1. health and fitness
2. therapy

PRACTICAL INFORMATION FOR TODAY’S PHARMACIST
A Supplement to:
10.10
®
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Fibromyalgia and
Savella (milnacipran hydrochloride):
An Overview for
the Pharmacist
Including Product Monograph
Kathryn L. Hahn, PharmD, CPE, DAAPM
Sponsored by Forest Laboratories, Inc. and Cypress Bioscience, Inc.
Important Safety Information: Savella (milnacipran HCl) Tablets
Savella is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), similar to some drugs used for the treatment of depression
and other psychiatric disorders. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in
children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone
considering the use of such drugs in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies
did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are
themselves associated with increases in the risk of suicide. Patients of all ages who are started on Savella should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior especially during the initial few months of
drug therapy or at times of dose changes, either increases or decreases. Families and caregivers should be advised of the need for close
observation and communication with the prescriber. Savella is not approved for use in the treatment of major depressive disorder. Savella
is not approved for use in pediatric patients.
Please see additional important Safety information inside.
© 2010. Pharmacy & Healthcare Communications, LLC
®
Contents
Vol. 76
president
Tighe Blazier
PUBLISHING STAFF
Editor-in-Chief
Fred M. Eckel, RPh, MS
Editorial director
Bea Riemschneider
Associate editor
Jennifer Whartenby
Assistant Editor
Laura Enderle
Pharmacy Law Editor
Joseph L. Fink III, BSPharm, JD
Director of scientific content,
custom publishing
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Clinical Projects manager
Kara L. Guarini, MS
Art Director
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Director of custom publishing
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Sales & Marketing CoordinatoRS
Carolyn Chen
Elaine Chu
ADVERTISING
REPRESENTATIVES
Carmel Burke-Bonesso
Fibromyalgia and
Savella (milnacipran hydrochloride):
An Overview
for the Pharmacist
Including Product Monograph
Kathryn L. Hahn, PharmD, CPE, DAAPM
Affiliate Faculty, Oregon State University College of Pharmacy
Chair, Oregon Pain Management Commission
American Pain Foundation State Action Leader
Pharmacy Manager, Bi-Mart Corporation,
Springfield, Oregon
Sponsored by Forest Laboratories, Inc. and Cypress Bioscience, Inc.
609-716-7777, ext. 154
Anthony Costella
609-716-7777, ext. 163
Ashley Hennessy
1 Introduction
609-716-7777, ext. 165
Heather Rogers
609-716-7777, ext. 147
classified Sales
REPRESENTATIVE
1
Section 1. Overview of Fibromyalgia
7
Section 2. Information About Savella
(milnacipran hydrochloride)
Susan Yeager
609-716-7777, ext. 153
CORPORATE
Chairman/Chief Executive Officer
Mike Hennessy
President/Chief Operating Officer
Herbert A. Marek
GROUP EDITORIAL DIRECTOR
Bill Schu
Business Manager
Butch Hollenback
EXECUTIVE DIRECTOR OF EDUCATION
Judy V. Lum, MPA
Executive Assistant
Marcie Ottinger
20 Section 3. The Role of the Pharmacist
24 Savella Quick Reference
25 Savella Prescribing Information
Please see Important Safety Information, including Boxed Warning, on pages 13-19.
Fibromyalgia and Savella (milnacipran HCl):
An Overview for the Pharmacist
Kathryn L. Hahn, PharmD, CPE, DAAPM
Introduction
Fibromyalgia (FM) is a multisymptom
condition characterized by chronic
widespread pain, functional disability,
physical deconditioning, and a variety
of other symptoms.1,2 FM has emerged
as a major diagnostic source of prescriptions for analgesics, muscle relaxants, reuptake inhibitors, and other
medications. Standards for diagnosis
and treatment remain controversial
in the medical community. Increasing
evidence supports FM as a specific
physical condition with demonstrated
chemical abnormalities and physiologic
processes that differ from other illnesses and those in healthy control
subjects.3,4 Recent laboratory, positron
emission tomography,5 voxel-based
morphometry,6 and functional magnetic
resonance imaging (fMRI) research has
supported the legitimacy of FM as a genuine, distinct disorder.7 Nevertheless,
that legitimacy is still not universally
accepted, perhaps in part because FM
cannot be diagnosed with a simple laboratory test.
FM is more prevalent than some pharmacists and physicians are aware. In the
United States, approximately 2% to 4%
of the population suffers from FM, and
up to 73% of patients are undiagnosed.8,9
Controversy in the medical community
about the definition and diagnosis of
FM, along with societal stigma attached
to psychophysical symptoms, make FM
an especially harsh condition for those
who suffer from it. Patients may meet
the criteria for FM without receiving
an accurate diagnosis for years.10-12 The
frustrating lack of diagnosis and physician skepticism can cause greater distress.13 It is not surprising that many
patients are confused about their condition, or that medication adherence is
generally poor.14
Many different treatments are used for
FM. Evidence-based guidelines recommend nonpharmacologic therapies and
several drugs that are not approved by
the US Food and Drug Administration
(FDA) for the treatment of FM. However,
the guidelines were issued before more
recent studies and the FDA approval
of Savella (milnacipran HCl), Cymbalta
(duloxetine), and Lyrica (pregabalin) for
FM. Milnacipran, a selective serotonin
and norepinephrine reuptake inhibitor
(SNRI), is the only agent indicated solely
for FM.
Community pharmacists can play an
important role in helping to identify
patients with FM and assisting clinicians with rational treatment plans that
incorporate the most effective treatments for the individual patient while
minimizing adverse effects and avoiding drug–drug interactions. Education
and counseling from pharmacists can
help patients understand FM, gain control over the stressors that cause flareups, and more successfully manage
symptoms. Importantly, through patient
counseling, pharmacists can promote
medication adherence and thus enable
better treatment outcomes.
This monograph will explore the symptoms and diagnosis of FM; epidemiology,
burden, and pathophysiology; and pharmacologic and nonpharmacologic treatment options. In addition, it will provide
a comprehensive description of Savella,
including its clinical pharmacology, clinical efficacy, dosing, and safety information. Lastly, it will offer practical information on the role of the pharmacist in the
care of patients with FM.
SECTION 1. Overview of Fibromyalgia
FM is a multisymptom condition characterized by chronic widespread pain
and diffuse tenderness, which can
contribute to decreased physical function1,15,16 and may lead to disability.17-19
Although sometimes confused with
rheumatoid arthritis, FM pain is not
centered in the joints, but appears
as a generalized muscular tenderness
in all 4 quadrants of the body (left
and right side, above and below the
waist).2,3,10,20 Patients with FM typically have both allodynia (pain from
normally non-noxious stimuli) and
hyperalgesia (increased response to
painful stimuli).17,21 Controlled studies
have demonstrated that patients with
FM do not detect thermal, electrical, or pressure stimuli more acutely
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than healthy control subjects, but the
pain threshold—the level of stimulus that causes pain—is lower.1,3,22
Repetition of the same level of a
stimulus in a series has been shown
to evoke greater subjective intensity of pain in patients with FM.22
Furthermore, patients with FM continue to experience “after-sensations”
of pain following complete cessation
of the stimulus. Approximately 78% of
patients with FM do not have major
depressive disorder (MDD) based
on diagnostic criteria cited in the
Diagnostic and Statistical Manual
of Mental Disorders, Fourth Edition,
Text Revision.23 Others suffer irritable
bowel or bladder symptoms, facial
pain, low back pain, chest pain, symp-
toms typical of restless legs syndrome,
and cognitive impairment.4,10,17
Epidemiology
In the United States, FM affects 2%
to 4% of the population, or as many
as 12 million people.7,8,10 FM is the
second most common disorder treated
by rheumatologists, after osteoarthri-
Patient Counseling Tips
The Cycle of FM
Pharmacists can remind patients that
symptoms of FM can all contribute to
each other.24 In addition to adhering
to medications and nonpharmacologic
therapy, patients need to manage all
the contributing elements in their daily
lives for best outcome.
