CNS Drugs 2008; 22 (12): 1061-1069

ADIS DRUG PROFILE 1172-7047/08/0012-1061/$48.00/0

© 2008 Adis Data Information BV. All rights reserved.

Desvenlafaxine Extended Release

Lily P.H. Yang and Greg L. Plosker
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer
Health, Conshohocken, Pennsylvania, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
1. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062
2. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
3. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1064
4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1066
5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1067
6. Desvenlafaxine Extended Release: Current Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1068

Abstract Features and properties of desvenlafaxine extended

release (Pristiq™)
▲ Desvenlafaxine extended release (ER) is a once-
daily selective serotonin-noradrenaline (norepine- Indication
phrine) reuptake inhibitor approved in the US for
the treatment of major depressive disorder in adult Approved in the US for the treatment of major depressive
disorder in adult patients
patients.
▲ In two of three well designed, 8-week clinical trials, Mechanism of action
desvenlafaxine ER 50 mg/day (the recommended
dosage) significantly improved depression at study Selective inhibition of serotonin and noradrenaline reuptake
end, as assessed by the 17-item Hamilton Rating Dosage and administration
Scale for Depression (primary endpoint), compared
with placebo. Recommended dose 50 mg
▲ A significant difference between desvenlafaxine ER
Route of administration Oral
50 mg/day and placebo treatment groups was
achieved in some, but not all, secondary measures Frequency of administration Once daily
of depression or anxiety in two of three trials,
including the Clinical Global Impression-Improve- Pharmacokinetic profile after oral administration
ment and -Severity scales, the Montgomery-Åsberg Absolute bioavailability 80.5%
Depression Rating Scale and the Covi Anxiety
Scale. Plasma protein binding 30%
▲ In two of three trials, patients receiving desven-
Mean time to maximum plasma ≈7.5 h
lafaxine ER 50 mg/day for 8 weeks experienced concentration
greater improvements in health-related quality of
life (as assessed by the Sheehan Disability Scale Time to steady state 4–5 days
and the WHO 5-item Well-Being Index) than those
receiving placebo. Mean elimination half-life ≈11 h

