4%

P vsPlacebo

<0.001

0.004<0.001

ITT = intent-to-t rea t ; LO CF = la st-o bserva t ion -ca rr ied -forward ; HFs = hot fl ush es.

vere hot flushes compared with those in the placebogroup (-6.62 vs -5.22; P = 0.013).3 9 The decrease inthe mean daily number of mild, moderate, and severehot flushes was significantly greater for patients re­ceiving desvenlafaxine 100, 150, and 200 mg com­pared with those receiving placebo at week 4 (P =

0.004, P = 0.006, and P = 0.016, respectively). Signifi­cance was also observed at week 4 in the percentageof women who achieved a ;::75% reduction from base­line in mean daily number of hot flushes in the desven­lafaxine 100-, 150-, and 200-mg groups comparedwith the placebo group (P = 0.005, P = 0.003, andP = 0.021, respectively).

At week 12, decreases from baseline in the meandaily number of moderate to severe hot flushes were55% (-6.10 hot flushes), 64% (-7.23 hot flushes; P =

0.005),60% (-6.94 hot flushes; P = 0.020), and 60%(-6.46 hot flushes) for the desvenlafaxine 50-, 100-,150-, and 200-mg groups, respectively, and 51 %(-5.50 hot flushes) for the placebo group.t? Signifi­cantly greater decreases in mean daily weighted severi­ty scores were observed in the desvenlafaxine 100-mg(31 % reduction; P = 0.002) and 200-mg (27% reduc­tion; P = 0.013) groups compared with placebo (18%reduction). There were significantly more patients inthe desvenlafaxine 100- and 200-mg groups with a75% responder rate than in the the placebo group (P =

0.003 and P = 0.022, respectively). The mean number

2009

of nighttime awakenings significantly decreased in thedesvenlafaxine 100-mg (-2.77; P = 0.013), 150-mg(-2.69; P = 0.034), and 200-mg (-2.68; P = 0.043)groups compared with those in the placebo group(-2.21). The previously defined median time to onsetof action occurred within 1 week for the desvenlafax­ine groups and between 3 and 4 weeks with placebo(P values not reported). Additionally, a significantlygreater number of women in the desvenlafaxine 100-mggroup reported being "satisfied" or "extremely satis­fied" with control of hot flushes during the day com­pared with the placebo group (P = 0.002). Similarsatisfaction rates for nighttime control of hot flusheswere found to be significant in the desvenlafaxine100-mg (P < 0.001), 150-mg (P = 0.018), and 200-mg(P = 0.029) groups compared with the placebo group.i''Although results included in this article only reportedefficacy findings at weeks 4 and 12, data from an ab­stract reported that patients observed in the desvenla­faxine 100-mg group experienced a statistically sig­nificant reduction in the frequency and number ofmoderate to severe hot flushes up to week 52 com­pared with placebo (P < 0.05, all cornparisonsj."!

The first 12 weeks of treatment were completedby 83.7% of the study population; 59.4% completed:e:50 weeks.I" The total number of discontinuationswas significantly greater in the desvenlafaxine groupsthan in the placebo group (P = 0.04). The most com-

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Clinical Therapeutics

Table V. Adverse event s occurring at ~5% incid ence during th e doubl e-b lind period in t rials eval uating desven-lafaxine (DVS) fo r t he treatment of vasomotor symptoms associated with menopause. Values aregiven as no . (%) of patients in th e safety population.