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
Figure 1
Figure 2
Alterations in Both Ascending and Descending
Pain Pathways in the Central Nervous System May
Contribute to Fibromyalgia25,26
Relationship Between
Stimulus Intensity and
Pain Magnitude as
Reported in Patients
with Fibromyalgia3
Descending
Pathway
Ascending
Pathway
tis, yet these specialists provide care
for fewer than 20% of patients with
FM.7,8 Additionally, as much as 6% of
general medicine visits are for FM.8
Women dominate the FM population,
with a female-to-male ratio as high
as 9:1.10,24 The age of onset is usually 20 to 55 years,10 but prevalence
increases with age, peaking at 70 to
79 years.8 Because the syndrome is
not well understood and difficult to
diagnose, the actual prevalence may
be considerably higher. An estimated
73% of patients with FM are undiagnosed9 and, therefore, untreated.
Pharmacists can play a role in the
identification and diagnosis of FM.
A pharmacist should discuss with
patients any prescription medications
or over-the-counter (OTC) products
they are taking, and if these therapies
adequately address their symptoms. If
a pharmacist suspects that a patient
has FM based on their discussions,
and the patient has not received a diagnosis, referral to a physician may be
appropriate.
Pathogenesis
The exact cause of FM is unknown. The
predominant theory of pathogenesis in
FM is associated with central sensitization, a condition of overreactivity
of the central nervous system (CNS)
2
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to a variety of stimuli, due to dysregulation of ascending and descending pain pathways (Figure 1).25,26 The
effects of altered pain processing and
central sensitization in FM have been
demonstrated in brain imaging studies
(Figure 2).3,7 In studies using fMRI,
patients with FM reported pain at half
the pressure required to register similar pain levels in control subjects.3
Stimuli resulting in subjective pain
sensations that were similar between
patients with FM and controls also
resulted in similar areas of brain activation on fMRI. In contrast, similar
levels of pressure that evoked greater
pain in patients with FM also resulted
in different areas of activation.3
Although the exact etiology is
unknown,11 recent research has expanded the understanding of FM as a condition involving both genetic and environmental factors. Genetics appears to play
a role in susceptibility.1 First-degree relatives of patients with FM have 8 times the
risk for FM as the general population.1
Evidence supports a role for polymorphisms of genes that affect the metabolism or transport of the inhibitory monoamine neurotransmitters serotonin and
norepinephrine.1 Concentrations of
norepinephrine markers were found to
be significantly lower in the cerebrospinal fluid of patients with FM compared
The graph shows mean pain rating plotted against
stimulus intensity of the experimental conditions. In
the fibromyalgia condition, a relatively low stimulus
pressure (2.4 kg/cm2) produced a high pain level
(mean ± SD 11.30 ± 0.90). In the stimulus pressure
control condition, administration of a similar stimulus
pressure (2.33 kg/cm2) to control subjects produced
a very low level of rated pain (mean ± SD 3.05 ± 0.85).
In the subjective pain control condition, administration of significantly greater stimulus pressures to the
control subjects (4.16 kg/cm2) produced levels of pain
(mean ± SD 11.95 ± 0.94) similar to those produced in
patients by lower stimulus pressures.
Reprinted with permission from Gracely RH et al.
Arthritis Rheum. 2002; 46(5):1333-1343.
with control subjects.27 Patients with
FM were also found to have increased
levels of the pronociceptive substance P
that amplify pain impulses in the ascending pain pathway.1 However, there is
more evidence for a decrease in activity of descending antinociceptive pain
pathways than for hyperactivity of pro-
Patient Counseling Tips
Realistic Expectations
Some patients with FM expect treatment to produce a completely painfree, energetic lifestyle, but that level
of improvement doesn’t happen for
everyone. Although pharmacists
should be understanding and supportive, it is important not to give
false hope. Pharmacists should inform
patients that their prescription will not
cure FM.20 Even with successful treatment, occasional symptomatic flareups can occur. Helping the patient
maintain realistically optimistic expectations can inspire greater adherence.
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Please see Important Safety Information, including Boxed Warning, on pages 13-19.
FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
nociceptive ascending pain pathways.1
Anticonvulsants such as gabapentin and
pregabalin may bind to the alpha 2-delta
subunit of neurons in the CNS, reducing
the release of several neurotransmitters
(eg, substance P, glutamate) involved in
pain perception.1,18,28
Evidence suggests that environmental stressors trigger the development
of FM in persons with a genetic predisposition.29 Among patients with FM
who identified an event that triggered
onset of symptoms, 73% reported
emotional trauma or chronic stress as
the trigger and 27% reported an acute
illness.30 Surgery, physical trauma,
peripheral pain conditions (eg, autoimmune diseases, osteoarthritis), and viral
infections have also been identified as
triggers.24,30 Thus, the current understanding of FM includes both genetic
and environmental components.
Figure 3
Illustration of Tender Points for Diagnosis of
Fibromyalgia2
Diagnosis
FM is not a diagnosis of exclusion and
should be diagnosed by its own clinical
characteristics.24 Because no objective
laboratory test or marker exists, diagnosis is based on history and physical examination.4 In 1990, the American
College of Rheumatology (ACR) published classification criteria for FM diagnosis including2:
• A history of chronic, widespread
pain, including axial skeletal pain
plus pain in all 4 quadrants, for at
least 3 months
• Pain in at least 11 of 18 predefined
Patient Counseling Tips
Recognizing FM Pain
Pharmacists may have an opportunity
to assist patients with undiagnosed
FM when they are filling a prescription
for pain medication. The pharmacist
can ask patients to describe their pain
in detail plus any other symptoms and
functional limitations. If FM seems
likely, the pharmacist can explain FM
and refer undiagnosed patients to
their primary care physician. If patients
already had a detailed discussion like
this with their primary provider, but
did not receive a diagnosis, seeing
a rheumatologist or other specialist
might be appropriate.
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Adapted from Wolfe F, et al. Arthritis Rheum. 1990;33(2):160-172.
muscle tendon sites of focal tenderness (“tender points”) on digital
palpation using a force of approximately 4 kg/cm2 (Figure 3).2
Because the criteria of 11 of 18
tender points was first designed as a
research tool, its use in clinical diagnosis has been questioned.1 The cutoff
of 11 tender points is considered arbitrary.22 Tender points may be associated with distress rather than pressure
pain threshold,1,22 and some patients,
particularly males, with fewer than 11
can still have FM.20 Some authors have
suggested that the large sex-related
disparity in FM diagnoses may be due
entirely to the 11 of 18 cutoff, since
women are 11 times more likely than
men to fulfill this criterion.1 In any
event, pain and tenderness, however
measured, do not capture other prominent symptoms of FM.
A stepwise approach for the management of FM was recently proposed, which takes into consideration
comorbid conditions and the use of
evidence-based medications (Figure
4).31 Following a trial with evidencebased medications, adjunctive nonpharmacologic treatments beneficial in the
management of FM are recommended,
Patient Counseling Tips
Polypharmacy
Patients with FM may require multiple
pharmacologic agents to adequately
treat their symptoms. The symptoms
of FM may come and go, with varying intensity. Appropriate management of FM is an ongoing process.
Pharmacists should routinely ask their
patients with FM what medications
they are currently taking and how well
those treatments are controlling their
FM symptoms and flare-ups.
Many agents used to treat FM
symptoms are not approved by the
FDA for the management of FM.
Pharmacists may hear from their
patients, or notice, that the medications they are currently taking do not
provide adequate relief of FM symptoms. In such a case, a pharmacist
should refer the patient to a physician, who will be able to determine
appropriate therapy.
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
Figure 4
Multistep Approach to the Management of
Fibromyalgia31
Patient Counseling Tips
“It hurts too much to exercise”
Patients may confide that their symptoms have not improved much, but
the treatment plan recommended by
their physician includes exercise as
well as prescribed medication, and
they are not exercising because of the
painful symptoms. They may have
stopped almost all activity because
any activity makes their symptoms
worse.18 The pharmacist can help by
clarifying the difference between hurt
and harm; that is, exercise may cause
discomfort but should eventually
increase endurance and may make
their FM condition better, not worse.18
Even if the patient can tolerate only a
few minutes to start, that is an important step toward improved function.
The pharmacist can emphasize that
pharmacologic and nonpharmacologic treatments are most effective
together and should not be substituted for each other. Exercise should
be increased gradually as tolerated.
Be sure to tell patients to talk to their
doctor before starting any exercise
program.
