Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00075
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Title: PharmaNote
Physical Description: Serial
Language: English
Creator: College of Pharmacy, University of Florida
Publisher: College of Pharmacy
Place of Publication: Gainesville, Fla.
Publication Date: July 2009
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Bibliographic ID: UF00087345
Volume ID: VID00075
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Holding Location: University of Florida
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Jessica Enogieru, Pharm.D. Candidate

Fibromyalgia (FM) is often misunderstood and
misdiagnosed with considerable socioeconomic
effects on patients and society. Historically,
treatment of this disease focused on correcting indi-
vidual symptoms (depression, pain, sleep distur-
bances). Treatments included tricyclic antidepres-
sants (TCAs), selective serotonin reuptake inhibitors
(SSRIs), benzodiazepines, tramadol, acetaminophen,
pregabalin and gabapentin. In January of this year,
milnacipran (Savella , a new selective serotonin and
norepinephrine reuptake inhibitor (SNRI), was ap-
proved by the FDA for the treatment of FM. This
article will describe the efficacy and safety profile of
milnacipran compared to standard treatments in fi-


Fibromyalgia patients present with a constella-
tion of symptoms and is the second most frequent
presenting problem in rheumatology practices. Fi-
bromyalgia affects approximately 2-4% of the U.S.
population (3.4% of women, 0.5% of men) and pre-
dominantly affects women in a ratio of 9:1 compared
to men. Fibromyalgia is most prevalent in women >
50 years; the rate of FM increases with age to a
maximum prevalence of 7.4% in women aged 70 to

79 years.
Research indicates that the socioeconomic impact
of FM is immense. Between 15%-44% of the people
with FM are receiving disability benefits and it is
estimated that FM costs the American economy over
$9 billion annually.3
The 1990 American College of Rheumatology
classification criteria defined FM as history of wide-
spread musculoskeletal pain that is present for > 3
months with significant tenderness or pain in 11 of
18 point sites on digital palpation.4
Several causative mechanisms have been postu-
lated to explain the abnormal pain perception. For
instance, disturbed sleep has been implicated as a
factor in FM pathogenesis. Nonrestorative sleep has
been observed in most patients with FM. Sleep stud-
ies in patients with FM show disruption of normal
stage 4 sleep (non-rapid eye movement sleep or
NREM) by repeated a-wave intrusions. The idea that
stage 4 sleep deprivation has a role in causing this
disorder was supported by the observation that symp-
toms of fibromyalgia developed in normal subjects
whose stage 4 sleep was disrupted artificially by in-
duced a-wave intrusions.3 Analyses of sleep electro-


,i ^ ^ ^ -^ ^ ^ ^ r ,



i -i

Volume 24, Issue 10 1 July2009


encephalographs (EEGs) demonstrate three types of
sleep: phasic (50% of FM patients versus 7% of nor-
mal patients), tonic (20% of FM patients versus 9%
of normal patients), and low (30% of FM patients
versus 84% of normals)5 Those with the phasic pat-
tern of intrusion in slow-wave sleep (SWS) are more
likely to have increased post-sleep tenderness and
subjective pain, poor sleep efficiency, and less SWS
than the other groups. Morning stiffness, diffuse
pain, and discomfort after awakening commonly oc-
cur in FM patients with phasic sleep. Although a
cause-effect relationship between pain and sleep can-
not be established, the data suggest that the phasic
sleep pattern is associated with longer duration of
pain symptoms, perception of poor sleep, and morn-
ing pain. The finding of this EEG sleep disorder in
children and their mothers suggests the possibility of
a familial or genetic influence in the pathogenesis of
the disorder.5
One key factor believed to cause abnormal pain
perception is central pain, which is defined as en-
hanced nociceptive sensation caused by neural activi-
ties in the absence of peripheral input. This assertion
is further supported by the lack of consistent periph-
eral abnormalities in patients with fibromyalgia.6
Biochemical studies of samples from patients
with fibromyalgia have supported the notion that the
pathology might be due to high levels of pronocicep-
tive (i.e. increase sensitivity to pain) compounds, low
levels of antinociceptive compounds, or both.6
The two principal descending antinociceptive
pathways in humans are the opioidergic and mixed
serotonergic-noradrenergic pathways. Current evi-
dence suggests that the opioidergic systems might be
maximally activated in individuals with fibromyal-
gia, as evidenced by high enkephalin levels noted in
the CSF of fibromyalgia patients.6 A decrease in de-
scending antinociceptive activity is likely to occur
because of deficiencies in the other antinociceptive
pathway, the serotonergic-noradrenergic pathway.
Studies show the principal metabolite of norepineph-
rine, 3-methoxy-4-hydroxyphenethylene, is at a low
level in the CSF of patients with fibromyalgia.6 Simi-
larly, there are data suggesting that patients with fi-
bromyalgia have low levels of serotonin and its pre-
cursor, L-tryptophan in their serum, as well as re-
duced levels of the principal serotonin metabolite, 5-
hydroxyindole acetic acid, in their CSF.
Many patients with FM have psychological ab-
normalities however there is disagreement as to

