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SYMBYAX: THE FIRST
MEDICATION APPROVED
FOR TREATMENT-
RESISTANT DEPRESSION

Lauren Ren6e Epstein, Pharm.D. Candidate


n 2003, Eli Lilly's Symbyax (olanzapine/
fluoxetine) was granted the first FDA-approved
indication for the treatment of depressive epi-
sodes in association with bipolar I disorder. In
March of this year, Symbyax became the first drug
approved for the acute treatment of treatment-
resistant depression (TRD), most often defined as
adults with Major Depressive Disorder (MDD) that
do not respond to two separate trials of different anti-
depressants of adequate dose and duration during the
current episode.1-2 This article will briefly discuss
TRD as well as the pharmacology, efficacy and
safety of the olanzapine/fluoxetine combination
(OFC).
It is estimated that up to 35% of patients with
depression (approximately 2% of the general popula-
tion) fail to achieve an adequate response after two
antidepressant drug therapy attempts.3 Untreated de-
pression often results in social, physical, psychologi-
cal and economic consequences. Those with MDD
are at an increased risk of alcohol and drug-related
problems, tobacco dependence, physical health prob-
lems, and premature death due to medical illness. Up
to 15% of individuals with MDD die by suicide.4 In
1990, it was estimated that depression-related costs
of direct treatment, lost earnings, and indirect work-
place costs translated into an economic burden be-


tween $44 and $53 billion per year. The total eco-
nomic burden of depression remained relatively sta-
ble between 1990 and 2000.5 A 2002 study of pa-
tients with TRD estimated the mean total cost of gen-
eral health care services at approximately $11,000
per patient year. Another study found that mean total
general health care expenditures increased from
$6,852 per year at the first medication change to
$13,980 per year at the eighth medication regimen,
suggesting that cost may be directly related to degree
of treatment resistance. Therefore, there is a need for
rapid, effective pharmacotherapy for TRD.6
Although the exact causes of depression and the
reasons behind pharmacological treatment failure
remain a mystery, evidence suggests that depression
is the result of a complex interaction among biologi-
cal, genetic, psychosocial, and environmental fac-
tors.5 According to the DSM-IV, MDD is defined as
the presence of a single major depressive episode in
a patient that has never experienced a manic episode,
mixed episode or hypomanic episode. A major de-
pressive episode must include > 5 out of 9 specific
symptoms present during the same 2-week period
and represent a change from previous functioning. At
least one of the symptoms must either be depressed
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PharmaNote Volume 24, Issue 11 I August 2009


PharmaNote


VOLUME 24, ISSUE 1 1 AUGUST 2009
ti -


INSIDE THIS ISSUE:
SYMBYAX: THE FIRST MEDICATION APPROVED
FOR TREATMENT-RESISTANT DEPRESSION



.ir


Volume 24, Issue 11 1 August 2009


PharmaNote







mood or loss of interest or pleasure.7
Years before the approval of OFC, the American
Psychiatric Association's (APA) 2005 Guideline
Watch, an update to the 2000 practice guideline:
Treatment of Patients With Major Depressive Disor-
der, mentioned OFC as a useful treatment for epi-
sodes of major depression with psychotic features as
well as TRD. The updated guideline, expected in De-
cember of 2009, will likely include OFC in its sec-
tion on TRD. According to the APA, initial treatment
failure is defined as a lack of at least moderate im-
provement after 4-8 weeks of antidepressant therapy.
The next step is to assess adherence, consider phar-
macokinetic or pharmacodynamic factors and, if nec-
essary, draw serum antidepressant medication levels,
and then revise the treatment plan. Treatment plan
revisions may include maximizing the initial thera-
peutic treatment dose; adding, changing or increasing
the frequency of psychotherapy; switching to another
non-monoamine oxidase inhibitor (MAOI) medica-
tion in either the same class or a different class; aug-
mentation; switching to an MAOI, or electroconvul-
sive therapy (ECT).8 According to the labeling, OFC
is indicated after the failure of 2 separate trials of dif-
ferent antidepressants of adequate dose and duration
in the current episode.9 Thus, the initiation of OFC
therapy for TRD is considered an augmentation strat-
egy.