Reprinted with permission from Arnold LM. J Clin Psychiatry. 2008;69(suppl 2):14-19.
including cognitive behavior strategies,
exercise, education about chronic pain,
and social support.20,31
Studies have shown that symptoms
and health satisfaction improve after
diagnosis of FM,1,7 in part because
patients finally have confirmation of
their illness.11 Appropriate FM treatment can be long delayed, with many
health care visits, referrals, diagnostic tests, and inaccurate diagnoses,
yielding little impact on symptoms.10-12
Diagnostic delay may result from uncertainty surrounding appropriate diagnostic methods and criteria. A need exists,
especially in primary care, for more education and better diagnostic criteria.
The Burden of FM
The chronic, impairing symptoms of
FM can lead to loss of function, which
negatively affects work, leisure, and
family/social activities,32 may increase
over time, and reduces health-related
quality of life.33 As much as 50% of
patients can work only a limited number of days because of the disorder.34-36
Almost one third of patients with
FM receive some disability or Social
Security payments.35,36 Eventually,
some patients become completely
disabled and incapable of continued
employment.
FM is also associated with a significant cost burden, including high direct
medical costs37 and high indirect costs
due to lost work productivity.12,37 A large
US claims database analysis using 2005
data demonstrated that:
• Patients with FM had mean total
Table 1a
FDA-Approved Agents for FM28,41,42
Savella
(milnacipran hydrochloride)
Indications
Fibromyalgia (see Section 2 on page 7
for additional information)
Cymbalta
(duloxetine hydrochloride)
Lyrica
(pregabalin)
Fibromyalgia
Fibromyalgia
Major depressive disorder, generalized anxiety disorder, diabetic
peripheral neuropathic pain
Neuropathic pain associated with diabetic
peripheral neuropathy, postherpetic neuralgia,
adjunctive therapy for partial-onset seizures
This table is not intended to imply that these drugs are clinically equivalent.
a
FDA = US Food and Drug Administration.
4
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
Table 2
Drugs Commonly Used, but Not FDA Approved, for FMa
Agent
Approved Indication(s)
Relief of symptoms of depression
Amitriptyline
43
Cyclobenzaprine
Relief of muscle spasm associated with acute, painful muscoskeletal conditions (as an adjunct to rest and physical
therapy)
Tramadol45
Management of moderate-to-moderately-severe pain in adults
Fluoxetine46
Acute and maintenance treatment of major depressive disorder in adult and pediatric patients aged 8 to 18 years; acute and
maintenance treatment of obsessive compulsive disorder in adult and pediatric patients aged 7 to 17 years; acute and maintenance treatment of bulimia nervosa in adult patients; acute treatment of panic disorder, with or without agoraphobia, in adult
patients
Venlafaxine47
Treatment of major depressive disorder, generalized anxiety disorder, social anxiety disorder, and panic disorder
Analgesics (paracetamol/
acetaminophen,48
hydrocodone49)
Temporary relief of minor aches and pains
Pramipexole
Treatment of the signs and symptoms of idiopathic Parkinson’s disease; treatment of moderate-to-severe primary restless
legs syndrome
44
50
Relief of moderate-to-moderately-severe pain
Forest Laboratories, Inc. does not support the off-label use of medications.
a
FDA = US Food and Drug Administration.
annual health care costs of $9573,
approximately 3 times higher than
controls.10
• Patients with FM had 4 times as
many doctor’s office and emergency
department visits as controls.10
Health care claims filed between 1996
and 1998 demonstrated that:
• Disability prevalence was twice as
high among employees with FM.38
• Total annual health care disability and absenteeism costs were
$14,100 per em­­
ployee who filed
disability claims for FM.38
Claims database analyses do not
include the costs of OTC medications
and uncovered alternative treatments,
which could bring total costs even higher. Moreover, these results may underestimate current figures.
MANAGEMENT OF FM
Because FM cannot be cured, the
goal of treatment is to reduce pain
and improve function. Currently, only
3 agents are approved by the FDA
for the treatment of FM—milnacipran,
duloxetine, and pregabalin. Numerous
other pharmacologic agents and nonpharmacologic therapies have been
reported to improve symptoms of FM,
but the scientific evidence for many
of these treatments is moderate to
none.7 After reviewing all available
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studies and systematically ordering
the evidence based on study design
(eg, controls, blinding), consistency
of findings, and other factors, the
American Pain Society (APS) recommended a multimodal approach,
including patient education, cognitivebehavioral therapy (CBT), aerobic and
strengthening exercise, and certain
medications.39 The recommendations
emphasize combining pharmacologic and nonpharmacologic therapies;
indeed, the efficacy of each strategy is
improved by use of the other.39
Nonpharmacologic Therapies
Inactivity due to pain or the fear of pain
causes physical deconditioning (loss of
muscle strength, endurance, and flexibility), which makes activity even more
painful. Guidelines of the APS and
European League Against Rheumatism
(EULAR) both recommend aerobic
exercise and strength training.39,40
Aerobic exercise may reduce pain,
improve sleep, and reduce depressed
mood in patients with FM.
The guidelines also recommend
CBT,39,40 which includes training in
understanding behaviors in response
to FM symptoms, coping skills (eg,
relaxation, distraction, visualization),
and setting goals and priorities for
activities to achieve a balance of work
and other activities.24
Many patients with FM try alternative treatments. Acupuncture has been
associated with significant increases
in serum serotonin,24 but studies in
patients with FM show mixed results.18
In general, massage therapy, herbal
therapies, and dietary supplements
have not demonstrated consistent efficacy in FM.18
Pharmacotherapy
Although many prescription drug
products are commonly prescribed for
the treatment of FM, only 3 have FDA
approval for that use. Milnacipran,
duloxetine, and pregabalin are the
only pharmacologic agents that have
gained FDA approval as safe and effective therapies for the management of
FM (Table 1).28,41,42 Other agents used
for the management of FM, but not
approved by the FDA for this indication, are listed in Table 2.43-50
Evaluating Clinical Efficacy of
Drug Therapy in FM
OMERACT (Outcome Measures in
Rheumatology Arthritis Clinical
Trials) is an international network of
researchers and other experts in the
field of rheumatology that convenes
biannually to discuss outcome measurement in clinical trials.51 Participants
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
Patient Counseling Tips
Complementary and Alternative
Treatments
It can be helpful to ask patients about
any alternative treatments they may
be using and to inform them of those
that have some limited supporting
scientific evidence (acupuncture) and
those that do not (almost all others).18 Some prescription medications can interact with ingredients of
herbal therapies and supplements,
and these interactions should be
researched using the prescribing
information and other compendia.
6
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at the OMERACT 8 FM syndrome workshop, held in 2006, identified several
core domains for the evaluation of FM
treatments.16 More than 85% of workshop participants, which included both
clinician-investigators and patients,
rated pain, patient global improvement, and multidimensional function
among the most important criteria that
should be evaluated in FM clinical trials. Overall, it was agreed that “the
ability to measure clinically meaningful
change in multiple dimensions of FM
utilizing a composite responder index
is desirable.”
Clinical trials supporting the approvals of duloxetine and pregabalin for
the treatment of FM had single–endpoint outcome measures. Outcome
measures in the Savella clinical trial
program included 2 primary end points
that were composite measures. These
measures were consistent with those
recommended by OMERACT, and provided a more comprehensive measure
of simultaneous efficacy across multiple domains.
The efficacy of Savella for the management of FM was demonstrated in 2
double-blind, placebo-controlled studies in nearly 2100 patients.52,53 Efficacy
results from the 2 pivotal US registration trials are discussed in Section 2
on page 9.
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
SECTION 2. Information About Savella (milnacipran hydrochloride)
INDICATIONS AND USAGE
Savella is indicated for the management
of FM in adults.41
PRODUCT DESCRIPTION
Milnacipran HCl is a racemic mixture with the chemical name: (±)-[1R
(S),2S(R)]-2-(aminomethyl)-N,Ndiethyl-1-phenylcyclopropanecarboxamide hydrochloride.41 The structural
formula of milnacipran is illustrated in
Figure 5.
Milnacipran HCl is a white to off-white
crystalline powder with a melting point
of 179°C.41 It is freely soluble in water,
methanol, ethanol, chloroform, and
methylene chloride and sparingly soluble in diethyl ether. It has an empirical
formula of C15H23ClN2O and a molecular
weight of 282.8 g/mol.