whether these abnormalities represent reactions to
the chronic pain or whether the symptoms of FM are
a reflection of psychiatric disturbance. Approxi-
mately 30% of FM patients fit a psychiatric diagno-
sis, the most common being depression, anxiety,
somatization, and hypochondriasis.7 However, FM
also occurs in patients without significant psychiatric


In FM patients, musculoskeletal and neurologic
examinations are normal and there are usually no
laboratory abnormalities. Symptoms are generalized
musculoskeletal aching, stiffness, and fatigue. Pa-
tients may feel muscle pain after mild exertion, and
some degree of pain is always present. The pain is
described as a burning or gnawing pain or as sore-
ness, stiffness, or aching. Patients awake frequently
at night and have trouble falling back to sleep. Pa-
tients may experience cognitive impairment with dif-
ficulty thinking and loss of short-term memory.
Headaches, including migraines, are also common.


The initial step in treatment is to improve the
quality of sleep. The use of TCAs amitriptylinee,
nortriptyline, doxepin, or cyclobenzaprine) 1-2 h
before bedtime will give the patient restorative sleep
(stage 4), resulting in clinical improvement.' Patients
should be started on a low dose and increased gradu-
ally as needed. Side effects of TCAs limit their use.
Depression and anxiety should be treated with appro-
priate drugs and, when indicated, with psychiatric
counseling. Duloxetine, fluoxetine, sertraline, par-
oxetine, citalopram, or other SNRI and SSRIs can be
used.' Other useful antidepressants include trazodone
and venlafaxine. Alprazolam and lorazepam are ef-
fective for anxiety.
For pain, duloxetine (Cymbalta) and pregabalin
(Lyrica) are FDA approved to treat fibromyalgia
pain; acetaminophen, tramadol, or gabapentin are
also useful. Salicylates or other nonsteroidal anti-
inflammatory drugs (NSAIDs) only partially im-
prove symptoms and opiate analgesics should be
avoided. Patients may benefit from regular low im-
pact aerobic and stretching exercises, which are
started after patients begin to have improved sleep
and less pain and fatigue.

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The exact mechanism of the central pain inhibi-
tory action of milnacipran and its ability to improve
the symptoms of FM in humans is unknown. How-
ever, milnacipran is a potent inhibitor of neuronal
norepinephrine and serotonin reuptake. Milnacipran
inhibits norepinephrine uptake with approximately 3-
fold higher potency in vitro than serotonin (5-HT)
without directly affecting the uptake of dopamine or
other neurotransmitters.
Acutely, milnacipran blocks 5-HT and NE reup-
take into the neuron, increasing 5-HT and NE ex-
tracellular concentrations. This activates 5-HT and
NE auto- and heteroreceptors culminating in a de-
crease in 5-HT and NE neuronal firing rates, synthe-
sis, and release.8 Chronically, milnacipran continues
to block 5-HT and NE transporters without desensiti-
zation, but 5-HT and NE auto- and heteroreceptors
are desensitized and thus, downregulated. Firing
rates of 5-HT and NE return to normal, and the
amount of 5-HT and NE released per nerve impulse
is increased.8
Unlike SSRIs and TCAs, milnacipran has no sig-
nificant affinity for a- and P-adrenergic, muscarinic
(M1-5), histamine (H1-4), dopamine (D1-5), opiate,
benzodiazepine, or y-aminobutyric acid (GABA) re-
ceptors in vitro.9 Pharmacologic activity at these re-
ceptors is hypothesized to be associated with the
various anticholinergic, sedative, and cardiovascular
side effects observed with other psychotropic drugs.
Milnacipran has no significant affinity for Ca2+, K+,
Na+ and Cl channels and does not inhibit the activity
of human monoamine oxidases (MAO-A and MAO-
B) or acetylcholinesterase.9