Study Adve rse Event Incidence

Speroff et aJ39 DVS DVS DVS DVS50 mg 100 mg 150 mg 200 mg Placebo

(n = 149) (n = 155) (n = 157) (n = 151) (n = 77)Ast henia 11 (7) 30 (19) 27 (17) 23 (15) 7 (9)Chills 5 (3) 8 (5) 6 (4) 11 (7) aHypert ension 6 (4) 8 (5) 10 (6) 12 (8) 1 (1)Anorexia 7 (5) 9 (6) 13 (8) 15 (10) 2 (3)Co nst ipatio n 16 (11) 27 (17) 25 (16) 27 (18) 8 (10)Diarrhea 17 (11) 12 (8) 9 (6) 14 (9) 6 (8)Dry mou t h 18 (12) 33 (21) 31 (20) 35 (23) 3 (4)Nau sea 41 (28) 60 (39) 75 (48) 68 (45) 5 (7)Vomiting 8 (5) 11 (7) 11 (7) 17 (11) aHyperchol esterolemia 6 (4) 9 (6) 5 (3) 9 (6) 3 (4)Hyperl ipidemia 5 (3) 8 (5) 4 (3) 9 (6) aWeight gain 4 (3) 9 (6) 12 (8) 5 (3) 3 (4)Confus ion 1 « 1) 4 (3) 8 (5) 2 (1) aDizziness 17 (11) 30 (19) 29 (19) 41 (27) 6 (8)Inso mnia 23 (15) 27 (17) 43 (27) 39 (26) 8 (10)Decreased libido 2 (1) 5 (3) 3 (2) 8 (5) 1 (1)Ner vou sness 11 (7) 12 (8) 20 (13) 19 (13) 2 (3)So mnolence 7 (5) 24 (16) 30 (19) 36 (24) 3 (4)Abnormal th inking 3 (2) 4 (3) 8 (5) 7 (5) 1 (1)Ra sh 9 (6) 3 (2) 4 (3) 1 « 1) 2 (3)Sweati ng 2 (1) 4 (3) 2 (1) 9 (6) aAbn o rmal visio n 5 (3) 9 (6) 14 (9) 1a (7) 1 (1)Mydr ia sis 1 « 1) 4 (3) 10 (6) 9 (6) a

Archer et a l42 DVS DVS100 mg 150 mg Placeb o

(n = 150) (n = 151) (n = 151)Asth enia 17 (11) 19 (13) 6 (4)Hypert ens ion 8 (5) 6 (4) 2 (1)Ano rexia 9 (6) 6 (4) 1 « 1)Co nst ipatio n 14 (9) 20 (13) 2 (1)Diarrhea 9 (6) 5 (3) 5 (3)Dry mo uth 30 (20) 19 (13) 4 (3)Nau sea 43 (29) 33 (22) 11 (7)Dizziness 17 (11) 18 (12) 11 (7)Inso mnia 9 (13) 17 (11) 9 (6)So mnolence 14 (9) 14 (9) 1 « 1)Mydria sis 8 (5) 1 « 1) a

(continued)

1396 Volume 31 Theme Issue

R. Perry and M. Cassagnol

Table V (co ntinu ed) .

St udy Adverse Event Incidence

Archer et a l43 DVS DVS100 mg 150 mg Placeb o

(n = 182) (n = 179) (n = 180 )Asth enia 21 (12) 31 (17) 9 (5)Chills 7 (4) 9 (5) 1 « 1)Hyper tension 13 (7) 5 (3) 7 (4)Ano rexia 9 (5) 16 (9) 3 (2)Co nstipation 21 (12) 28 (16) 1a (6)Diarrhea 17 (9) 14 (8) 5 (3)Dry mou t h 26 (14) 33 (18) 5 (3)Nau sea 82 (45) 79 (44) 15 (8)Vo mit ing 17 (9) 20 (11) 3 (2)Hyperc holest ero lemia 8 (4) 11 (6) 7 (4)Dizziness 35 (19) 41 (23) 12 (7)Inso mnia 29 (16) 35 (20) 18 (10)Nervou sness 15 (8) 20 (11) 4 (2)Som no lence 22 (12) 20 (11) 4 (2)Abn orma l vision 4 (2) 9 (5) 2 (1)Mydriasis 3 (2) 11 (6) a

mon reason for discontinuation in all groups was ad­verse events, which was significantly higher in thedesvenlafaxine 150- and 200-mg groups comparedwith the placebo group (P < 0.001). During the firstweek on therapy, all desvenlafaxine groups had sig­nificantly higher numbers of discontinuations due toadverse events compared with placebo (P < 0.001).Although an exact number was not provided, nauseawas a common reason for discontinuation.