Savella is available for oral administration as film-coated tablets containing
12.5, 25, 50, and 100 mg milnacipran.41
Each tablet also contains dibasic calcium
phosphate, povidone, carboxymethylcellulose calcium, colloidal silicon dioxide,
magnesium stearate, and talc as inactive
ingredients. Additionally, the following
inactive ingredients are also present as
components of the film coat: FD&C Blue
#2 Aluminum Lake, hypromellose, polyethylene glycol, titanium dioxide (12.5
mg); hypromellose, polyethylene glycol,
titanium dioxide (25 mg); hypromellose,
polyethylene glycol, titanium dioxide
(50 mg); and FD&C Red #40 Aluminum
Lake, hypromellose, polyethylene glycol,
and titanium dioxide (100 mg).
CLINICAL PHARMACOLOGY
The exact mechanism of the central pain
inhibitory action of milnacipran and its
ability to improve the symptoms of FM
in humans are unknown.41 Preclinical
studies have shown that milnacipran is a
potent inhibitor of neuronal norepinephrine and serotonin reuptake; milnaci­pran
inhibits norepinephrine uptake with an
approximately 3-fold higher potency
than serotonin without directly affecting
the uptake of dopamine or other neurotransmitters in vitro (clinical significance of in vitro data is unknown).
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Figure 5
Savella (milnacipran
HCl): Chemical
Structure41
Savella PI, 2010.
Milnacipran has no significant affinity for serotonergic (5-HT1-7), a- and
b-adrenergic, muscarinic (M1-5), histamine (H1-4), dopamine (D1-5), opiate,
benzodiazepine, and g-aminobutyric
acid receptors in vitro. Pharmacologic
activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other
psychotropic drugs. Milnacipran has
no significant affinity for Ca++, K+,
Na+, and Cl– channels and does not
inhibit the activity of human monoamine oxidases (MAO-A and MAO-B) or
acetylcholinesterase.
Pharmacodynamics
Cardiovascular Electrophysio­logy
The effect of Savella on the Fridericiacorrected QT interval (QTcF) was measured in a double-blind, placebo- and
positive-controlled parallel study in 88
healthy subjects using 600 mg/day of
Savella (3-6 times the recommended
therapeutic dose for FM).41 After baseline and placebo adjustment, the maximum mean QTcF change was 8 ms
(2-sided 90% confidence interval, 3-12
ms). This increase is not considered to
be clinically significant.
Pharmacokinetics
Milnacipran is well absorbed after oral
administration with an absolute bioavailability of approximately 85% to
90%.41 The exposure to milnacipran
increased proportionally within the
therapeutic dose range. It is excreted
primarily by renal excretion, as it is predominantly unchanged in urine (55%)
and has a terminal elimination half-life
of about 6 to 8 hours. Steady-state levels are reached within 36 to 48 hours
and can be predicted from single-dose
data. The active enantiomer, d-milnacipran, has a longer elimination halflife (8-10 hours) than the l-enantiomer
(4-6 hours). There is no interconversion
between the enantiomers.
Absorption and Distribution
Savella is absorbed following oral administration with maximum concentration of
drug (Cmax) reached within 2 to 4 hours
postdose.41 Absorption of Savella is not
affected by food. The absolute bioavailability is approximately 85% to 90%. The
mean volume of distribution of milnaci­
pran following a single intravenous dose
to healthy subjects is approximately 400
L. Plasma protein binding is 13%.
Metabolism and Elimination
Milnacipran and its metabolites are
eliminated primarily by renal excretion.41 Following oral administration of
14
C-milnacipran hydrochloride, approximately 55% of the dose was excreted in
urine as unchanged milnacipran (24%
as l-milnacipran and 31% as d-milnacipran). The l-milnacipran carbamoyl-Oglucuronide was the major metabolite
excreted in urine and accounted for
approximately 17% of the dose; approximately 2% of the dose was excreted
in urine as d-milnacipran carbamoylO-glucuronide. Approximately 8% of
the dose was excreted in urine as the
N-desethyl milnacipran metabolite.
Pharmacokinetics in Special
Populations
Renal Impairment
Milnacipran pharmacokinetics were
evaluated following single oral administration of 50 mg Savella to subjects
with mild (creatinine clearance [CLcr]
50-80 mL/min), moderate (CLcr 30-49
mL/min), and severe (CLcr 5-29 mL/
min) renal impairment and to healthy
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
subjects (CLcr >80 mL/min).41 The
mean area under the curve from zero
to time infinity (AUC0-∞) increased by
16%, 52%, and 199%, and terminal elimination half-life increased by 38%, 41%,
and 122% in subjects with mild, moderate, and severe renal impairment,
respectively, compared with healthy
subjects.
No dosage adjustment is necessary in
patients with mild renal impairment.41
Caution should be exercised in patients
with moderate renal impairment. For
patients with severe renal impairment
(indicated by an estimated CLcr of 5-29
mL/min), the maintenance dose should
be reduced by 50% to 50 mg/day (25 mg
twice daily). Based on individual patient
response, the dose may be increased to
100 mg/day (50 mg twice daily). Savella
is not recommended for patients with
end-stage renal disease.
Drug–Drug Interactions
In Vitro Studies
In general, milnacipran, at concentrations that were at least 25 times those
attained in clinical trials, did not inhibit human CYP1A2, CYP2A6, CYP2C9,
CYP2C19, CYP2D6, CYP2E1, and
CYP3A4 or induce human CYP1A2,
CYP2B6, CYP2C8, CYP2C9, CYP2C19,
and CYP3A4/5 enzyme systems, indicating a low potential of interactions with
drugs metabolized by these enzymes.41
In vitro studies have shown that the
biotransformation rate of milnacipran
by human hepatic microsomes and
hepatocytes was low.41 A low biotransformation was also observed following
incubation of milnacipran with cDNAexpressed human CYP1A2, CYP2A6,
CYP2B6, CYP2C9, CYP2C19, CYP2D6,
CYP2E1, and CYP3A4 isozymes.
In Vivo Studies
Hepatic Impairment
Milnacipran pharmacokinetics were evaluated following single oral administration
of 50 mg Savella to subjects with mild
(Child-Pugh A), moderate (Child-Pugh B),
and severe (Child-Pugh C) hepatic impairment and to healthy subjects.41 AUC0-∞
and half-life (T½) were similar in healthy
subjects and subjects with mild and moderate hepatic impairment. However, subjects with severe hepatic impairment had
a 31% higher AUC0-∞ and a 55% higher T½
than healthy subjects. Caution should be
exercised in patients with severe hepatic
impairment.
Elderly
Cmax and AUC parameters of milnaci­
pran were approximately 30% higher in
elderly (>65 years) subjects compared
with young subjects because of agerelated decreases in renal function.41 No
dosage adjustment is necessary based
on age unless renal function is severely
impaired.
The drug interaction studies described in
this section were conducted in healthy
adult subjects.41
Carbamazepine: There were no clinically significant changes in the pharmacokinetics of milnacipran following
coadministration of Savella (100 mg/
day) and carbamazepine (200 mg twice
a day).41 No changes were observed in
the pharmacokinetics of carbamazepine
or its epoxide metabolite because of
coadministration with Savella.
Clomipramine: Switching from clomipramine (75 mg once a day) to
milnacipran (100 mg/day) without a
washout period did not lead to clinically significant changes in the pharmacokinetics of milnacipran.41 Because an
increase in adverse events (AEs) (eg,
euphoria and postural hypotension)
was observed after switching from clomipramine to milnacipran, monitoring
of patients during treatment switch is
recommended.
Gender
Cmax and AUC parameters of milnacipran were about 20% higher in female
subjects compared with male subjects.41
Dosage adjustment based on gender is
not necessary.