Milnacipran is well absorbed after oral admini-
stration with an absolute bioavailability of approxi-
mately 85% to 90%; absorption is not affected by
food. Milnacipran and its metabolites are excreted
predominantly unchanged in urine (55%) with a ter-
minal elimination half-life (Ti/2) of 6 to 8 hours.
Milnacipran achieves maximum blood concentra-
tions (Cmax) within 2 to 4 hours post dose. The
mean volume of distribution of milnacipran follow-
ing a single IV dose in healthy subjects is approxi-
mately 400 L and plasma protein binding is 13%.9
Milnacipran's excretion was evaluated following a
single oral administration of 50 mg in mild
(creatinine clearance [CLcr] 50-80 mL/min), moder-
ate (CLcr 30-49 mL/min), and severe (CLcr 5-29
mL/min) renal impairment and in healthy subjects
(CLcr > 80 mL/min). The mean area under the curve
(AUCo-,) increased by 16%, 52%, and 199%, and
elimination half-life increased by 38%, 41%, and
122% in subjects with mild, moderate, and severe
renal impairment, respectively, compared with
healthy subjects.9 No dosage adjustment is necessary
for patients with mild renal impairment but caution
should be exercised in moderate renal impairment.
Dose adjustment is necessary in severe renal impair-
ment patients.
Milnacipran's metabolism was evaluated follow-
ing single oral administration of 50 mg in mild
(Child-Pugh A), moderate (Child-Pugh B), and se-
vere (Child-Pugh C) hepatic impairment and in
healthy subjects. AUCo-, and T1/2were similar in
healthy subjects and subjects with mild and moderate
hepatic impairment. However, subjects with severe

Table 1. Fibromyalgia composite response at week 15.1

Milnacipran 100 mg (%) Milnacipran 200 mg (%) Placebo (%)
> 30% improvement in PED- LOCF 149/399 (37.3)* 158/396 (39.9)t 115/401 (28.7)
24h AM-recallpain OC 124/237 (52.3)* 119/217 (54.8)t 101/263 (38.4)
PGIC < 2 LOCF 138/399 (34.6)* 151/396(38.10) t 100/401 (24.9)
OC 125/263 (47.5)t 129/255 (50.6)t 92/289 (31.8)
> 6 point increase from LOCF 129/399 (32.3)$ 109/396 (27.5) 102/401 (25.4)
baseline in SF-36 PCS
baseline in SF-36 PCSOC 108/263 (41.1)* 89/255 (34.9) 86/290 (29.7)
PED = patient experience diary; LOCF=last observation carried forward; OC=observed cases; PGIC=patient global impression of
change; SF-36=36-item short form health survey; PCS=physical component summary.
For comparisons to Placebo: *P< 0.01; tP< 0.001; tP< 0.05

---- r* *-- 1- . n r % I I I n n a



lrIaII 0 I el UL

hepatic impairment had a 31% higher AUCo-, and a
55% higher T1/2 than healthy subjects. Caution
should be exercised in patients with severe hepatic
Compared to SSRIs, TCAs, and duloxetine, mil-
nacipran has less risk for drug interactions involving
the cytochrome P450 enzyme system. Neither mil-
nacipran nor pregabalin induce or inhibit CYP en-
zymes, but duloxetine is metabolized by CYP 2D6
and 1A2 isoenzymes.