Archer et a142 conducted a 12-week, randomized,double-blind, fixed-dose, placebo-controlled trial atmultiple sites in the United States in postmenopausalwomen with ::::50 moderate to severe hot flushes perweek. Patients were randomly assigned to 1 of 3 treat­ment groups to receive daily, oral desvenlafaxine 100 mg(n = 143) or 150 mg (n = 143) or placebo (n = 150).Patients in the desvenlafaxine 100-mg group had theirdose titrated to the study dose after 3 days of receivingdesvenlafaxine 50 mg/d. Patients in the desvenlafaxine150-mg group received desvenlafaxine 50 mg/d forthe first 3 days, then 100 mg/d for 4 days, and then150 mg/d for the remainder of the study. After the12-week study period, the treatments were taperedover 2 weeks. The primary efficacy evaluations were

2009

the change from baseline to weeks 4 and 12 in the meandaily number and severity of moderate to severe hotflushes compared with placebo. Secondary efficacy evalua­tions included a change from baseline in: (1) the weeklyweighted severity score calculated as 2 times the numberof moderate hot flushes plus 3 times the number of severehot flushes; (2) total number of hot flushes (mild, moder­ate, and severe); and (3) the number of nighttime awak­enings due to hot flushes. Additionally, the median timeto reach a ::::50% decrease in number of hot flushes frombaseline (considered time to onset of efficacy) and therate of a ::::50% and ::::75% reduction of moderate tosevere hot flushes were secondary end points. The meanage of patients in the desvenlafaxine 100- and 150-mggroups and the placebo group were 53.29,53.43, and53.36 years, respectively. At baseline, the mean dailynumber of moderate and severe hot flushes in the des­venlalaxine 100- and 150-mg groups and the placebogroup was 11.1,10.5, and 10.9, respectively. At baseline,the mean number of nighttime awakenings due to hotflushes in the desvenlafaxine 100 mg, desvenlafaxine150 mg, and placebo groups were 3.3,3.1, and 3.2, re­spectively. At baseline, the mean daily severity score ofhot flushes in all groups was 2.4.

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Clinical Therapeutics

At week 12, the desvenlafaxine groups reportedsignificantly more improvement in the primary andsecondary end-point evaluations compared with theplacebo group (Tables III and IV).42 The number ofhot flushes at week 12 was reduced by 65% and 67%from baseline in the desvenlafaxine 100- and 150-mggroups, respectively, compared with a 51 % reductionin the placebo group (P = 0.005 and P = 0.012, respec­tively). The daily severity score decreased by a meanscore of 0.65 and 0.66 from baseline in the desvenla­faxine 100- and 150-mg groups, respectively, com­pared with a mean score reduction of 0.33 in theplacebo group (both desvenlafaxine groups comparedwith placebo, P < 0.001).

The study was completed by 83.4% and 90.1 % ofpatients in the desvenlafaxine 100- and 150-mg groups,and by 87.3% in the placebo group.v Adverse eventswere the main reason for discontinuation in all groups,although the specific adverse events leading to discon­tinuation were not reported. The number of patientsreporting adverse events during the first week was sig­nificantly greater in the desvenlafaxine groups com­pared with placebo (53% vs 31 %; P < 0.001). Adverseevents occurring in the desvenlafaxine groups at ::::5%incidence are shown in Table V.

Archer et a143 conducted a 26-week, randomized,double-blind, fixed-dose, placebo-controlled trial atmultiple sites in the United States in postmenopausalwomen (mean age, 53.7 years) with ::::50 moderate tosevere hot flushes per week. Patients were randomlyassigned to 1 of 3 groups to receive daily oral desven­lafaxine 100 mg (n = 162) or 150 mg (n = 144) orplacebo (n = 178). There was no titration period at thebeginning or taper period at the end of the trial. Theprimary efficacy evaluations were the change frombaseline to weeks 4 and 12 in the mean daily numberand severity of moderate to severe hot flushes com­pared with placebo. Secondary efficacy evaluationsincluded a change from baseline in: (1) the weeklyweighted severity score calculated as 2 times the num­ber of moderate hot flushes plus 3 times the numberof severe hot flushes; (2) total number of hot flushes(mild, moderate, and severe); and (3) the number ofnighttime awakenings due to hot flushes. Additionally,the median time to reach a ::::50% decrease in the num­ber of hot flushes from baseline (considered time toonset of efficacy) and the rate of a ;:::50% and ;:::75%reduction of moderate to severe hot flushes were as­sessed. The mean age of patients in the desvenlafaxine

1398

100-mg, desvenlafaxine 150-mg, and placebo groupswas 53.29, 53.43, and 53.36 years, respectively. Atbaseline, the mean daily number of moderate and se­vere hot flushes in the desvenlafaxine 100-mg, desven­lafaxine 150-mg, and placebo groups was 11.1, 10.5,and 10.9, respectively. At baseline, the mean numberof awakenings per night due to hot flushes in the des­venlafaxine 100-mg, desvenlafaxine 150-mg, and pla­cebo groups was 3.3, 3.1, and 3.2, respectively. Atbaseline, the mean daily severity score of hot flushesin all groups was 2.4.