▲ Desvenlafaxine ER 50 mg/day was generally well Most common adverse events (≥5% incidence and >2-fold
tolerated by patients in 8-week trials. Most cases of that of placebo)
nausea, the most common adverse event, were of
Nausea, dizziness, hyperhidrosis, constipation, decreased
mild to moderate severity. appetite
1062
OH
CH3
N
CH3
OH
Desvenlafaxine
Major depressive disorder is characterized by a
mood change to sadness or irritability, accompanied
by other changes including disturbances in sleep,
appetite or sexual desire.[1] It is a common condi-
tion, with recent estimates of lifetime prevalence of
12.8% in Europe[2] and 13.2% in the US,[3] and
poses a significant global disease burden, account-
ing for 4.5% of total disability-adjusted life-years.[4]
Although the underlying mechanism of depres-
sion is not known, it is thought that a deficiency in
monoamines (particularly of serotonin and norad-
renaline [norepinephrine]) plays a role.[1] Antide-
pressants with established clinical efficacy enhance
the levels of monoamines by various mechanisms,
such as inhibition of serotonin reuptake.[1] The re-
commended treatment of major depressive disorder
includes pharmacotherapy with antidepressants such
as TCAs, MAOIs, selective serotonin reuptake in-
hibitors (SSRIs) and selective serotonin-noradrena-
line reuptake inhibitors (SNRIs).[5,6]
Until recently, only two SNRIs (venlafaxine[7]
and duloxetine[8]) were indicated for major depres-
sive disorder. In February 2008,[9] a third SNRI,
once-daily desvenlafaxine extended release (ER)
[Pristiq™]1, received US FDA approval for the treat-
ment of major depressive disorder.[10] This profile
provides an overview of the pharmacological
properties, therapeutic efficacy and tolerability of
desvenlafaxine ER in adult patients with major de-
pressive disorder. Medical literature on the use of
desvenlafaxine in major depressive disorder was
identified using MEDLINE and EMBASE, supple-
mented by AdisBase (a proprietary database of
Wolters Kluwer Health | Adis). Additional refer-
1 The use of trade names is for product identification purposes only and does not imply endorsement.
© 2008 Adis Data Information BV. All rights reserved.
Yang & Plosker
ences were identified from the reference lists of
published articles.
1. Pharmacodynamic Profile
The pharmacodynamic properties of desven-
lafaxine discussed in this section are based on the
US prescribing information,[10] a fully published in
vitro study,[11] and an abstract and poster.[12]
● Desvenlafaxine ER contains the succinate salt
form of desvenlafaxine (O-desmethylvenlafax-
ine),[10] which is the major active metabolite of
venlafaxine.[7]
● Like venlafaxine,[7] the mechanism of action of
desvenlafaxine is selective inhibition of serotonin
and noradrenaline reuptake.[10] In in vitro studies,
desvenlafaxine has shown greater inhibition of sero-
tonin (concentration required for 50% inhibition
[IC50] 47.3 nmol/L) and noradrenaline (IC50
531.3 nmol/L) reuptake than that of dopamine (62%
inhibition at 100 μmol/L).[11] Desvenlafaxine does
not have significant in vitro affinity for other neuro-
transmitter receptors, such as α1-adrenergic, H1-
histaminergic or muscarinic-cholinergic recep-
tors.[10]
● The relationship between serotonin and norad-
renaline reuptake inhibition and the dose of
desvenlafaxine ER has not been reported; however,
desvenlafaxine ER 50 mg/day is associated with
some gastrointestinal adverse events (section 4),
which may indicate that this dosage inhibits seroto-
nin reuptake.[13]
● Although desvenlafaxine does not inhibit mono-
amine oxidase activity, potential drug interactions
between SNRI agents and other serotonergic drugs
can lead to serotonin syndrome.[10] Therefore, care
must be taken to avoid concomitant administration
of desvenlafaxine ER and MAOIs (see section 5).
Systematic evaluation of concomitant administra-
tion of desvenlafaxine ER and other CNS-active
drugs has not been performed; caution is recommen-
ded when desvenlafaxine ER is coadministered with
other CNS-active (including serotonergic) drugs.[10]
CNS Drugs 2008; 22 (12)
Desvenlafaxine Extended Release: Adis Drug Profile
● The effects of desvenlafaxine ER on QT interval
prolongation are not considered clinically signif-
icant. In 71 healthy female volunteers aged
18–55 years, a single oral dose of desvenlafaxine ER
200 or 600 mg did not prolong the QT interval to a
clinically relevant degree; the QT interval was
corrected by Fridericia’s formula or by a population
correction.[12]
● As with all SSRIs and SNRIs, concomitant ad-
ministration of NSAIDs (including aspirin) or war-
farin with desvenlafaxine ER may increase the risk
of bleeding; therefore, careful monitoring is recom-
mended for patients receiving these medications,
particularly during the initiation and discontinuation
of desvenlafaxine ER.[10]
● The concomitant administration of desvenlafax-
ine ER with electroconvulsive therapy has not been
evaluated.[10]
2. Pharmacokinetic Profile
As no pharmacokinetic parameters have been
reported for the US-recommended dosage of
desvenlafaxine ER (50 mg/day), this section in-
cludes discussion of studies that utilized higher, off-
label dosages; the discussion is based on the US
prescribing information,[10] a fully published
study,[14] abstracts,[15,16] and abstracts and pos-
ters.[17,18]
● The absolute bioavailability following a single
oral dose of desvenlafaxine ER 100 mg is 80.5% of
that of a single intravenous dose of desvenlafaxine
50 mg given over 1 hour.[17] Following oral adminis-
tration, the maximum plasma concentration (Cmax)
is reached after a mean of ≈7.5 hours.[10]
● At single oral doses of 100–600 mg, desven-
lafaxine ER demonstrated linear pharmacokinetic
properties.[10] Following oral administration, the
plasma concentration and systemic exposure to the
R- and S-enantiomers of desvenlafaxine were ap-
proximately equal.[17]
● Following once-daily administration, steady
state is reached in 4–5 days.[10] Multiple dosages of
desvenlafaxine ER demonstrate linear dose accumu-
lation, which can be predicted from the single-dose
profile.[10]
© 2008 Adis Data Information BV. All rights reserved.
1063
● Administration of desvenlafaxine ER with food
did not have clinically significant effects on system-
ic exposure.[10]
● Plasma protein binding of desvenlafaxine is