8
n
Digoxin: There was no pharmacokinetic
interaction between Savella (200 mg/day)
and digoxin (0.2 mg/day Lanoxicaps) following multiple-dose administration to
healthy subjects.41
Fluoxetine: Switching from fluoxetine
(20 mg once a day), a strong inhibitor
of CYP2D6 and a moderate inhibitor of
CYP2C19, to Savella (100 mg/day) without a washout period did not affect the
pharmacokinetics of Savella.41
Lithium: Multiple doses of Savella (100
mg/day) did not affect the pharmacokinetics of lithium.41
Lorazepam: There was no pharmacokinetic interaction between a single
dose of Savella (50 mg) and lorazepam
(1.5 mg).41
Warfarin: Steady-state milnacipran
(200 mg/day) did not affect the pharmacokinetics of R-warfarin and S-warfarin
or the pharmacodynamics (as assessed
by measurement of prothrombin international normalized ratio) of a single
dose of 25 mg warfarin.41 The pharmacokinetics of milnacipran were not
altered by warfarin.
Clinically Important Interactions
with Other Drugs
Clinically important interactions may
occur with monoamine oxidase inhibitors (MAOIs), serotonergic drugs (including other selective serotonin reuptake
inhibitors [SSRIs], SNRIs, lithium, tryptophan, antipsychotics, and dopamine
antagonists), triptans, catecholamines
(epinephrine and norepinephrine), CNSactive drugs (including clomipramine),
and select cardiovascular agents (digoxin and clonidine).
Lithium: Serotonin syndrome may
occur when lithium is coadministered
with Savella and with other drugs that
impair metabolism of serotonin.41
Epinephrine and Norepinephrine:
Savella inhibits the reuptake of norepinephrine. Therefore, concomitant use of
Savella with epinephrine and norepinephrine may be associated with paroxysmal
hypertension and possible arrhythmia.41
Serotonergic Drugs: Coadministration
of Savella with other inhibitors of serotonin reuptake may result in hyper-
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
tension and coronary artery vasoconstriction, through additive serotonergic
effects.41
Figure 6
Design of Pivotal Trials: Mease et al and Clauw et al
Digoxin: Use of Savella concomitantly with digoxin may be associated
with potentiation of adverse hemodynamic effects.41 Postural hypotension
and tachycardia have been reported
in combination therapy with intravenously administered digoxin (1 mg).
Coadministration of Savella and intravenous digoxin should be avoided.
Clonidine: Because Savella inhibits norepinephrine reuptake, coadministration
with clonidine may inhibit clonidine’s
antihypertensive effect.41
Clomipramine: In a drug–drug interaction study, an increase in euphoria
and postural hypotension was observed
in patients who switched from clomipramine to Savella.41
CNS-Active Drugs: Given the primary
CNS effects of Savella, caution should
be used when it is taken in combination
with other centrally acting drugs, including those with a similar mechanism of
action.41
MAOIs: Concomitant use of Savella in
patients taking MAOIs is contraindi­
cated.41
CLINICAL EXPERIENCE WITH
SAVELLA
The efficacy of Savella for the management of FM was established in 2
randomized, double-blind, placebo-controlled, multicenter pivotal trials completed in the United States by Mease and
colleagues53 (Study 1) and Clauw and
colleagues52 (Study 2).
US Pivotal Trials
Study 1 (N = 888), published by Mease et
al in the Journal of Rheumatology, and
Study 2 (N = 1196), published by Clauw
et al in Clinical Therapeutics, were replicate clinical trials designed to evaluate
the efficacy and safety of Savella in the
management of FM (Figure 6).52,53 The
duration of treatment was 6 months in
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Landmark end point for both studies.
a
Study 1 and 3 months in Study 2; landmark data analyses were conducted at 3
months in both trials.
Study participants were 18 to 70 years
of age and met the 1990 ACR criteria for
FM (a history of widespread pain for 3
months and pain present at 11 or more
of 18 specific tender point sites).52,53
More than 94% were women. Individuals
with severe psychiatric illness, a current
major depressive episode, significant
risk of suicide, or evidence of alcohol and/or drug abuse were excluded.
Approximately 35% of study participants had a history of MDD, although
none were experiencing a current major
depressive episode at the time of enrollment. Both pivotal trials consisted of
4 phases: a 2-week washout period; a
2-week baseline period; a 3-week, doseescalation period to Savella 50 mg twice
daily, Savella 100 mg twice daily, or placebo twice daily; and a 12-week period
of stable-dose treatment at Savella 100
mg/day, Savella 200 mg/day, or placebo
to the landmark end point at 15 weeks.
otal trials were unique because they
employed a composite measure of pain,
global improvement, and physical function improvement as a primary efficacy
end point, making Savella the only currently approved drug for the management of FM to be studied using this
approach.28,42,52,53 To qualify as a responder, each patient in the Savella pivotal
trials had to demonstrate simultaneous
and clinically meaningful improvements
in the following domains (Figure 7):
Primary Efficacy Assessments
• Pain. Evidence shows that a reduction
of 30% on a pain intensity numeric rating scale constitutes a clinically meaningful improvement in FM and other
rheumatologic conditions.55 This criterion was applied in the Savella clinical
trials; therefore, response was defined
as a ≥30% decrease in pain from baseline via the 0- to 100-point VAS, with
“no pain” (0) and “worst pain” (100) as
anchors.41,52,53 Assessment was based on
a weekly average of the 24-hour morning recall pain (the average level of pain
in the previous 24 hours), rated on the
VAS in a patient electronic diary.
Primary efficacy in the pivotal trials
was assessed using composite responder an­­alysis, which required concurrent,
clinically meaningful improvements
across multiple symptom domains on
a patient-by-patient basis.52,53 The piv-
• Global Improvement. The PGIC is a
validated, single-item, patient-reported
outcome measure that evaluates overall change in FM on a 7-point scale;
patients rate overall change on a scale
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
Figure 7
Primary End Points in the Savella Clinical Trial
Program41,52,53
A. 2-Measure Composite Responder Rate
Each 2-Measure Responder Achieved Simultaneous
Improvements Across 2 Separate Measures41,53
points, a 2-measure composite responder analysis, and a 3-measure composite
responder analysis.52,53 Responders for
the “2-measure composite” end point
were required to show simultaneous
improvement in pain relief and global
improvement versus placebo, whereas
responders for the “3-measure composite” end point were required to demonstrate concurrent improvement across
all 3 assessments of pain relief, global
improvement, and physical function
versus placebo.
Results
PGIC (Patient Global Impression of Change): Asks patients to rate their overall change in fibromyalgia status using a
7-point scale ranging from 1 (very much improved) to 7 (very much worse). A rating of 1 or 2 is considered clinically
meaningful.52,53,55
In Study 1, randomization of subjects
at a 1:1:2 ratio yielded the following
patient allocation: placebo (n = 223),
Savella 100 mg (n = 224), and Savella
200 mg (n = 441).53 At baseline, mean
VAS pain scores were 68.3 for placebo,
68.3 for Savella 100 mg/day, and 69.4 for
Savella 200 mg/day. A total of 57.7% of
subjects receiving Savella completed
the 27-week study. However, the landmark end point was established at 15
weeks, and 3-month data were assessed
accordingly.
In Study 2, randomization of subjects
at a 1:1:1 ratio yielded the following
patient allocation: placebo (n = 401),
Savella 100 mg (n = 429), and Savella 200
mg (n = 426).52,59 At baseline, mean VAS
pain scores were 65.7 for subjects randomized to placebo, 64.6 for those randomized to Savella 100 mg/day, and 64.5
for those randomized to Savella 200 mg/
day.52 Of patients randomized to Savella,
66.2% completed the 15-week trial.
SF-36 PCS (Short Form-36 Physical Component Summary): Used to assess changes in physical function in Savella
clinical studies. A 6-point improvement in SF-36 PCS is considered clinically meaningful.41,52,53,56
Composite Responder Analysis
B. 3-Measure Composite Responder Rate
Each 3-Measure Responder Achieved Simultaneous
Improvements Across 3 Separate Measures41,52
VAS (visual analog scale): 0 to 100 scale with a range of 0 (no pain) to 100 (worst possible pain); a 30% VAS pain
reduction is considered clinically meaningful.41,54
ranging from 7 (“very much worse”)
to 1 (“very much improved”).54,55 A rating of 1 (“very much improved”) or 2
(“much improved”) on the PGIC is considered indicative of clinically meaningful global improvement.55 In the Savella
trials, a score of 1 or 2 was required on
the PGIC-defined response.41
• Physical Function. The SF-36 is a
widely used patient-reported outcome measure assessing mental and
physical health.56,57 The PCS of the
SF-36 comprises physical functioning,
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n
role limitations caused by physical
problems, bodily pain, and general
health perceptions.57 In the Savella
clinical trials, a ≥6-point improvement
on the SF-36 PCS was used as the
criterion for a clinically meaningful
response52,53—higher than the 2.5- to
5-point improvement that has been
shown to represent a minimally clinically important difference in rheumatologic disorders.53,56,58
Primary assessments in the pivotal
trials consisted of 2 co-primary end
Findings in the pivotal trials were based
on the FDA-recommended Uniform
Program Analysis, which included a
baseline-observation-carried-forward
(BOCF) method of data imputation,
a more stringent definition of PGIC
response, and the SF-36 PCS for physical function.59 Last-observation-carriedforward (LOCF) and observed cases
(OC) analyses were also used in the
pivotal trials; the latter approach evaluates all patients for whom there are no
missing observations.52,53 All pivotal trial
analyses were derived from intent-to-
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
treat populations.