Tables III and IV present the efficacy results in thedesvenlafaxine groups on the primary and secondaryend-point evaluations compared with the placebogroup at week 12. The number of hot flushes at week12 was reduced by 60% and 66% from baseline in thedesvenlafaxine 100- and 150-mg groups, respectively,compared with a 47% reduction in the placebo group(P = 0.002 and P < 0.001, respectivelyl.f The dailyseverity score decreased by a mean score of 0.54 and0.71 from baseline in the desvenlafaxine 100- and150-mg groups, respectively, compared with a meanscore reduction of 0.28 in the placebo group (P =

0.002 and P < 0.001, respectively).By the end of the study, 67 patients discontinued

treatment in the desvenlafaxine 100-mg group and 42discontinued treatment in the desvenlafaxine 150-mggroup; 64 were discontinued from the placebo group. 43Significantly more patients discontinued treatment inthe desvenlafaxine groups compared with the placebogroup (P = 0.009). Adverse events were the main rea­son for discontinuation in the desvenlafaxine groups;the most common reasons were nausea, dizziness, in­somnia, nervousness, and headache. Adverse eventsoccurring in the desvenlafaxine groups at ::::5% inci­dence are shown in Table V.

A pooled analysis was conducted from two 12-week,double-blind, placebo-controlled trials evaluating oraldesvenlafaxine 100 and 150 mg compared with pla­cebo for VMS in postmenopausal women (N = 843)experiencing ::::50 hot flushes per week.r" Profile ofMood States total mood disturbance scores improvedin both the desvenlafaxine 100- and 150-mg groupscompared with placebo (P < 0.001 and P < 0.002,respectively). One trial from the analysis reporteda significant decrease in frequency of hot flushes inboth desvenlafaxine groups compared with placebo(P < 0.05).46 Adverse events were not reported in ei­ther abstract.

Volume 31 Theme Issue

ADVERSE EVENTSTreatment-emergent adverse events (TEAEs) foundduring clinical studies were consistent with thosereported for other SNRIs.11,47 Common (>5% inci­dence) TEAEs include dizziness, dry mouth, constipa­tion, insomnia, decreased appetite, hyperhidrosis, fatigue,abdominal pain, anxiety, blurry vision, asthenia, andabnormal ejaculation/orgasm. Nausea was reportedin 17% to 50% of patients; it was more commonlyreported in patients taking doses of desvenlafaxine>200 mg.28-32,34

NauseaThe incidence of nausea was highest during the first

week of use, with a mean duration of 14 to 17 days.28,39Parks et al 16 found that desvenlafaxine 750 mg pro­duced less nausea than did venlataxine ER 150 mg ina cohort of 6 patients; however, vomiting occurred in2 patients. Desvenlafaxine also exhibited a dose­dependent relationship, with higher doses (>200 mg/d)causing the most nausea and vomiting.

Parker et al17 conducted a randomized, crossoverstudy of 35 healthy male and female subjects who weregiven 4 oral doses of venlataxine ER 75 and 150 mgand desvenlafaxine 75 and 150 mg after a medium-fatbreakfast. Nausea induction was evaluated using a100-mm VAS for nausea. Desvenlafaxine at doses of75 and 150 mg by mouth yielded 6- and 2-fold lowerVAS scores, respectively.

Cardiovascular EffectsThe hypertensive effects of SNRIs have been de­

scribed previously, 11,47and the introduction of this newdrug into the SNRI class makes evaluating desvenlatax­ine and its cardiovascular safety profile essential.