Several randomized, placebo-controlled trials
have illustrated milnacipran's efficacy in treating FM
and FM pain, but not sleep problems. Clauw and col-
leagues conducted a phase III, 15 week, multicenter,
randomized, double-blind, placebo-controlled, multi-
ple-dose clinical trial.1 Of 2270 patients screened,
1196 patients were randomized to receive milnacip-
ran 100mg/d (n = 399), milnacipran 200mg/d (n =
396), or placebo (n = 401). The primary endpoints
were rates of FM composite responders and rates of
FM pain composite responders. FM composite re-
sponders were defined as patients experiencing con-
current changes in the following domains: pain (>
30% improvement from baseline in the morning-
recall visual analog scale [VAS] pain score), patients'
global status (a Patient Global Impression of Change
[PGIC] rating of 'very much improved' or 'much
improved' at week 15), and physical function (a > 6-
point improvement on the 36-item Short-Form
Health Survey [SF-36] Physical Component Sum-

mary score). FM pain composite responders were
defined as those who met the pain and PGIC criteria.
The majority of patients were female (96.2%) and
white (93.5%), with an mean age of 50.2 years, base-
line weight of 180.8 lbs, and baseline body mass in-
dex of 30.6 kg/m2. There were no significant differ-
ences in baseline demographic and clinical character-
istic between the 3 treatment arms.
Compared with placebo, a significantly greater
proportions of milnacipran-treated patients were FM
composite responders (100 mg/d: P = 0.01; 200 mg/
d: P = 0.02) and FM pain composite responders (100
mg/d: P = 0.03; 200 mg/d: P = 0.004) as described in
Table 1. Milnacipran was associated with significant
improvements in pain after 1 week of treatment (100
mg/d: P = 0.004; 200 mg/d: P = 0.04), as well as sig-
nificant improvements in multiple secondary efficacy
end points, including global status (PGIC: P<0.001
for both doses), physical function (SF-36 physical
functioning domain-100 mg/d: P < 0.001; 200 mg/
d: P = 0.02), and fatigue (Multidimensional Fatigue
Inventory- 100 mg/d: P = 0.04). A significant re-
duction in pain was observed as early as 1 week after
the start of double-blind treatment in both milnacip-
ran arms compared to placebo. Maximal pain relief
was achieved within 9 weeks and was maintained
throughout the study.1
The Medical Outcomes Study (MOS) sleep prob-
lems Index II evaluated changes from baseline in
sleep between patients on 100 mg/d, 200 mg/d, or
placebo. No significant change from baseline was
seen in patients taking 100 mg and 200 mg versus

Table 2. Fibromyalgia composite response at 15 and 27 weeks.10

Placebo Milnacipran Milnacipran Placebo Milnacipran Milnacipran
Placebo Placebo
(n= ) 100mg 200mg 1n= 00mg 200mg
(n=224) (n=441) (n=224) (n=441)
BOCF/LOCF % 12.1 19.6 (0.028) 19.3 (0.017) 13% 18.3 (0.245) 18.1 (0.105)
Observed cases % 17.3 32.8 (0.003) 32.8 (<0.001) 19.4% 33.3 (0.056) 31.9 (0.017)
Fibromyalgia pain
BOCF/LOCF % 19.3 27.2 (0.056) 26.8 (0.032) 18.4% 25.9 (0.072) 25.6 (0.034)
Observed cases % 27.2 45.2 (0.003) 45.4 (<0.001) 27.9% 43.8 (0.021) 45.2 (0.001)

BOCF=baseline observation carried forward; LOCF= last observation carried forward.
Data in ()'s represent p-value compared to placebo.

rE3, ri \/I||* i I') A 1 r% I i..**., anna


0ri l olte0 iWL

Table 3. Depression trials involving milnacipran vs. SSRIs.
Clerc, et al.14 Fluvoxamine HAD 113 6 No (p=0.05) Milnacipran trended toward
Fluvoxamine HAMD 113 6 No (p=0.05)
(2001) > reduction in HAMD score
Sechter, et a.13
ehter eta Paroxetine HAMD 302 6 No (p=0.85)
Lee, et al.12 Small sample size, Asian
SFluoxetine HAMD 70 6 No (p>0.05)
(2005) population, short duration