30%; binding is independent of drug concentra-
tion.[10] Following intravenous administration, the
volume of distribution at steady state is 3.4 L/kg.[10]
● Desvenlafaxine is metabolized primarily by con-
jugation (mediated by uridine 5′-diphospho-
glucuronosyltransferases) and, to a lesser extent,
through oxidative N-demethylation (mediated by
cytochrome P450 [CYP] 3A4 but not CYP2D6).[10]
● The mean elimination half-life of desvenlafaxine
ER is ≈11 hours.[10] Following oral administration of
desvenlafaxine ER, ≈45% is excreted as unchanged
drug in the urine at 72 hours, ≈19% is excreted as the
glucuronide metabolite, and <5% as the oxidative
metabolite (N, O-didesmethylvenlafaxine).[10] Urin-
ary excretion of the unchanged R- and S- enanti-
omers of desvenlafaxine and their conjugated meta-
bolites was approximately equal.[17]
Drug Interactions and Special
Patient Populations
● As the CYP3A4 pathway has a role in desven-
lafaxine metabolism, there is potential for drug in-
teractions between desvenlafaxine ER and drugs
that affect, or are substrates of, CYP3A4. In
15 healthy adult volunteers receiving the potent
CYP3A4 inhibitor ketoconazole (200 mg every
12 hours for 7 days), systemic exposure to a single
oral dose of desvenlafaxine ER 400 mg was higher
than in those who did not receive ketoconazole
(mean increases of 8% in Cmax and 43% in area
under the plasma concentration-time curve
[AUC]).[15] This increase in systemic exposure was
not deemed clinically relevant, indicating that a
dosage adjustment of desvenlafaxine ER would not
be needed when administered concomitantly with
CYP3A4 inhibitors.[15]
● In vitro studies indicate that desvenlafaxine does
not inhibit CYP3A4, as assayed with the CYP3A4
substrates midazolam and testosterone;[18] however,
coadministration of desvenlafaxine ER 400 mg/day
with a single dose of midazolam 4 mg decreased the
CNS Drugs 2008; 22 (12)
1064
systemic exposure (by 16% [Cmax] and 31% [AUC])
of midazolam.[10] As desvenlafaxine is only partially
metabolized by CYP3A4, any potential in vivo ef-
fect of desvenlafaxine ER on CYP3A4 substrates is
expected to be small.[18]
● Although desvenlafaxine did not inhibit
CYP2D6 in vitro,[18] coadministration of
desvenlafaxine ER 100[14] or 400[10] mg/day with a
single dose of the CYP2D6 substrate desipramine
50 mg was associated with increased systemic expo-
sure (by ≈20% for both Cmax and AUC) to desipra-
mine; however, the increase was not considered
significant.[14] As desvenlafaxine metabolism is in-
dependent of CYP2D6,[10] an individual’s CYP2D6
genotype or phenotype does not affect systemic
exposure to desvenlafaxine ER.[16]
● Desvenlafaxine did not inhibit the activity of
CYP1A2, CYP2A6, CYP2C8 or CYP2C19 in vi-
tro;[18] however, there are no clinical evaluations of
the effect of desvenlafaxine ER on these CYP iso-
enzymes.
● As desvenlafaxine is not a substrate or an inhibi-
tor of the P-glycoprotein transporter in vitro,[18]
pharmacokinetic drug interactions between
desvenlafaxine ER and substrates or inhibitors of the
P-glycoprotein transporter are not expected.[10]
● As the elimination of desvenlafaxine is highly
correlated with creatinine clearance, renal impair-
ment increases systemic exposure to desvenlafaxine
ER and prolongs the terminal elimination half-
life;[10] therefore, dosage adjustments are recom-
mended for some patients with renal impairment
(see section 5).
● Dosage adjustments are not required on the basis
of age, sex, race or hepatic impairment.[10]
3. Therapeutic Efficacy
The efficacy of desvenlafaxine ER has been eval-
uated in several well designed trials;[19-24] however,
only three 8-week, randomized, double-blind, place-
bo-controlled, multicentre, fixed-dose (desvenlafax-
ine ER 50 or 100 mg/day) trials[19-21] included the
US recommended dosage of 50 mg/day. Of the three
trials, two[19,20] are fully published; available data
are limited for the other trial, which also included
© 2008 Adis Data Information BV. All rights reserved.
Yang & Plosker
duloxetine as an active reference.[21] Additional data
discussed in this section are obtained from pooled
analyses of two[19,20] of the three trials, and are
available as an abstract and poster.[25] Of note, al-
though desvenlafaxine ER has been evaluated at
dosages of 50–400 mg/day, dosages higher than
50 mg/day have not been shown to be more effec-
tive[10] (the efficacy of higher dosages has not been
evaluated in patients who do not respond to 50 mg/
day); therefore, this section will focus on the trials
that evaluated desvenlafaxine ER 50 mg/day.[19-21]
Patients aged ≥18 years with a diagnosis of major
depressive disorder (according to the DSM-IV crite-
ria[26]) were enrolled if they had a total score of ≥20
on the 17-item Hamilton Rating Scale for Depres-
sion (HAM-D17), a score of ≥2 on item 1 (depressed
mood) of HAM-D17 and a score of ≥4 (moderately
ill) on the Clinical Global Impression-Severity
(CGI-S) scale.[19-21] The main exclusion criteria
were recent treatment with antidepressants or pre-
vious treatment with desvenlafaxine, hypersensitivi-
ty to venlafaxine, significant risk of suicide, other
significant mental or physical disorder, current drug
abuse and pregnancy.[19,20]
In two trials, 474[19] or 485[20] patients were ran-
domly assigned to receive desvenlafaxine ER 50 or
100 mg/day, or placebo once daily. In the remaining
trial,[21] 638 patients were randomly assigned to
receive desvenlafaxine ER 50 or 100 mg/day, dulox-
etine 60 mg/day or placebo.
The primary endpoint in these trials was the
reduction from baseline in the HAM-D17 total score
at study end, analyzed using analysis of co-variance
(ANCOVA) of the final on-therapy evaluation (day
56) in the last observation carried forward, intent-to-
treat (ITT) population (n = 447,[19] 483[20] or 615[21]).
The HAM-D17 results were also analyzed using the
mixed effects model for repeated measures
(MMRM). Secondary endpoints included the Clin-
ical Global Impression-Improvement (CGI-I) scale
(rated from 1 [very much improved] to 7 [very much
worse]), the Montgomery-Åsberg Depression Rat-
ing Scale (MADRS), the CGI-S score, the 6-item
HAM-D score (HAM-D6) and the Covi Anxiety
Scale; these endpoints were analyzed by the
CNS Drugs 2008; 22 (12)
Desvenlafaxine Extended Release: Adis Drug Profile 1065