In Studies 1 and 2, a significantly
greater proportion of patients randomized to Savella 100 mg/day met the criteria for improvement on the 2-measure
composite end point (pain and PGIC)
relative to placebo at the 3-month landmark visit.52,53 In the OC analysis, 45%
of those in Study 1 and 42% of those in
Study 2 who were randomized to Savella
100 mg/day met the criteria for improvement on the 2-measure composite end
point at the 3-month landmark visit,
compared to 27% and 25%, respectively,
for placebo (P <.05). In the more stringent BOCF analysis, 23% in Study 2 who
were randomized to Savella 100 mg/day
met the criteria for improvement on this
composite, compared to 16% for placebo (P <.05).52 In Study 1, improvement
was seen in 27% of patients randomized
to Savella 100 mg/day compared with
19% for placebo in the BOCF analysis
(Figure 8).53
A significantly greater proportion of
patients randomized to Savella 200 mg/
day in both studies also met the criteria
for improvement on the 2-measure composite end point relative to placebo (P
<.05) (Figure 8).52,53 Significant improvement was seen with the dose of 200 mg/
day in both the BOCF and OC analyses.
In both studies, Savella 100 mg/day
and 200 mg/day significantly increased
the 3-measure composite responder
end point rate at the 3-month landmark
visit.52,53 Significantly more patients
demonstrated concurrent improvement
in all 3 domains (pain, PGIC, and physical function) compared with placebo (P
<.05) (Figure 9).
Clinical Trials: Adverse Reactions
In clinical trials, the most common AE
was nausea (37% vs 20% for placebo).41
Nausea was generally mild to moderate in nature. The most commonly
occurring adverse reactions (≥5% and
greater than placebo) were headache
(18% vs 14%), constipation (16% vs 4%),
dizziness (10% vs 6%), insomnia (12%
vs 10%), hot flush (12% vs 2%), hyperhidrosis (9% vs 2%), vomiting (7% vs
2%), palpitations (7% vs 2%), heart rate
increased (6% vs 1%), dry mouth (5%
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Figure 8
Responder Rates (%) in Pivotal Trials for 2-Measure
Composite End Point Using BOCF and OC Analyses52,53
BOCF = baseline observation carried forward; OC = observed cases.
Study 1: Randomized, multicenter, double-blind, placebo-controlled, 6-month study (N = 888) comparing efficacy
and safety of Savella 100 mg (n = 224) and 200 mg (n = 441) vs placebo (n = 223) in the treatment of patients with
fibromyalgia.
Study 2: Randomized, multicenter, double-blind, placebo-controlled, 3-month study (N = 1196) comparing efficacy
and safety of Savella 100 mg (n = 399) and 200 mg (n = 396) vs placebo (n = 401) in the treatment of patients with
fibromyalgia.
P <.05 vs placebo. bP ≤.01. cP ≤.001 vs placebo.
a
Table 3
Treatment-Emergent Adverse Events Reported in ≥5% and
Occurring at Twice the Rate of Placebo41
Nauseaa
Savella
100 mg/d
(n = 623)
%
Savella
200 mg/d
(n = 934)
%
Placebo
(n = 652)
%
35
39
20
Constipation
16
15
4
Hot flush
11
12
2
Hyperhidrosis
8
9
2
Palpitations
8
7
2
Hypertension
7
4
2
Vomiting
6
7
2
Dry mouth
5
5
2
Heart rate increased
5
6
1
In placebo-controlled fibromyalgia trials, the most frequently occurring adverse event was nausea.
a
vs 2%), and hypertension (5% vs 2%).
Table 3 lists treatment-emergent AEs
that occurred in at least 5% of patients
treated with Savella at either 100 or
200 mg/day and at an incidence twice
the rate of placebo. Table 4 lists AEs
resulting in premature discontinuation
in at least 1% of patients treated with
Savella and at an incidence greater
than that of placebo.
At the 3-month landmark visit in
Study 1, Savella treatment was associPharmacy Times | 10.10
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
Figure 9
Responder Rates (%) in Pivotal Trials for 3-Measure
Composite End Point Using BOCF and OC Analyses52,53
BOCF = baseline observation carried forward; OC = observed cases.
Study 1: Randomized, multicenter, double-blind, placebo-controlled, 6-month study (N = 888) comparing efficacy
and safety of Savella 100 mg (n = 224) and 200 mg (n = 441) vs placebo (n = 223) in the treatment of patients with
fibromyalgia.
Study 2: Randomized, multicenter, double-blind, placebo-controlled, 3-month study (N = 1196) comparing efficacy
and safety of Savella 100 mg (n = 399) and 200 mg (n = 396) vs placebo (n = 401) in the treatment of patients with
fibromyalgia.
P <.05 vs placebo. bP ≤.01. cP ≤.001 vs placebo.
a
Table 4
Adverse Events Leading to Discontinuation in ≥1% of
Patients in the Savella Treatment Group and With an
Incidence Greater than Placebo41
Nausea
Savella
(n = 1557)
%
Placebo
(n = 623)
%
6
1
Palpitations
3
1
Headache
2
0
Constipation
1
0
Heart rate increased
1
0
Hyperhidrosis
1
0
Vomiting
1
0
Dizziness
1
0.5
ated with decreases in weight in relation
to placebo.53 The mean change (leastsquares mean) from baseline to the
3-month visit (LOCF) was an increase
of 0.94 lb in the placebo group, compared with a decrease of 1.79 lb in the
Savella 100-mg/day group (P <.001 vs
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n
placebo) and a decrease of 1.47 lb in the
Savella 200-mg/day group (P <.001 vs
placebo). Findings on weight variations
at 3 months were similar in Study 2.52
In the placebo-controlled FM studies, the following treatment-emergent
adverse reactions related to the geni-
tourinary system were observed in at
least 2% of male patients treated with
Savella, and occurred at a rate greater
than in placebo-treated male patients:
dysuria, ejaculation disorder, erectile
dysfunction, ejaculation failure, libido
decreased, prostatitis, scrotal pain, testicular pain, testicular swelling, urinary
hesitation, urinary retention, urethral
pain, and urine flow decreased.41
Treatment with either dose of Savella
resulted in mean increases in end-ofstudy supine blood pressure and pulse
rate relative to placebo in Study 1 (endof-study values are LOCF) (Table 5).59
At study end, the mean increases from
baseline in supine systolic blood pressure were 3.3 mm Hg in either Savella
treatment group, compared with an
increase of 0.1 mm Hg in the placebo
group. The mean increases in end-ofstudy diastolic blood pressure were
3.5 mm Hg and 2.5 mm Hg in patients
receiving Savella 100 mg/day and 200
mg/day, respectively, compared with
an increase of 0.4 mm Hg for placebo
recipients. In addition, the mean supine
pulse rate increased by 6.1 beats per
minute and 7.6 beats per minute following treatment with Savella 100 mg/day
and Savella 200 mg/day, respectively,
relative to an increase of 0.5 beats per
minute with placebo.
Findings on end-of-study vital sign
variations were similar in Study 2.59
At the 3-month visit, treatment with
Savella 100 mg/day and 200 mg/day
resulted in mean increases in supine
systolic blood pressure of 3.7 mm Hg
and 1.8 mm Hg, respectively, compared
to a decrease of 0.2 mm Hg with placebo. Mean increases in supine diastolic
blood pressure were 3.3 mm Hg and
2.7 mm Hg with Savella 100 mg/day and
Savella 200 mg/day, respectively, compared to a decrease of 0.1 mm Hg with
placebo. For pulse rate, mean changes
from baseline were an increase of 7.7
beats per minute and 7.0 beats per
minute with Savella 100 mg/day and
Savella 200 mg/day, respectively, compared to a decrease of 0.4 beats per
minute with placebo.