PHARMACOLOGY AND PHARMACOKINETICS

Olanzapine is an atypical antipsychotic and
fluoxetine is a selective serotonin reuptake inhibitor
(SSRI). In animal studies, OFC synergistically in-
creases norepinephrine and dopamine release in the
prefrontal cortex, along with increases in serotonin.10
Although OFC's exact mechanism of action is un-
known; it is proposed that activation of serotonin,
norepinephrine, and dopamine is responsible for the
antidepressant effect.9
Regarding the pharmacodynamics of OFC, olan-
zapine has a high binding affinity for serotonin
5HT2A/2C, 5HT6 as well as histamine Hi (antagonism
here may explain somnolence) and adrenergic ac re-
ceptors (antagonism here may explain orthostatic
hypotension). It is also an antagonist with moderate
binding affinity for serotonin 5HT3 and muscarinic
M1.5 receptors (a possible cause of anticholinergic
effects). It only weakly binds GABAA, BZD, and 3-
adrenergic receptors. Fluoxetine is a serotonin trans-
porter inhibitor as well as a weak inhibitor of norepi-
nephrine and dopamine transporters. It has a rela-
tively low affinity for muscarinic, ac adrenergic, and
histamine Hi receptors.9
The pharmacokinetics of olanzapine and fluoxet-
ine are listed separately in Table 1. The pharmacoki-
netics of each component are expected to represent


Table 1. Pharmacokinetics of olanzapine and fluoxetine9

ABSORPTION DISTRIBUTION METABOLISM ELIMINATION
Olanzapine Peak plasma 93% plasma pro- Extensive 1t-pass metabolism 57% recovered in urine
concentration tein bound Highly metabolized (-7% as unchanged drug)
-4 hrs* direct glucuronidation 30% recovered in feces
Unaffected by CYP450 (1A2, 2D6, flavin-
food containing monooxygenase sys-
tem)
Mean t1/2 = 30 hrs
tl/2 ~1.5x greater in elderly

Fluoxetine Peak plasma 94.5% bound to Extensively metabolized to active Hepatic metabolism to
concentration plasma proteins metabolite (norfluoxetine) via inactive metabolites, ex-
"6 hrs* CYP2D6 creation by kidney
Food may delay t/2 elimination
absorption by 1- 1-3 days (acute use)
2 hrs (clinically 4-6 days (chronic use)
insignificant) 9.3 days (norfluoxetine)

*Following a single oral 12/50 mg dose of olanzapine/fluoxetine

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the pharmacokinetics of the combination. Although
both drugs are highly protein-bound, the in vitro
binding to plasma proteins of the combination is
similar to the binding of the individual components.
However, the interaction between the two and other
highly protein-bound drugs has not been fully evalu-
ated. When the two drugs are combined, minor
changes in olanzapine clearance have been observed,
but this is of unclear clinical significance. The de-
creased clearance is likely due to fluoxetine's inhibi-
tion of CYP2D6, a minor metabolic pathway for
olanzapine.9
The plasma concentrations, half-life, and clear-
ance of olanzapine may vary based on smoking
status, gender, and age. Olanzapine clearance is
-40% higher in smokers than nonsmokers, but dos-
age modification is not routinely necessary. Al-
though olanzapine clearance is about 30% lower in
women than in men, no apparent difference in effec-
tiveness or adverse effects were found; therefore,
dose modification is probably unnecessary. How-
ever, because the mean elimination half-life of olan-
zapine is 1.5 times greater in subjects >65 years of
age, caution should be used in dosing the elderly.
The combined effects of age, smoking status and
gender could lead to substantial pharmacokinetic dif-
ferences in populations; therefore, it may be neces-
sary to modify the dose in patients who exhibit a
combination of factors that may results in a slower
metabolism of olanzapine.9
Dose adjustment of OFC in renal impairment is
not required. Olanzapine is highly metabolized prior
to excretion with only 7% excreted unchanged. Ad-
ditionally, a fluoxetine study in dialysis patients pro-
duced plasma concentrations comparable to those in
patients with normal renal function. In hepatic im-
pairment, however, the pharmacokinetics of OFC
might be altered and the lowest starting dose should
be considered in these patients.9