DES
Cochran-Mantel Haenszel test and analysis of vari- PL
ance. Response rate (a 50% reduction from baseline 2.9
HAM-D17 or MADRS scores, or a study-end score 18 2.5 (1.6, 4.1)

HAM-D17 total score at study end

2.5 (0.9, 4.1)
of 1 or 2 for CGI-I) and remission rate (a study-end 16 1.9

Reduction from baseline in

(0.3, 3.5) (1.1, 4.0)
HAM-D17 score of ≤7) were also analyzed, using 14 **
**

the logistic regression model and the Fisher exact 12 * **

test. Health-related quality of life (HR-QOL) was 10
assessed by the Sheehan Disability Scale (SDS) and 8
the WHO 5-item Well-Being Index (WHO-5).[19-21] 6
● Desvenlafaxine ER was superior to placebo in 4
improving the symptoms of depression. In two 2 150 150 104 115 164 161 145 138

8-week trials[19,20] in adult patients with major de- 0

pressive disorder, desvenlafaxine ER 50 mg/day
recipients experienced greater improvement as as-
sessed by HAM-D17 than those receiving placebo,
as analyzed by ANCOVA (primary analysis) and
MMRM (figure 1).
● However, in another 8-week, placebo-controlled
trial,[21] desvenlafaxine ER 50 mg/day was not sig-
nificantly better than placebo in treating major de-
pressive disorder as assessed by HAM-D17 (actual
data not reported; p = 0.198 [ANCOVA], p = 0.056
[MMRM]). The duloxetine arm was significantly
better than placebo (actual data not reported;
p = 0.047 [ANCOVA], p = 0.001 [MMRM]).[21]
● Desvenlafaxine ER was an effective treatment
for depression as assessed by some secondary mea-
sures. In two[19,20] of three[19-21] trials, a significant
(p ≤ 0.022) difference between desvenlafaxine ER
50 mg/day and placebo was reported for the change
in MADRS (–15.0 vs –12.3,[19] –16.4 vs –13.3[20]),
CGI-S (–2.1 vs –1.6[20]) and HAM-D6 (–6.4 vs
–5.1[19]) scores. However, secondary endpoints (e.g.
MADRS, CGI-S) were not significantly different
between desvenlafaxine ER 50 mg/day and placebo
groups in the third trial (actual data not reported).[21]
● Desvenlafaxine ER was associated with some
benefits in response and remission rates. The HAM-
D17 response rate with desvenlafaxine ER 50 mg/
day was significantly higher than with placebo in
one trial (65% vs 50%; p = 0.005),[20] as was the
HAM-D17 remission rate in another trial (34% vs
24%; p = 0.027).[19] Not all response or remission
ANCOVA MMRM ANCOVA MMRM
Study 1 Study 2
Fig. 1. Efficacy of desvenlafaxine extended release (DES) in pa-
tients (pts) with major depressive disorder. Mean reduction from
baseline in the 17-item Hamilton Rating Scale for Depression
(HAM-D17) score at study end, as analyzed by analysis of co-
variance (ANCOVA) [primary analysis] or mixed effects model for
repeated measures (MMRM), in two randomized, double-blind,
multicentre trials. In both study 1[19] and study 2,[20] pts received
DES 50 mg or placebo (PL) orally once daily for 8 weeks (data for
DES 100 mg/day treatment group are not shown). Numbers in
columns indicate the number of intent-to-treat pts; numbers above
columns indicate the mean difference between treatments, with the
95% confidence interval in parentheses. Data for another 8-week
trial[21] are not published. * p = 0.018, ** p ≤ 0.002 vs PL.
in all three trials; for example, the HAM-D17,
MADRS or CGI-I response rates,[19] the HAM-D17
remission rate[20] and the HAM-D17 response or
remission rates[21] did not differ.
● Desvenlafaxine ER was effective in improving
anxiety in patients with major depressive disorder.
In a pooled analysis[25] of two trials,[19,20] patients
receiving desvenlafaxine ER 50 mg/day (n = 314)
had a greater reduction in baseline HAM-D17 anxie-
ty scores at study end than those receiving placebo
(n = 311) [–3.87 vs –3.16; p < 0.001]. The between-
group difference was –0.72 (95% CI –1.13, –0.31).
A significant result was also seen with the Covi
Anxiety Scale (–1.56 in desvenlafaxine ER 50 mg/
day recipients vs –1.09 in placebo recipients;
p < 0.001 [between-group difference –0.46; 95% CI
–0.71, –0.22]; n = 312 and 311).[25]
● Desvenlafaxine ER was associated with greater