SNRIs, including Savella, have been
associated with cardiovascular effects,
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
Table 5
Changes in Vital Signs59
Study 1
Study 2 ...
Placebo
(n = 218)
Savella
100 mg/d
(n = 221)
Savella
200 mg/d
(n = 432)
Placebo
(n = 397)
Savella
100 mg/d
(n = 393)
Savella
200 mg/d
(n = 388)
Mean ± SD
Mean ± SD
Mean ± SD
Mean ± SD
Mean ± SD
Mean ± SD
122.3 ± 13.9
123.9 ± 16.0
122.5 ± 14.1
122.1 ± 14.7
122.2 ± 13.5
121.8 ± 13.9
0.1 ± 13.9
3.3 ± 15.0
3.3 ± 13.3
–0.2 ± 12.9
3.7 ± 13.1
1.8 ± 12.5
Supine SBP, mm Hg
Baseline
Change
Supine DBP, mm Hg
Baseline
76.3 ± 8.9
Change
0.4 ± 9.5
77.8 ± 9.0
3.5 ± 10.2
77.1 ± 8.3
75.8 ± 9.0
76.9 ± 8.8
76.3 ± 8.7
2.5 ± 9.1
–0.1 ± 8.7
3.3 ± 9.0
2.7 ± 9.2
72.0 ± 9.2
72.5 ± 9.9
72.6 ± 8.9
72.1 ± 8.8
Supine pulse rate,
beats/min
Baseline
72.1 ± 8.9
Change
0.5 ± 9.8
72.9 ± 9.3
6.1 ± 11.9
7.6 ± 11.6
–0.4 ± 10.2
7.7 ± 12.3
7.0 ± 11.3
DBP = diastolic blood pressure; SBP = systolic blood pressure.
Data on file. Forest Laboratories, Inc.
including cases of elevated blood pressure, requiring immediate treatment.41
In clinical trials, sustained increases in
systolic and diastolic blood pressure
occurred more frequently in Savellatreated patients compared to placebo.
Among patients who were nonhypertensive at baseline, approximately twice as
many patients receiving Savella, versus
placebo, became hypertensive at the
end of the study. Clinically significant
increases in pulse (≥20 bpm) occurred
more frequently in Savella-treated than
placebo-treated patients. Blood pressure and heart rate should be monitored prior to initiating treatment with
Savella and periodically throughout
treatment. Preexisting hypertension,
tachyarrhythmias, and other cardiac
diseases should be treated before starting therapy with Savella. Savella should
be used with caution in patients with
significant hypertension or cardiac disease. Concomitant use of Savella with
drugs that increase blood pressure and
pulse has not been evaluated, and such
combinations should be used with caution. For patients who experience a
sustained increase in blood pressure
or heart rate while receiving Savella,
either dose reduction or discontinuation
should be considered.
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Important Safety Information: Savella (milnacipran hydrochloride)
Tablets
Savella is a selective serotonin and norepinephrine reuptake inhibitor
(SNRI), similar to some drugs used for the treatment of depression and
other psychiatric disorders. Antidepressants increased the risk compared
to placebo of suicidal thinking and behavior (suicidality) in children,
adolescents, and young adults in short-term studies of major depressive
disorder (MDD) and other psychiatric disorders. Anyone considering the
use of such drugs in a child, adolescent, or young adult must balance this
risk with the clinical need. Short-term studies did not show an increase
in the risk of suicidality with antidepressants compared to placebo in
adults beyond age 24; there was a reduction in risk with antidepressants
compared to placebo in adults aged 65 and older. Depression and certain
other psychiatric disorders are themselves associated with increases in
the risk of suicide. Patients of all ages who are started on Savella should
be monitored appropriately and observed closely for clinical worsening,
suicidality, or unusual changes in behavior especially during the initial
few months of drug therapy or at times of dose changes, either increases
or decreases. Families and caregivers should be advised of the need for
close observation and communication with the prescriber. Savella is not
approved for use in the treatment of major depressive disorder. Savella
is not approved for use in pediatric patients.
Contraindications
MAOIs
Concomitant use of Savella in patients
taking MAOIs is contraindicated.41 In
patients receiving a selective serotonin reuptake inhibitor in combination with an MAOI, there have been
reports of serious, sometimes fatal,
reactions, including hyperthermia, rigid-
ity, myoclonus, autonomic instability
with possible rapid fluctuations of vital
signs, and mental status changes that
include extreme agitation progressing
to delirium and coma. These reactions
have also been reported in patients who
have recently discontinued SSRIs and
have been started on an MAOI. Some
cases presented with features resemPharmacy Times | 10.10
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
bling neuroleptic malignant syndrome.
The effects of combined use of Savella
and MAOIs have not been evaluated in
humans. Therefore, it is recommended
that Savella should not be used in combination with an MAOI, or within 14
days of discontinuing treatment with an
MAOI. Similarly, at least 5 days should
be allowed after stopping Savella before
starting an MAOI.
Uncontrolled Narrow-Angle
Glaucoma
In clinical trials, Savella was associated
with an increased risk of mydriasis.41
Mydriasis has been reported with other
dual reuptake inhibitors of norepinephrine and serotonin; therefore, Savella
should not be used in patients with
uncontrolled narrow-angle glaucoma.
Warnings and Precautions
Suicide Risk
Savella is a selective SNRI, similar to
some drugs used for the treatment of
depression and other psychiatric disorders.41
Patients, both adult and pediatric,
with depression or other psychiatric
disorders may experience worsening of
their depression and/or the emergence
of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking these
medications, and this risk may persist
until significant remission occurs.41
Suicide is a known risk of depression
and certain other psychiatric disorders,
and these disorders themselves are the
strongest predictors of suicide. There
has been a long-standing concern, however, that antidepressants, including
drugs that inhibit the reuptake of norepinephrine and/or serotonin, may have
a role in inducing worsening of depression and the emergence of suicidality in
certain patients during the early phases
of treatment.
In the placebo-controlled clinical trials
of adults with FM, among the patients
who had a history of depression at treatment initiation, the incidence of suicidal
ideation was 0.5% in patients treated
with placebo, 0% in patients treated with
Savella 100 mg/day, and 1.3% in patients
14
n
treated with Savella 200 mg/day.41 No
suicides occurred in the short-term or
longer-term (up to 1 year) FM trials.
Pooled analyses of short-term placebo-controlled trials of drugs used to
treat depression (SSRIs and others)
showed that these drugs increase the
risk of suicidal thinking and behavior
(suicidality) in children, adolescents,
and young adults (ages 18-24) with MDD
and other psychiatric disorders.41 Shortterm studies did not show an increase
in the risk of suicidality with these
drugs compared with placebo in adults
beyond age 24; there was a reduction
in suicidality risk with antidepressants
compared to placebo in adults aged 65
and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive
disorder, or other psychiatric disorders
included a total of 24 short-term trials
of 9 drugs used to treat depression in
more than 4400 patients.41 The pooled
analyses of placebo-controlled trials
in adults with MDD or other psychiatric disorders included a total of 295
short-term trials (median duration of
2 months) of 11 antidepressant drugs
in more than 77,000 patients. There
was considerable variation in risk of
suicidality among drugs, but a tendency toward an increase in the younger
patients for almost all drugs studied.
There were differences in absolute
risk of suicidality across the different
indications, with the highest incidence
in MDD. The risk differences (drug
vs placebo), however, were relatively
stable within age strata and across
indications. For patients younger than
18 years, there were 14 additional cases
of suicidality per 1000 patients treated
with drug versus placebo. For patients
aged 18 to 24 years, there were 5 additional cases of suicidality per 1000
patients treated with drug versus placebo. For patients aged 25 to 64 years,
there was 1 fewer case of suicidality
per 1000 patients treated with drug versus placebo. For patients aged 65 years
and older, there were 6 fewer cases of
suicidality per 1000 patients treated
with drug versus placebo.