CLINICAL TRIALS

Five clinical studies were conducted to evaluate
OFC as a treatment strategy for TRD, three of which
are included in the official label. These studies have
observed mixed results, complicated by inconsistent
definitions of TRD. A small pilot study conducted
between April 1997 and June 1998 found that pa-
tients with a history of TRD treated with OFC
showed a significantly greater reduction in depres-


sive symptoms than patients treated with olanzapine
(p=0.03) or fluoxetine (p=0.006) monotherapy.11 In
this study, TRD was defined retrospectively as a his-
tory of failure to respond to antidepressants of two
different classes, (one of which was not an SSRI),
after at least four weeks of therapy at an acceptable
therapeutic dose. A failure to respond was then con-
firmed during a screening period where fluoxetine
was given.
These results were not duplicated in two larger
trials in which initial antidepressant failure was not
required during the current depressive episode. With
the intent of replicating the results of the pilot study
with a larger sample size, Shelton et al. studied OFC
in 500 patients, but failed to find a statistically sig-
nificant change in the primary outcome.12 However,
OFC versus olanzapine reached significance in a post
hoc analysis of a subgroup of patients with SSRI fail-
ure during the current depressive episode (p=0.005).
Unfortunately, this subgroup was not specified a pri-
ori. This study defined TRD as a failure to respond
to an SSRI followed by failure to respond to nortrip-
tyline during an open-label lead-in phase.12 Corya et
al. found a statistically significant improvement in
the primary outcome, but only for OFC compared to
olanzapine (p<0.001).6 This study also performed a
subgroup analysis similar to the Shelton et al. study
and found a statistically greater improvement with
OFC compared to both olanzapine (p<0.001) and
fluoxetine (p=0.006). The investigators determined
that the subgroup, this time specified a priori, repre-
sented a more conservative, real-world criteria under
which TRD patients would likely present to clini-
cians. This study specified TRD as a historical fail-
ure to achieve satisfactory SSRI antidepressant re-
sponse for at least 6 weeks at an acceptable dose, and
prospective failure to achieve satisfactory partial re-
sponse to venlafaxine during the 7-week lead-in
phase.6
In the two most recent studies, TRD was defined
as a documented history of failure to achieve a satis-
factory response to an antidepressant (except fluoxet-
ine) after at least 6 weeks of therapy at a therapeutic
dose as well as a prospective failure on fluoxetine
during the current depressive episode. These also
generated conflicting results as one found a signifi-
cant improvement in the primary endpoint (p<0.001)
and the other did not. The pooled results, however,
revealed significant differences for OFC versus
fluoxetine (p<0.001) and olanzapine (p<0.001).13,14


PhraoeVoue2,Isu 1 IAuut20


Volume 24, Issue 11 i August 2009


PharmaNote







Table 2. Summary of Clinical Trials for OFC.6'11'15
1 OUTCOME
TRIAL DESIGN U E RESULTS
MEASURE


8-week R, DB
study comparing:
. OFC (n=10)
. OLZ (n=8)
. FLX (n=10)
8-week R, DB, MC
study comparing:
. OFC (n=146)
. OLZ(n=144)
. FLX (n=142)
. NTP (n=68)


Subgroup analysis
(n=314)



Corya, et al. 12-week R, DB,
(2006)6 MC study com-
paring:
(n=483) OFC (n=243)
OLZ (n=62)
FLX (n=60)
VNL(n=59)
OFC 1/5b (n=59)

Subgroup analysis
(n=334)


Thase, et al. 2 parallel 8-wk R,
(2007)13 DB studies com-
paring:
(n=605) OFC(n=200)
OLZ (n=199)
FLX (n=206)


Corya, et al.
(2003)15

(n=560)