rates were significantly different between the improvements in HR-QOL than placebo. In
desvenlafaxine ER 50 mg/day and placebo groups two[19,20] of three trials,[19-21] a significantly greater

© 2008 Adis Data Information BV. All rights reserved. CNS Drugs 2008; 22 (12)
1066 Yang & Plosker

25 DES
improvement was seen with desvenlafaxine ER PL
50 mg/day than with placebo, as assessed by 20

Incidence (% of pts)
changes in the total SDS (–9.0 vs –6.6
[p = 0.012];[19] –10.3 vs –7.6 [p = 0.003][20]) and the 15

WHO-5 (6.7 vs 5.2 [p = 0.020];[19] 7.5 vs 5.8 10

[p = 0.006][20]) scores (actual data not reported in the
third trial[21]). 5

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4. Tolerability

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The tolerability of desvenlafaxine ER 50 mg/day

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has been investigated in three 8-week clinical

re
ec
trials[19-21] (see section 3 for full study design de-

tails). Data discussed in this section were obtained
from the individual trials,[19-21] pooled analyses of
two of these trials[19,20] (available as abstracts and
posters[27,28]) and pooled analyses reported in the US
prescribing information.[10]
● Desvenlafaxine ER was generally well tolerated
by patients with major depressive disorder. The
most commonly reported adverse events derived
from a pooled analysis[10] of the desvenlafaxine ER
50 mg/day groups of two 8-week trials[19,20] and the
combined placebo groups of several trials are pre-
sented in figure 2. The incidence of some adverse
events (e.g. nausea, dry mouth, headache) appear to
be dose dependent;[10] for this reason (and the lack of
increased efficacy; see section 3), higher dosages of
desvenlafaxine ER are not recommended (section
5).
● The most frequently reported adverse events
with a ≥5% incidence and at least twice that of
D
Fig. 2. Tolerability of desvenlafaxine extended release (DES) in
patients (pts) with major depressive disorder. Pooled analysis[10] of
the most common adverse events (with an incidence of ≥5% in any
treatment arm) occurring in two 8-week, randomized, double-blind,
placebo-controlled, multicentre trials.[19,20] Pts received DES 50 mg/
day (n = 317) or placebo (PL) [n = 636] orally once daily (data for
higher DES dosage groups are not shown). Data for another
8-week trial[21] are not published.
day and placebo groups, 4.1% and 3.8% of patients
withdrew because of an adverse event;[10] higher
dosages of desvenlafaxine ER were associated with
numerically higher rates of discontinuation due to
adverse events[27] (the combined rate for desven-
lafaxine ER 50–400 mg/day was 12% [n = 317] vs
3% [n = 636] with placebo[10]). The most common
adverse events associated with study withdrawal
were nausea and vomiting; both occurred with an
incidence of ≤1% in the desvenlafaxine ER 50 mg/
day and placebo groups.[27]
● Serious adverse events were uncommon in pa-

placebo in the desvenlafaxine ER 50 mg/day group
were nausea, dizziness, hyperhidrosis, constipation
and decreased appetite (figure 2).[10]
● Nausea was the most common adverse event in
the desvenlafaxine ER 50 mg/day group, reported in
22% of 317 patients (figure 2).[10,27] Of these cases,
68.2% were mild, 27.3% were moderate and 4.5%
were severe.[27] The occurrence of nausea was high-
est during the first week of therapy (≈16%), but was
consistently low thereafter (<5% for weeks 2–4)
tients treated with desvenlafaxine ER. In one
trial,[19] the incidence of serious adverse events (in-
cluding intentional overdose, depression with or
without suicidal ideation, thrombosis and migraine)
was low (3% vs 0% of placebo recipients). In an-
other trial,[21] one suicide attempt was reported in the
duloxetine group. No deaths were reported in the
three clinical trials that evaluated desvenlafaxine ER
50 mg/day.[19-21]
● The approved dosage of desvenlafaxine ER had a

[values estimated from a figure].[27] generally minimal effect on the sexual functioning
● Few patients receiving the approved dosage of of patients with major depressive disorder. The inci-
desvenlafaxine ER discontinued treatment because dence of spontaneously reported sexual dysfunction
of adverse events. In the desvenlafaxine ER 50 mg/ (e.g. anorgasmia, decreased libido, abnormal or-