Mease and colleagues, conducted a 27-week, ran-
domized, double-blind, multicenter study comparing
milnacipran at doses of 100 and 200 mg to placebo.10
The two primary endpoints were rates of FM re-
sponders and FM pain responders (concurrently sat-
isfied response criteria for pain, PGIC, and SF-36).
Composite responder rates are presented in Table 2.
The percentage of patients who met the criteria as
FM composite responders was significantly higher
with both doses of milnacipran compared to placebo
[15 weeks: placebo = 17.3%, 200 mg/d = 32.8% (p<
0.001), 100 mg/d = 32.8% (p< 0.003); and 27 weeks:
placebo = 19.4%, 200 mg/d = 31.9% (p = 0.017),
100 mg/d = 33.3% (p = 0.056)]. Similarly, the pro-
portion of patients meeting criteria as FM pain com-
posite responders was significantly higher with mil-
nacipran compared to placebo at 15 and 27 weeks.
No difference was noted between placebo and mil-
nacipran treatment in terms of quality or quantity of
sleep as measured by the MOS-Sleep Problems Indi-
Recent studies in depressed patients have sug-
gested that newer drugs like milnacipran, which en-
hance NE and 5HT neurotransmission, result in
higher response and remission rates than the SSRIs;
however these findings contrast a meta-analysis that
found no significant differences in antidepressant
A variety of head to head trials have compared
milnacipran to an SSRI to determine milnacipran's
efficacy in depression. Lee and colleagues, com-
pared milnacipran to fluoxetine in 70 patients for 6
weeks. Both treatments produced a significant de-
crease in Hamilton Depression Scale (HAM-D)
score, but no significant difference was found be-
tween the two treatment groups.12 However, these
findings are limited by methodological flaws, includ-
ing a small sample size, high drop out rate, and un-
balanced depression history at baseline. Sechter et al,
compared milnacipran to paroxetine in 302 patients

for 6 weeks and found a significant decrease in aver-
age HAM-D scores with both milnacipran and par-
oxetine. However, the two groups were not statisti-
cally different from each other.13 Clerc and col-
leagues, compared milnacipran to fluvoxamine in
113 patients for 6 weeks. Milnacipran showed
greater reduction in HAM-D scores (62.1% vs.
49.3%) but the difference did not reach statistical
significance.14 Overall, milnacipran has shown simi-
lar or greater efficacy than SSRIs in treating depres-
sion and depressive symptoms (Table 3).


Table 4 summarizes the most frequently reported
adverse events (frequency > 5% of patients in either
milnacipran treatment group and at an incidence
rate> twice that of placebo).10 Most frequently re-
ported adverse events were nausea, headache and
constipation. Although the absolute rates of occur-

Table 4. Percentage of trial subjects experiencing
adverse effects.10
100 MG/DAY 200 MG/DAY
Nausea 21.1 32.6 40.1
Headache 11.7 15.6 17.7
Constipation 2.7 18.3 14.3
Hyperhidrosis 2.2 9.8 12.5
Dizziness 6.7 11.6 11.3
Hot Flush 2.7 9.8 10.4
Insomnia 6.7 10.7 9.3
Vomiting 1.8 4.9 8.2
Sinusitis 8.1 4.9 7.3
Tachycardia 2.2 5.4 7.3
Dry mouth 2.7 5.8 7.0
URTI 7.2 8.9 6.8
Palpitations 0.9 8.0 5.7
Diarrhea 7.2 4.5 5.2

Ir o V

Volume 24, Issue 10 1 July2009


rence were small, palpitations tachycardia, and blood
pressure increases occurred at least twice as much in
the milnacipran groups than placebo.9
Adverse events resulted in the premature discon-
tinuation of 10.3%, 19.6%, and 27.0% of placebo
and milnacipran 100 and 200 mg/day patients, re-
spectively.10 The discontinuation rates of milnacip-
ran are similar to the discontinuation rates of placebo
and other FDA approved FM drugs.15'16 Contraindi-
cations include the use of monoamine oxidase inhibi-
tors concomitantly or uncontrolled narrow-angle
glaucoma.9 Since milnacipran has very little mus-
carinic, histaminergic, or adrenergic activities, it ex-
hibits a better safety profile compared with TCAs
and at least a similar, if not better, safety profile
when compared to SSRIs.8


The most commonly studied milnacipran dose is
50 mg twice daily. A one month supply of such a
dose of Savella costs approximately $119.99.17