A pooled analysis from all double-blind, 8-weektrials of outpatients with MDD was evaluated formean changes in blood pressure associated with fixeddoses of desvenlafaxine.ff Patients were randomized toreceive oral desvenlafaxine (50, 100,200, or 400 mg/d;n = 1365) or placebo (n = 636). Mean blood pressurechanges from baseline to FOT evaluation, incidence ofpotentially clinically important blood pressure chang­es, and incidence of sustained systolic blood pressure(SBP) ~140 mm Hg or a diastolic blood pressure(DBP) ~90 mm Hg for 2 or 3 consecutive visits wereassessed. Desvenlafaxine caused statistically, but notclinically, significant changes in blood pressure. Meansupine SBP increased in a dose-dependent fashion

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R. Perry and M. Cassagnol

from baseline with desvenlafaxine (50 mg, 1.2 mm Hg[P = 0.05]; 100 mg, 2.0 mm Hg [P = 0.001]; 200 mg,2.5 mm Hg [P = 0.001]; 400 mg, 2.1 mm Hg [P =

0.01]) compared with mean decreases in those takingplacebo (-1.4, P < 0.001 vs each desvenlafaxine group).Mean increases from baseline in supine DBP with des­venlataxine (50 mg, 0.7 mm Hg [P = NS]; 100 mg,0.8 mm Hg [P = 0.05]; 200 mg, 1.8 mm Hg [P = 0.001];400 mg, 2.3 mm Hg [P = 0.001]) were significant atdoses >100 mg compared with the mean decreasewith placebo (-0.6, P < 0.05 vs each desvenlafaxinegroup). Potentially clinicallysignificant sustained increasesin DBP (~10 mm Hg change from baseline or value~90 mm Hg for 3 consecutive visits) were more com­mon with desvenlafaxine (50 mg, 1.3 %; 100 mg,0.7%; 200 mg, 1.1 %; 400 mg, 2.3%) than with pla­cebo (0.5 %). In this study, postural hypotension wasdefined as a decrease in DBP ::::15 mm Hg or a de­crease in SBP ::::30 mm Hg from last supine to firststanding position. Postural decreases in blood pressurewere observed in the desvenlafaxine group comparedwith placebo for both DBP (50 mg, 2.3%; 100 mg,1.5%; 200 mg, 2.1 %; 400 mg, 4.0%; placebo, 1.9%)and SBP (50 mg, 1.6%; 100 mg, 0.5%; 200 mg, 1.8%;400 mg, 2.7%; placebo, 0.8%).48

Paul et a149 conducted a randomized, double-blind,single-center, single-dose, 4-period, crossover study in71 healthy women aged 18 to 55 years to determinethe effect of desvenlafaxine at therapeutic and supra­therapeutic doses on QT interval. Subjects were admin­istered a single oral dose of desvenlafaxine 200 mg,desvenlafaxine 600 mg, moxifloxacin 400 mg, or pla­cebo, separated by a ::::5-day washout period. QT in­tervals were recorded using an electrocardiogram. Theprimary end point was the 90% CI for the differencebetween the active treatment and placebo on the changefrom baseline in QT interval 8 hours after administra­tion. Baseline-adjusted QT intervals were analyzedusing a mixed-effects repeated measures analysis ofcovariance model. Desvenlafaxine did not affect theQT interval as measured by Fridericia's correction andthe population-based correction at the primary effi­cacy end point for both doses of desvenlafaxine.

WeightA pooled analysis of 7 short-term, double-blind,

placebo-controlled studies and 1 longer-term relapseprevention study was conducted to determine the ef­fects of desvenlafaxine on weight. 50 Adult outpatients

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Clinical Therapeutics

with MDD were randomized to receive desvenlatax­ine or placebo for 8 weeks in the short-term studiesand for 12 weeks in the longer-term study. Meanweight changes and the incidence of potentially clini­cally important changes (±7% from baseline) wereevaluated. Statistically significant small decreasesfrom baseline mean weight occurred during bothshort-term studies (desvenlafaxine, -1.0 kg; placebo,0.1 kg [P < 0.001]) and the longer-term study (desven­lafaxine, -0.8 kg; placebo, 0.1 kg [P < 0.001]). Lessthan 1% of patients taking desvenlafaxine experienceda potentially clinically important weight gain. The FOTchange in weight with desvenlafaxine across the totalexposure period was similar to that seen with placebo.Desvenlafaxine thus has a minimal effect on weightgains or losses in both short-term and long-term use.