© 2008 Adis Data Information BV. All rights reserved. CNS Drugs 2008; 22 (12)
Desvenlafaxine Extended Release: Adis Drug Profile
gasm and erectile dysfunction) was low in both the
pooled desvenlafaxine ER 50 mg/day (0–4%) and
placebo (0–1%) groups.[10]
● Treatment with desvenlafaxine ER was asso-
ciated with discontinuation symptoms in some pa-
tients. In a pooled analysis,[28] the scores of the 43-
item Discontinuation-Emergent Signs and Symp-
toms (DESS) checklist were significantly different
between desvenlafaxine ER 50 mg/day (n = 250)
and placebo (n = 303) recipients at the 1-week post-
trial period (2.54 vs 1.04; p < 0.001), but not at study
end or at the 2- and 3-week periods. It should be
noted that the DESS checklist does not rate the
severity of discontinuation symptoms,[29] and that
studies comparing the discontinuation of
desvenlafaxine ER to any other antidepressant agent
have not been published.
● Taper-emergent adverse events (e.g. dizziness,
nausea, headache, irritability) were reported in
45%[20] or 50%[19] of desvenlafaxine ER 50 mg/day
recipients, and 21%[20] or 36%[19] of placebo recipi-
ents.
● Although abnormalities in lipid levels of poten-
tial clinical significance were observed with the use
of desvenlafaxine ER in clinical trials, and monitor-
ing of lipid levels is recommended during treatment
with desvenlafaxine ER, the incidence of abnormal
total cholesterol (2% vs 3% of placebo recipients),
low-density lipoprotein cholesterol (0% vs 1%) and
triglyceride (3% vs 2%) levels was low in recipients
of the recommended dosage of desvenlafaxine ER
50 mg/day.[10]
● Sustained hypertension (defined as treatment-
emergent supine diastolic BP of ≥90 mmHg and
≥10 mmHg above baseline at three consecutive on-
therapy assessments) was reported in 1.3% of
desvenlafaxine ER 50 mg/day recipients.[10] How-
ever, supine pulse rate and fasting high-density lipo-
protein cholesterol and fasting triglyceride levels
were not significantly different between the treat-
ment arms.[27]
● Clinical experience with overdosage of
desvenlafaxine ER is limited. No fatal acute over-
dose cases were reported in premarketing clinical
studies, although adverse events (such as headache,
© 2008 Adis Data Information BV. All rights reserved.
1067
vomiting, agitation, dizziness or nausea) were re-
ported; all overdose patients (n = 5; desvenlafaxine
ER 600–5200 mg) recovered.[10]
5. Dosage and Administration
In the US, the recommended dosage of
desvenlafaxine ER is 50 mg/day, administered once
daily.[10] Patients should swallow the tablets whole,
at approximately the same time each day.
Patients receiving desvenlafaxine ER, as with all
antidepressants, should be regularly monitored for
clinical worsening, suicidality and unusual changes
in behaviour.[10] Changing the treatment regimen, or
discontinuing therapy, may be considered in patients
who do not respond adequately to desvenlafaxine
ER treatment, or in those who develop suicidality.
To avoid discontinuation symptoms, a gradual re-
duction in frequency of administration instead of
immediate cessation is recommended.[10]
As with all antidepressant agents, there is a
black-box warning in the US prescribing informa-
tion concerning the increased risk of suicidality in
younger patients; desvenlafaxine ER is not ap-
proved for the treatment of paediatric patients.[10]
Although no dosage adjustments of desvenlafax-
ine ER are required for patients with mild (creati-
nine clearance [CLCR] 50–80 mL/min [3–4.8 L/h])
or moderate (CLCR 30–50 mL/min [1.8–3 L/h])
renal impairment, the recommended dosage in pa-
tients with severe renal impairment (CLCR <30 mL/
min [<1.8 L/h]) or end-stage renal disease is 50 mg
every other day.[10]
To reduce the risk of serotonin syndrome, con-
comitant administration of desvenlafaxine ER and
MAOIs is contraindicated.[10] In addition, a mini-
mum period of 14 days is recommended between
discontinuation of an MAOI and initiation of
desvenlafaxine ER, and a minimum of 7 days is
recommended between discontinuation of
desvenlafaxine ER and initiation of an MAOI.[10]
Local prescribing information should be con-
sulted for further details on dosage and administra-
tion information, including contraindications, warn-
ings, precautions, drug interactions, use in special
CNS Drugs 2008; 22 (12)
1068