Milnacipran is effective in FM, FM pain, and de-
pression but has shown no efficacy in treating sleep
disturbances in FM. Its greatest advantage over du-
loxetine is its low risk for pharmacokinetic drug in-
teractions. This is especially important for FM pa-
tients who may be on other medications for sleep
problems or depression. An important advantage
over pregabalin is milnacipran's weight neutrality.
Milnacipran can cause GI problems (nausea, consti-
pation) and cardiovascular issues (tachycardia, hy-
pertension), but its greatest disadvantage may be its


1. Clauw DJ, Mease P, Palmer RH et al. Milnacipran for the Treat-
ment of Fibromyalgia in Adults: A 15-Week, Multicenter, Ran-
domized, Double-Blind, Placebo-Controlled, Multiple-Dose
Clinical Trial. Clin Therap 2008;30:1988-2004.
2. Lawrence RC, Felson DT et al. Estimates of the prevalence of
arthritis and other rheumatic conditions in the United States. Part
II. Arthritis Rheum 2008;58(1):26-35.
3. Arnold LM, Crofford LJ, Mease PJ, et al. Patient perspectives on
the impact of fibromyalgia. Patient Educ Couns 2008;73:114-20.
4. Wolfe F, Smythe HA, Yunus MB, et al. The American College of
Rheumatology 1990 Criteria for the Classification of Fibromyal-
gia. Report of the Multicenter Criteria Committee. Arthritis
Rheum 1990;33:160-72.

5. Moldofsky H. Role of the Sleeping/Waking Brain in the Patho-
genesis of Fibromyalgia, Chronic Fatigue Syndrome, and Related
Disorders Primary Psychiatry 2006;13(9):52-58.
6. Dadabhoy D Clauw DJ. Therapy Insight: Fibromyalgia---
Different Type of Pain Needing A Different Type of Treatment.
Nat Clin Pract Rheumatol 2006;2(7):364-372.
7. Langford CA, Gilliland BC, "Chapter 329. Fibromyal-
gia" (Chapter). Harrison's Principles of Internal Medicine, 17th
8. Baldessarini RJ, "Chapter 17. Drug Therapy of Depression and
Anxiety Disorders" (Chapter). Laurence L. Brunton, John S.
Lazo, Keith L. Parker: Goodman & Gilman's The Pharmacologi-
cal Basis of Therapeutics, 11th Edition
9. Savella Package Insert. Forest Pharmaceuticals, Inc. 1/8/2009.
10. Mease PJ, Clauw DJ, Gendreau RM, Rao SG, Kranzler J, Chen W
et al. The Efficacy and Safety of Milnacipran for Treatment of
Fibromyalgia. A Randomized, Double-blind, Placebo-controlled
Trial. Dec 15 2008; J Rheumatol 2009;36:398-409.
11. Papakostas GI, Thase ME, Fava M, Nelson JC, Shelton RC. Are
Antidepressant Drugs That Combine Serotonergic and Noradren-
ergic Mechanisms of Action More Effective Than the Selective
Serotonin Reuptake Inhibitors in Treating Major Depressive Dis-
order? A Meta-analysis of Studies of Newer Agents. Biol Psy-
chiatry 2007;62:1217-1227.
12. Lee MS, Ham BJ, Kee BS, Kim JB, Yeon BK, Oh KS, et al.
Comparison of efficacy and safety of milnacipran and fluoxetine
in Korean patients with major depression. Curr Med Res Opin
2005;21:1369 -1375.
13. Sechter D, Vandel P, Weiller E, Pezous N, Cabanac F, Tournoux
A, et al. A comparative study of milnacipran and paroxetine in
outpatients with major depression. JAffect Disord 2001;83:233.
14. Clerc G, et al. Antidepressant efficacy and tolerability of mil-
nacipran, a dual serotonin and noradrenaline reuptake inhibitor: A
comparison with fluvoxamine. Int Clin Psychopharmacol
15. Mease, PJ. A Randomized, Double-blind, Placebo-Controlled,
Phase III Trial of Pregabalin in the Treatment of Patients with
Fibromyalgia. J Rheumatol 2008;35:502-14.
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cessed 6/29/09.

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

John G. Gums Editor
PharmD, FCCP

R. Whit Curry, MD Associate Editor

Steven M. Smith Assistant Editor
; _ _ _ _ _ _ _ _ _ _ _

Phraoe oue2, su 0 I uy20


Volume 24, Issue 10 1 July2009

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