76-week, MC,
open-label study
of safety & effi-
cacy of OFC in
MDD patients

Without TRD
n=415 (74%)

With TRD:
n=145 (26%)


Mean A from base-
line in MADRS


Shelton, et al.
Pilot Study
(2001)1
(n=28)

Shelton, et al.
(2005)12

(n=500)


MADRS mean total
A score at endpoint


Baseline-to-
endpoint mean A in
MADRS


Mean A from base-
line in MADRS &
CGI-S


Primary analysis:
OFC -13.6 vs
. OLZ-2.8 (p=0.03)
. FLX -1.2 (p=0.006)


Primary analysis:
OFC -8.71 (0.70)a vs:
. OLZ -6.95 (0.71) [p=0.077]
. FLX -8.51 (0.70) [p=0.841]
. NTP -7.46 (0.98) [p=0.298]


Post-hoc analysis (SSRI failure during current depressive episode):
OFC -9.1 vs:
. OLZ-5.6 (p=0.005)
. FLX-7.9 (p=0.33)
. NTP -7.1 (p=0.18)
Primary analysis:
OFC -14.06 (0.59)a vs:
. OLZ-7.71 (1.17) [p<0.001]
. FLX -11.70 (1.14) [p=0.062]
. VNL-13.73 (1.16) [p=0.795]
. OFC 1/5 -11.97 (1.13) [p=0.095]

Subgroup analysis (SSRI failure during current depressive episode):
OFC -14.6 vs:
. OLZ-9.4 (p<0.001)
. FLX -10.7 (p=0.006)
. VNL-14.7 (p=0.98)


Study 1:
OFC -11.0 (10.0)c vs:
. OLZ-10.5 (9.5) [p=0.739]
. FLX -9.4 (10.0) [p=0.253]

Study 2:
OFC -14.5 (10.4) vs:
. OLZ -7.0 (8.5) [p<0.001]
. FLX -8.6 (9.6) [p<0.001]
Entire cohort:
. MADRS -21.8 (p=0.0001)
. CGI-S -2.2 (p=0.0001)

Without TRD:
. MADRS -22.3 (p=0.0001)
. CGI-S -2.3 (p=0.0001)

With TRD:
. MADRS -19.2 (p=0.0001)
. CGI-S -2.0 (p=0.0001)


Pooled analysis:
OFC -12.7 (10.3) vs:
. OLZ-8.8 (9.1) [p<0.001]
. FLX -9.0 (9.8) [p<0.001]


A = change; CGI-S = Clinical Global Impressions-Severity of Illness Scale; DB = double-blind; MADRS = Montgomery-Asberg Depression Rating Scale; FLX = fluoxet-
ine; MC = multicenter; NTP = nortriptyline; OFC = olanzapine/fluoxetine combination; OLZ = olanzapine; pts = patients; R = randomized; SD = standard deviation;
Stat sig. = statistically significant; TRD = treatment-resistant depression; VNL = venlafaxine; w = with.
a Mean change (SE).
bOLZ 1/5 was included as a "pseudoplacebo" arm.7
cMean change (SD).

Phara~ot Volme 2, Isue 1 I Agust200


Baseline-to-
endpoint mean A in
MADRS


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PharmaNote







An integrated analysis of the five studies found
the same pattern of results for OFC in each study and
attributed the previously mixed results to inconsis-
tencies in the definitions of TRD, study designs and
measures.14 This analysis examined the efficacy of
OFC in all five clinical trials using only the Mont-
gomery-Asberg Depression Rating Scale (MADRS)
and a standardized definition of TRD: 2 documented
antidepressant failures in the current depressive epi-
sode, including > 1 prospective antidepressant fail-
ure. After methods standardization and exclusion of
patients that no longer met the new inclusion criteria,
the analysis found that patients treated with OFC ex-
perienced significantly greater improvement in de-
pressive symptoms than those treated with olanzap-
ine (p<0.001) or fluoxetine (p<0.001) monother-
apy.14 This was based on a mean change in MADRS
from baseline to endpoint, response and remission
rates, and the percentage of days spent in response
and in remission. The advantage of OFC depressive
symptom improvement was apparent early in treat-
ment. There was a statistically significant separation
between patients treated with OFC and those treated
with fluoxetine (p<0.001) or olanzapine (p<0.001) at
week 1. The baseline demographics for the 1,146
patients included in the integrated analysis from the
five trials did not significantly differ between treat-
ment groups. The mean age was 44 years; slightly
over half were female, and a majority were Cauca-
sion.14 These five clinical trials along with a 76-week
open-label safety and efficacy trial are summarized
in Table 2.