patient populations and patient monitoring recom-
mendations.
6. Desvenlafaxine Extended Release:
Current Status
Desvenlafaxine ER has been approved in the US
for the treatment of major depressive disorder in
adult patients.[10] In two[19,20] of three[19-21] well de-
signed 8-week clinical trials, desvenlafaxine ER
50 mg/day was effective in improving the clinical
symptoms of depression (as assessed by HAM-
D17). Short-term administration of desvenlafaxine
ER 50 mg/day was generally well tolerated.
Acknowledgements and Disclosures
The manuscript was reviewed by: P. Bech, Psychiatry
Research Unit, Frederiksborg General Hospital, Hillerød,
Denmark; J.C. Nelson, Department of Psychiatry, University
of California, San Francisco, California, USA.
The preparation of this review was not supported by any
external funding. During the peer review process, the manu-
facturer of the agent under review was offered an opportunity
to comment on this article. Changes resulting from comments
received were made on the basis of scientific and editorial
merit.
References
1. Belmaker RH, Agam G. Major depressive disorder. N Engl J
Med 2008 Jan 3; 358 (1): 55-68
2. Alonso J, Angermeyer MC, Bernert S, et al. Prevalence of
mental disorders in Europe: results from the European Study of
the Epidemiology of Mental Disorders (ESEMeD) project. The
ESEMeD/MHEDEA 2000 Investigators. Acta Psychiatr Scand
Suppl 2004 Jun; 109 Suppl. 420: 21-7
3. Hasin DS, Goodwin RD, Stinson FS, et al. Epidemiology of
major depressive disorder: results from the National Epidemi-
ologic Survey on Alcoholism and Related Conditions. Arch
Gen Psychiatry 2005 Oct; 62 (10): 1097-106
4. Üstün TB, Ayuso-Mateos JL, Chatterji S, et al. Global burden of
depressive disorders in the year 2000. Br J Psychiatry 2004
May; 184: 386-92
5. American Psychiatric Association. Practice guideline for the
treatment of patients with major depressive disorder: second
edition [online]. Available from URL: http://www.psychiatry-
online.com/pracGuide/loadGuidelinePdf.aspx?file=MDD2-
e_05-15-06 [Accessed 2008 Jul 3]
6. National Institute for Health and Clinical Excellence. NICE
clinical guideline 23 (amended): management of depression in
primary and secondary care [online]. Available from URL:
http://www.nice.org.uk/nicemedia/pdf/CG23NICEguidelinea-
mended.pdf [Accessed 2008 Jul 3]
© 2008 Adis Data Information BV. All rights reserved.
Yang & Plosker
7. Wellington K, Perry CM. Venlafaxine extended-release: a re-
view of its use in the management of major depression. CNS
Drugs 2001; 15 (8): 643-69
8. Frampton JE, Plosker GL. Duloxetine: a review of its use in the
treatment of major depressive disorder. CNS Drugs 2007; 21
(7): 581-609
9. Wyeth Pharmaceuticals Inc. FDA approves Pristiq for the treat-
ment of adult patients with major depressive disorder [online].
Available from URL: http://www.wyeth.com/news?nav=dis-
play&navTo=/wyeth_html/home/news/pressreleases/2008/
1204331198948.html [Accessed 2008 Jul 29]
10. Wyeth Pharmaceuticals Inc. Pristiq (desvenlafaxine) extended-
release oral tablets: US prescribing information [online].
Available from URL: http://www.wyeth.com/content/showla-
beling.asp?id=497 [Accessed 2008 Jul 1]
11. Deecher DC, Beyer CE, Johnston G, et al. Desvenlafaxine
succinate: a new serotonin and norepinephrine reuptake inhibi-
tor. J Pharmacol Exp Ther 2006 Aug; 318 (2): 657-65
12. Paul J, Behrle JA, Richards LS, et al. Double-blind, placebo-
and moxifloxacin-controlled crossover study of the effects of
desvenlafaxine succinate on QT interval in healthy adult fe-
male subjects [abstract no. NR571 plus poster]. 159th Annual
Meeting of the American Psychiatric Association; 2006 May
20-25; Toronto (ON), 238
13. Schatzberg AF. Safety and tolerability of antidepressants:
weighing the impact on treatment decisions. J Clin Psychiatry
2007; 68 Suppl. 8: 26-34
14. Patroneva A, Connolly SM, Fatato P, et al. An assessment of
drug-drug interactions: the effect of desvenlafaxine and dulox-
etine on the pharmacokinetics of the CYP2D6 probe desipra-
mine in healthy subjects. Drug Metab Dispos. Epub 2008 Sep
22
15. Patat A, Baird-Bellaire S, Behrle J, et al. Lack of clinically
relevant effect of pharmacokinetic interaction between ketoco-
nazole on and desvenlafaxine-SR pharmacokinetics [abstract
no. PII-50]. Clin Pharmacol Ther 2007 Mar; 81 Suppl. 1: S64