Discontinuation SymptomsDiscontinuation symptoms commonly occur when

either SSRIs or SNRIs are abruptly stopped. In apooled analysis of 9 short-term (8-week), double-blind,placebo-controlled studies and 1 longer-term (12-week)relapse prevention study, the following were as­sessed: discontinuation symptoms, Discontinuation­Emergent Signs and Symptoms (DESS) checklist, andtaper/poststudy-ernergent adverse events (TPAEs) withdesvenlafaxine.28,30-32.51 The most common TPAEs inthe desvenlafaxine group were dizziness, nausea, head­ache, irritability, diarrhea, anxiety, abnormal dreams,fatigue, and hyperhidrosis, which occurred in up to50% patients within 1 week of discontinuation. DESSscores in the short-term studies (50 mg/d, n = 259;100 mg/d, n = 239; 200 mg/d, n = 39; 400 mg/d, n =

34; placebo, n = 319) were significantly higher in thedesvenlafaxine 50-mg tapering dose group (50 mgtapered to 0 mg, 2.5 vs 1.0 [P < 0.001]) and the 100-mgtapering dose group (50 mg tapered to 0 mg, 1.9 vs1.1 [P = 0.028]). In the longer-term trial, DESS scoreswere significantly higher at week 3 in patients receiv­ing desvenlafaxine 400 mg/d (tapering from 100 toomg, 2.2 vs 1.2 [P = 0.016]) and 200 mg/d (0 mg/dat weeks 2-3,2.3 vs 7 [P = 0.016]) versus those con­tinuing desvenlafaxine. After week 3, patients whoseregimen was tapered from desvenlafaxine 400 mg/dhad significantly higher DESS scores than those con­tinuing desvenlafaxine (3.1 vs 1.1; P = 0.022). Theseresults indicate that discontinuation symptoms occurwith cessation of desvenlafaxine use in both short­term and longer-term treatment.

1400

Suicide and Suicidal IdeationOf all the short-term (8-week), double-blind, placebo­

controlled studies and the longer-term (12-week) re­lapse prevention study, only 4 studies reported any inci­dences of suicide, suicidal attempts, or suicidal ide­ation.28,30-32 There were 4 incidences of suicidal ideation,3 intentional overdoses, 2 attempts at suicide, and1 death. The suicidal ideation began 12 days after thestart of therapy (dose not specified) in 1 case and led totreatment discontinuation.v- Two cases of suicidal ide­ation were considered not to be caused by desvenlatax­ine therapy. One case of depression with suicidal ide­ation was reported in a patient taking desvenlatax­ine 50 mg/d.28 Of the 2 reported cases of attempted sui­cide, 1 patient taking 100 mg/d intentionally overdosedon desvenlafaxine. The patient had been started on a100-mg/d regimen of desvenlafaxine; 5 days after start­ing therapy, the patient committed suicide. These find­ings show a compelling relationship between desvenla­faxine and suicidal thoughts and behaviors. As withother antidepressants, all patients taking desvenlafaxineshould be closely monitored for these behaviors, espe­cially during the first few weeks of therapy.

DOSAGE AND ADMINISTRATIONThe recommended dose of desvenlafaxine is 50 mgonce daily by mouth with or without food. 10 Althoughdoses of 50 to 400 mg/d have been shown to be ef­fective, no additional benefit was observed at doses>50 mg/d, and adverse events and discontinuationrates increased with higher doses. Long-term studieshave not evaluated the efficacy and tolerability ofdesvenlafaxine 50 mg/d. A 100-mg desvenlafaxine tab­let is available.l? but based on clinical evidence, thisdaily dose should not be regularly recommended.

Desvenlafaxine should not be used concomitantlywith venlataxine, monoamine oxidase inhibitors(MAOIs), or other SSRIs or SNRIs. Desvenlafaxineshould not be started within 14 days of stopping anMAOL In addition, there should be a minimum 7-daywashout period when switching from desvenlafaxineto an MAOL10 In patients with severe renal impair­ment (CrCI, 0:;30 mL/min) or ESRD, desvenlafaxineshould be initiated at 50 mg every other day. Dosesshould not exceed 100 mg in patients with moderateto severe hepatic impairment. When discontinuingdesvenlafaxine, it should be tapered over at least a2- to 3-week period. Desvenlafaxine has not beenevaluated in pregnant patients.