Table 3. Treatment-Emergent Adverse Events Occurring
cebo9,14


SAFETY & MONITORING


The benefits of OFC for TRD should be weighed
against the potential adverse effects. The most com-
mon treatment-emergent adverse events (> 5% and at
least twice that for placebo) are summarized in Table
3. OFC was generally similar to olanzapine mono-
therapy regarding adverse events.14 In a 76-week
safety and efficacy study of OFC in patients with
MDD, the most commonly reported adverse events
leading to study discontinuation were weight gain (N
= 45; 8%) and somnolence (N = 27; 4.8%).15 In the
integrated analysis that examined the safety and effi-
cacy data from 1,146 patients, the mean change in
weight for the OFC group was +4.42 kg and 40.4%
of OFC patients had a weight gain of > 7% of total
body weight. This was significantly higher than the
fluoxetine group (p<0.001), but not the olanzapine
group (p=0.515).14
Laboratory findings for OFC were also generally
similar to those for olanzapine monotherapy except
for random total cholesterol. The mean change was
significantly greater for OFC than for fluoxetine
(p<0.001) and olanzapine (p<0.001) alone.14 The
mechanism of this finding is unclear. Clinically sig-
nificant elevations in triglyceride levels have been
observed with OFC use. Hyperglycemia has been
reported in patients treated with atypical antipsychot-
ics including olanzapine as well as OFC. Some cases
were associated with ketoacidosis, coma or death.
Olanzapine's metabolic effects must be considered
carefully in those with cardiovascular risk factors,



in 2> 5% of OFC patients and at least twice that of pla-


p-value


Event
Weight Increased
Increased appetite
Dry mouth
Somnolence
Fatigue
Peripheral edema
Tremor
Sedation
Hypersomnia


OFC (%)
27.9
24.3
18.6
15.6
14.0
11.2
9.7
8.5
6.1


Fluoxetine (%) Olanzapine (%)
7.1 33.5
6.3 29.2
6.5 21.2
6.5 13.5
9.4 16.0
1.1 7.4
6.3 5.4
2.8 10.6
2.0 8.3


Attention disturbance 5.5
OFC = olanzapine/fluoxetine combination.


Overall
<0.001
<0.001
<0.001
<0.001
0.024
<0.001
0.047
<0.001
<0.001
0.142


OFC vs Fluoxetine
<0.001
<0.001
<0.001
<0.001
0.051
<0.001
0.075
<0.001
0.005
0.181


OFC vs Olanzapine
0.091
0.128
0.376
0.426
0.428
0.074
0.026
0.333
0.270
0.553


PharmaNote Volume 24, Issue 11 I August 2009


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PharmaNote






Table 4. OFC Drug Interactions9
DRUG/CLASS INTERACTION RECOMMENDATION
MAO-I Reports of serious, sometimes fatal re- Concomitant use C/I; do not use OFC
actions in patients receiving fluoxetine within 14 days of DC an MAOI; allow 5
and an MAOI weeks after DC OFC before starting an
MAOI

Pimozide Potential for drug interactions or QTc Concomitant use C/I
prolongation
Thioridazine QTc prolongation or potential for ele- Concomitant use C/I; do not use thioridaz-
vated thioridazine plasma levels ine within 5 weeks of DC OFC
Tryptophan Serotonin syndrome Concomitant use not recommended
Triptans, linezolid, lithium, tramadol, St. Serotonin syndrome Use caution
John's Wort
C/I = contraindicated; DC = discontinuing; MAOI = monoamine oxidase inhibitor; OFC = olanzapine/fluoxetine combination.