16. Preskorn S, Patroneva A, Nichols A, et al. A comparison of
the pharmacokinetics of venlafaxine extended release and
desvenlafaxine succinate in healthy subjects [abstract no.
P.2.b.013]. Eur Neuropsychopharmacol 2007 Oct; 17 Suppl. 4:
S339
17. Parker VD, Richards LS, Nichols AI, et al. The absolute bio-
availability of an oral sustained-release formulation of
desvenlafaxine succinate in healthy subjects [abstract no. PI-
149]. Clin Pharmacol Ther 2005 Feb; 77 (2): P47. Plus poster
presented at the 2005 Annual Meeting of the American Society
for Clinical Pharmacology and Therapeutics; 2005 Mar 2-6;
Orlando (FL)
18. Shilling AD, Oganesia A, Young-Sciame R, et al. Desvenlafax-
ine succinate, venlafaxine, duloxetine, paroxetine, sertraline,
and bupropion: comparing inhibitory effects on human cyto-
chrome P450 and P-glycoprotein activities [abstract no.
P02.050]. Int J Neuropsychopharmacol 2006 Jul; 9 Suppl. 1:
S177. Plus poster presented at the 25th Congress of the Col-
legium Internationale Neuro-Psychopharmacologicum; 2006
Jul 9-13; Chicago (IL)
19. Liebowitz MR, Manley AL, Padmanabhan SK, et al. Efficacy,
safety, and tolerability of desvenlafaxine 50 mg/day and
100 mg/day in outpatients with major depressive disorder.
Curr Med Res Opin 2008 Jul; 24 (7): 1877-90
20. Boyer P, Montgomery S, Lepola U, et al. Efficacy, safety, and
tolerability of fixed-dose desvenlafaxine 50 and 100 mg/day
CNS Drugs 2008; 22 (12)
Desvenlafaxine Extended Release: Adis Drug Profile
for major depressive disorder in a placebo-controlled trial. Int
Clin Psychopharmacol 2008 Sep; 23 (5): 243-53
21. Wyeth Pharmaceuticals Inc. Final report: a multicenter, ran-
domized, double-blind, placebo-controlled, duloxetine-refer-
enced, parallel-group study to evaluate the efficacy and safety
of 2 fixed doses (50 mg, 100 mg) of desvenlafaxine sustained
release tablets in adult outpatients with major depressive disor-
der; synopsis based on final report (protocol 3151A1-335)
[online]. Available from URL: http://www.clinicalstudyre-
sults.org/documents/company-study_3949_0.pdf [Accessed
2008 Jul 23]
22. Liebowitz MR, Yeung PP, Entsuah R. A randomized, double-
blind, placebo-controlled trial of desvenlafaxine succinate in
adult outpatients with major depressive disorder. J Clin Psy-
chiatry 2007 Nov; 68 (11): 1663-72
23. DeMartinis NA, Yeung PP, Entsuah R, et al. A double-blind,
placebo-controlled study of the efficacy and safety of
desvenlafaxine succinate in the treatment of major depressive
disorder. J Clin Psychiatry 2007 May; 68 (5): 677-88
24. Septien-Velez L, Pitrosky B, Padmanabhan SK, et al. A ran-
domized, double-blind, placebo-controlled trial of desven-
lafaxine succinate in the treatment of major depressive disor-
der. Int Clin Psychopharmacol 2007 Nov; 22 (6): 338-47
25. Ahmed S, Patroneva A, Graepel J, et al. Improvement of anxiety
symptoms in patients with major depressive disorder treated
with desvenlafaxine: a pooled analysis [abstract no. NR3-145
plus poster]. 161st Annual Meeting of the American Psychiat-
ric Association; 2008 May 3-8; Washington, DC, 156
© 2008 Adis Data Information BV. All rights reserved.
1069
26. American Psychiatric Association. Diagnostic and statistical
manual of mental disorders. 4th ed. Washington, DC: Ameri-
can Psychiatrtic Association, 1994
27. Clayton A, Kornstein SG, Rosas G, et al. Pooled analysis of the
safety and tolerability of desvenlafaxine compared with place-
bo in the treatment of major depressive disorder [abstract no.
NR5-083 plus poster]. 161st Annual Meeting of the Ameri-
can Psychiatric Association; 2008 May 3-8; Washington, DC,
250-1
28. Montgomery SA, Fava M, Tourian KA, et al. Discontinuation
symptoms and taper/poststudy-emergent adverse events with
desvenlafaxine treatment for major depressive disorder [ab-
stract no. NR5-038 plus poster]. 161st Annual Meeting of the
American Psychiatric Association; 2008 May 3-8; Washing-
ton, DC, 229-30
29. Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin
reuptake inhibitor discontinuation syndrome: a randomized
clinical trial. Biol Psychiatry 1998 Jul 15; 44 (2): 77-87
Correspondence: Lily P.H. Yang, Wolters Kluwer Health |
Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay,
North Shore 0754, Auckland, New Zealand.
E-mail: demail@adis.co.nz
CNS Drugs 2008; 22 (12)