Volume 31 Theme Issue

PHARMACOECONOM IC CONSI DERATIONSThe literature search did not yield any pharrnacoeco­nomic studies. Cost-effectiveness of desvenlafaxinealone or compared with other treatments has not beenevaluated. The average wholesale price (AWP) for30 tablets of desvenlafaxine is $122.76 at either the50- or 100-mg strength. 52 The AWP for 30 capsules ofvenlataxine ER 75 mg and 150 mg is $127.37 and$138.72, respectively, while 30 capsules of both du­loxetine 30 mg and 60 mg is $134.78. Based on theAWP, desvenlafaxine is the least expensive SNRI, al­though this may change after venlafaxine ER becomesgeneric in 2011.53

DISCUSSIONCurrent evidence supports the efficacy of desvenlatax­ine 50 mg/d in the management of MDD, as well as aninconsistent additional benefit from treatment usinglarger doses.28-34 Use of doses >50 mg/d was associ­ated with increased adverse events and discontinua­tions in clinical studies.

With respect to treatment of VMS, preliminary in­formation regarding desvenlafaxines efficacy andtolerability has been reported in clinical trials. Its ap­proval on the US market is pending; the FDA has re­quested an additional randomized, placebo-controlledstudy of ~1 year's duration in postmenopausal womento assess the potential of desvenlafaxine to cause seri­ous cardiovascular and hepatic adverse events.f Cur­rently, the role of desvenlafaxine in the treatment ofVMS is difficult to assess due to the limited dataavailable.

In Europe, Wyeth Europa Ltd. has withdrawn itsapplication to market desvenlafaxine, for the treat­ment of MDD, in a letter to the Committee for Medi­cinal Products for Human Use (CHMP) of the Euro­pean Medicines Agency.54,55 At the time of applicationwithdrawal, the CHMP had concerns regarding therisks and benefits reported in studies evaluating des­venlaiaxines use in the treatment of VMS associatedwith menopause. According to Wyeth Pharmaceuti­cals, Inc., these concerns will be addressed in futureclinical trials. 56

Desvenlafaxines adverse-event rates regarding nau­sea, hypertension, and weight changes are similar tothose of venlataxine ER. There are no head-to-headstudies comparing the effectiveness of desvenlafaxinewith venlataxine ER, and, therefore, no current thera­peutic advantages are known. However, desvenlatax-

2009

R. Perry and M. Cassagnol

ine bypasses the drug interactions and polymorphicchanges in pharrnacokinetic and pharmacodynamicproperties seen with venlataxine ER, which may pro­vide practitioners with an alternative treatment option.Cost-effectiveness of treatment still must be addressed,as venlataxine ER will soon become generic.

According to postmarketing commitments to the FDA,the manufacturer of desvenlafaxine plans to: (1) as­sess the tolerability and effectiveness of desvenla­faxine as a treatment for MDD in children and ado­lescents; (2) conduct a randomized trial of oraldesvenlafaxine 10, 25, and 50 mg/d and placebo; (3)conduct long-term efficacy studies at lowest effectivedoses; (4) further assess desvenlafaxine and its effecton sexual functioning; and (5) conduct additionalembryo-fetal toxicity studies in rats.57

CONCLUSIONSThe recommended daily dose of desvenlafaxine is 50 mg,with no additional benefits observed at higher doses.The most common adverse events reported were nausea,suicidal ideation, and changes in blood pressure andweight. Future studies will need to be conducted to as­sess desvenlafaxines role in the management of MDDand its efficacy compared with other antidepressants.

ACKNOWLEDGMENTThe authors have indicated that they have no conflictsof interest regarding the content of this article.

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1403

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1404

Address correspondence to: Richard Perry, PharmD, Arnold & MarieSchwartz College of Pharmacy and Health Sciences, Long IslandUniversity, 75 DeKalb Avenue, Brooklyn, NY 11201. E-mail: Richard.Perry@UU.edu

Volume 31 Theme Issue