established diabetes mellitus, or prediabetes.16
As with all antipsychotic medications, a poten-
tially fatal condition, Neuroleptic Malignant Syn-
drome (NMS), has been reported with olanzapine.
Immediate discontinuation is warranted upon signs
and symptoms of NMS such as hyperpyrexia, muscle
rigidity, altered mental status and evidence of auto-
nomic instability. Other signs may include elevated
creatinine phosphokinase, myoglobinuria and acute
renal failure. Antipsychotic treatments also carry the
risk of Tardive Dyskinesia (TD). As the duration of
treatment and the total cumulative dose increase, the
risk of developing TD and the likelihood that it will
become irreversible are believed to increase as well.
Fortunately, the incidence of dyskinetic movements
in OFC-treated patients has been infrequent.9'16
Fasting blood glucose, Aic, and lipid profiles
should be monitored at the beginning of treatment
and periodically thereafter.9 Clinicians should moni-
tor for symptoms of hyperglycemia including
polydipsia, polyuria, polyphagia, and weakness.16
Due to the high incidence of weight increase, base-
line weight and BMI should be recorded and moni-
tored periodically.17


DRUG INTERACTIONS


Table 4 summarizes serious potential drug inter-
actions along with the strength of recommendation
regarding concomitant use of OFC.



PharmaNote


COST


The average retail price and range for each
strength of Symbyax from 3 pharmacies in Gaines-
ville, FL is included in Table 5. In general, the cost
of olanzapine and fluoxetine separately was not
cheaper than the combination. At times the combina-
tion was actually cheaper. Also, the exact strengths
of the combination product are not available for the
individual components.

SUMMARY

Untreated depression often results in social,
physical, psychological and economic consequences
and up to 15% of individuals with Major Depressive
Disorder die by suicide.4 Olanzapine/fluoxetine com-
bination is the first FDA-approved drug for the acute
treatment of treatment-resistant depression as defined


Table 5. Symbyax Retail Price
STRENGTH (OLAN/FLUox) AVERAGE COST* RANGE
3mg/25mg $272.55 $265.72 $283.95
6mg/25mg $371.13 $359.46 $376.99
6mg/50mg $368.87 $352.68 $376.99
12mg/25mg $542.80 $525.46 $557.99
12mg/50mg $542.80 $525.46 $557.99


*Cost data based on 30-day supply at 3 Gainesville community pharmacies

Volume 24, Issue 11 1 August 2009










by nonresponse to two separate trials of different an-
tidepressants of adequate dose and duration during
the current depressive episode.1-2 Future guidelines
will likely include OFC in their armamentarium of
agents to battle TRD.8 Clinical trials evaluating OFC
have had mixed results, but an integrated analysis
that standardized five studies found that patients
treated with OFC experienced significantly greater
improvement in depressive symptoms than those
treated with olanzapine (p<0.001) or fluoxetine
(p<0.001) monotherapy.14 Except for random total
cholesterol, the adverse effect profile of OFC resem-
bles that of each agent alone.9'14 Fasting blood glu-
cose, Aic, lipid profiles, weight, and BMI should be
monitored at baseline and periodically thereafter.9'17
For patients in whom the benefits of OFC therapy
outweigh the risks of adverse effects, OFC provides
another option when first-line antidepressant thera-
pies have failed.






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14. Madhukar HT, Thase ME, Osuntokun 0, Henley DB,
Case M, Watson SB, et al. An Integrated Analysis of
Olanzapine/Fluoxetine Combination in Clinical Trials
of Treatment-Resistant Depression. J Clin Psychiatry
2009;70(3):387-396.
15. Corya SA, Andersen SW, Detke HC, Kelly LS, Van
Campen LE, Sanger TM, Williamson DJ, Dube S:
Long-term antidepressant efficacy and safety of olan-
zapine/fluoxetine combination: a 76-week open-label
study. J Clin Psychiatry 2003; 64:1349-1356.
16. FDA Approves Symbyax for Treatment-Resistant
Depression. Available at: http://www.drugs.com/
newdrugs/fda-approves-symbyax-as-first-medication-
for-treatment-resistant-depression-1296.html. Ac-
cessed May 8, 2009.
17. Lexi-Comp [database online]. Hudson, OH: Lexi-
Comp, Inc.; 2009. URL: http://www.crlonline.com.
Updated May 19, 2009.


Phama~teVolme 4,Isse 1 IAugst 00


Volume 24, Issue 11 i August 2009


PharmaNote






%
DRUG UPDATES



Prasugrel (Effient) Eli Lilly and Company

In July, 2009, the FDA approved prasugrel, an
oral thienopyridine platelet aggregation inhibitor,
Sfor use in patients with unstable angina or
myocardial infarction who undergo percutaneous
coronary intervention (PCI). Prasugrel is the third
Drug in its class to be approved, following
ticlopidine and clopidogrel; however, prasugrel is
believed to be a more effective adenosine e
diphosphate (ADP) receptor inhibitor than its
counterparts owing to a more efficient metabolism
Resulting in greater levels of active metabolite
delivery to the platelet. Although this may translate
into improve efficacy, significant concern has been
k raised over the potential for a corresponding
k increase in bleeding rates. Data from the TRITON-
STIMI 38 trial suggests three subgroups at a,
particularly elevated risk: elderly, underweight and
Those with a previous history of stroke/TIA
, Consequently, the FDA has required a black-box
warning regarding the risk of bleeding. In those
weighing > 60kg, the recommended dose is 10 mg
Once daily in combination with aspirin. A dose of 5 I
z mu once daily has been recommended (but not
Sp i ospectl\ el studied) Ifo those X eiulhinu hi-1 ku ,-
" i


k Levonorgestrel (Plan B) Going Generic

The FDA recently approved the first generic \
k version of Plan B, an emergency contraceptive ,
containing 0.75 mg levonorgestrel given within 72 ,
hours of intercourse. The approval comes nearly f
two years after the approval of an over-the-counter f
Plan B product for women aged > 18 years of age; i
however, those aged < 18 years still require a
prescription.
k The recent approval allows marketing of a
k prescription-only generic product. A generic over- I
k the-counter product is not expected to be available f
until approximately September when marketing
exclusivity held by Duramed Pharmaceuticals for ,
, the nonprescription use expires f
%
\ ..


Dronedarone (Multaq) sanofi-aventis

Dronedarone, a benzofuran derivative with an
electropharmacologic profile similar to
amiodarone, was approved in July of this year for
use in paroxysmal or persistent atrial fibrillation or
atrial flutter. Structurally, dronedarone differs
from amiodarone by the removal of iodine and the
addition of a methane-sulfonyl group which
decreases lipophilicity and shortens the half-life
(-24 hours), thereby reducing tissue accumulation
which occurs with amiodarone use due to its
exceedingly long half-life. Dronedarone is
believed to offer similar efficacy as amiodarone but
with an improved safety/tolerability profile.
However, limited long term (>12 month) data is
available to adequately assess the safety and
toxicity of dronedarone. Moreover, available data
only compares dronedarone to placebo rather than
amiodarone. In the DIONYSOS trial, dronedarone
was reportedly less effective than amiodarone in
reducing atrial fibrillation following electrical
cardioversion but significantly better tolerated;
however, the full report of this trial has not been
published. One phase III study, ANDROMEDA,
was halted early after an interim safety analysis
revealed an excess risk of death in the dronedarone
group (as compared with placebo). These results
were not duplicated in several other large-scale
clinical trials.
The recommended dose for dronedarone is 400
mg by mouth twice daily. Administration with
meals is recommended.




The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and

John G. Gums Editor
PharmD, FCCP

R. Whit Curry, MD Associate Editor

Steven M. Smith Assistant Editor
PharmD


m:m


Volume 24, Issue 11 1 August 2009


PharmaNote




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