No suicides occurred in any of the
pediatric trials.41 There were suicides in
the adult trials, but the number was not
sufficient to reach any conclusion about
drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use (ie,
beyond several months).41 However,
there is substantial evidence from placebo-controlled maintenance trials in
adults with depression that the use of
antidepressants can delay the recurrence of depression.
All patients being treated with
drugs inhibiting the reuptake of
norepinephrine and/or serotonin for
any indication should be monitored
appropriately and observed closely
for clinical worsening, suicidality,
and unusual changes in behavior,
especially during the initial few
months of a course of drug therapy,
or at times of dose changes, either
increases or decreases.41
The following symptoms—anxiety,
agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, and mania—have been
reported in adult and pediatric patients
being treated with drugs inhibiting the
reuptake of norepinephrine and/or serotonin for MDD as well as for other indications, both psychiatric and nonpsychiatric.41 Although a causal link between the
emergence of such symptoms and either
the worsening of depression and/or the
emergence of suicidal impulses has not
been established, there is concern that
such symptoms may represent precursors to emerging suicidality.
Consideration should be given to
changing the therapeutic regimen,
including possibly discontinuing the
medication, in patients who may experience worsening depressive symptoms,
or who are experiencing emergent
suicidality or symptoms that might be
precursors to worsening depression
or suicidality, especially if these symptoms are severe or abrupt in onset, or
were not part of the patient’s presenting
symptoms.41
If the decision has been made to discontinue treatment because of wors-
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
ening depressive symptoms or emergent suicidality, medication should
be tapered, as rapidly as is feasible,
but with recognition that abrupt discontinuation can produce withdrawal
symptoms.41
Families and caregivers of pa­­­
tients being treated with drugs
inhibiting the reuptake of norepinephrine and/or serotonin for MDD
or other indications, both psychiatric and nonpsychiatric, should be
alerted about the need to monitor
patients for the emergence of agitation, irritability, unusual changes
in behavior, and the other symptoms described above, as well as
the emergence of suicidality, and to
report such symptoms immediately to health care providers.41 Such
monitoring should include daily
observation by families and caregivers. Prescriptions for Savella should
be written for the smallest quantity of tablets consistent with good
patient management, in order to
reduce the risk of overdose.
Serotonin Syndrome or
Neuroleptic Malignant
Syndrome (NMS)-Like Reactions
The development of a potentially lifethreatening serotonin syndrome or
NMS-like reactions have been reported
with SNRIs and SSRIs alone, including
Savella, but particularly with concomitant use of serotonergic drugs (including
triptans), with drugs that impair metabolism of serotonin (including MAOIs), or
with antipsychotics or other dopamine
antagonists.41 Serotonin syndrome symptoms may include mental status changes
(eg, agitation, hallucinations, coma),
autonomic instability (eg, tachycardia,
labile blood pressure, hyperthermia),
neuromuscular aberrations (eg, hyperreflexia, incoordination) and/or gastrointestinal symptoms (eg, nausea, vomiting,
diarrhea). Serotonin syndrome, in its
most severe form, can resemble NMS,
which includes hyperthermia, muscle
rigidity, autonomic instability with possible rapid fluctuation of vital signs, and
mental status changes. Patients should
be monitored for the emergence of serowww.PharmacyTimes.com
tonin syndrome or NMS-like signs and
symptoms.
The concomitant use of Savella with
MAOIs is contraindicated.41 If concomitant treatment of Savella with a
serotonin receptor agonist (triptan)
is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation
and dose increases. The concomitant
use of Savella with serotonin precursors (such as tryptophan) is not recommended. Treatment with Savella
and any concomitant serotonergic or
antidopaminergic agents, including
antipsychotics, should be discontinued immediately if the above events
occur, and supportive symptomatic
treatment should be initiated.
Effects on Blood Pressure
Inhibition of the reuptake of norepinephrine and serotonin can lead to
cardiovascular effects. SNRIs, including Savella, have been associated with
reports of increase in blood pressure.41
In a double-blind, placebo-controlled
clinical pharmacology study in healthy
subjects designed to evaluate the effects
of Savella on various parameters, including blood pressure at supratherapeutic doses, there was evidence of mean
increases in supine blood pressure at
doses up to 300 mg twice daily (600 mg/
day).41 At the highest 300-mg twice-daily
dose, the mean increase in systolic blood
pressure was up to 8.1 mm Hg for the
placebo group and 10.0 mm Hg for the
Savella-treated group over the 12-hour,
steady-state dosing interval. The corresponding mean increase in diastolic
blood pressure over this interval was up
to 4.6 mm Hg for placebo and up to 11.5
mm Hg for the Savella-treated group.
In the 3-month, placebo-controlled
FM clinical trials, Savella treatment was
associated with mean increases of up
to 3.1 mm Hg in systolic blood pressure
and diastolic blood pressure.41
In the placebo-controlled trials,
among patients with FM who were nonhypertensive at baseline, approximately
twice as many patients in the Savella
treatment arms became hypertensive
at the end of the study (systolic blood
pressure ≥140 mm Hg or diastolic blood
pressure ≥90 mm Hg) compared with
the placebo patients: 7.2% of patients
in the placebo arm versus 19.5% of
patients treated with Savella 100 mg/
day and 16.6% of patients treated with
Savella 200 mg/day.41 Among patients
who met systolic criteria for prehypertension at baseline (systolic blood pressure 120-142 mm Hg), more patients
became hypertensive at the end of the
study in the Savella treatment arms
than placebo: 9% of patients in the placebo arm versus 14% in both the Savella
100-mg/day and the Savella 200-mg/day
treatment arms.
Among patients with FM who were
hypertensive at baseline, more patients
in the Savella treatment arms had a
greater than 15-mm Hg increase in systolic blood pressure than placebo at the
end of the study: 1% of patients in the
placebo arm versus 7% in the Savella
100-mg/day and 2% in the Savella 200mg/day treatment arms.41 Similarly,
more patients who were hypertensive at
baseline and were treated with Savella
had diastolic blood pressure increases
of more than 10 mm Hg than placebo at
the end of study: 3% of patients in the
placebo arm versus 8% in the Savella
100-mg/day and 6% in the Savella 200mg/day treatment arms.
Sustained increases in systolic blood
pressure (increase of ≥15 mm Hg on
3 consecutive postbaseline visits) occurred in 2% of placebo patients versus 9% of patients receiving Savella
100 mg/day and 6% of patients receiving Savella 200 mg/day.41 Sustained
increases in diastolic blood pressure
(increase of ≥10 mm Hg on 3 consecutive postbaseline visits) occurred in 4%
of patients receiving placebo versus
13% of patients receiving Savella 100
mg/day and 10% of patients receiving
Savella 200 mg/day.
Sustained increases in blood pressure could have adverse consequences.41 Cases of elevated blood pressure
requiring immediate treatment have
been reported.
Concomitant use of Savella with
drugs that increase blood pressure and
pulse has not been evaluated, and such
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
combinations should be used with caution.41
Effects of Savella on blood pressure in patients with significant hypertension or cardiac disease have not
been systematically evaluated. Savella
should be used with caution in these
patients.41
Blood pressure should be measured
prior to initiating treatment and periodically measured throughout Savella
treatment.41 Preexisting hypertension
and other cardiovascular disease should
be treated before starting therapy with
Savella. For patients who experience
a sustained increase in blood pressure
while receiving Savella, either dose
reduction or discontinuation should be
considered.
Effects on Heart Rate
SNRIs have been associated with reports
of increase in heart rate. In clinical trials,
relative to placebo, Savella treatment
was associated with mean increases in
pulse rate of approximately 7 to 8 beats
per minute.41
Increases in pulse of 20 or more beats
per minute occurred more frequently in
Savella-treated patients when compared
with placebo: 0.3% in the placebo arm
versus 8% in the Savella 100-mg/day and
8% in the 200-mg/day treatment arms.41
The effect of Savella on heart rate did
not appear to increase with increasing
dose.
Savella has not been systematically
evaluated in patients with a cardiac
rhythm disorder.41
Heart rate should be measured prior
to initiating treatment and periodically measured throughout Savella treatment.41 Preexisting tachyarrhythmias
and other cardiac diseases should be
treated before starting therapy with
Savella. For patients who experience
a sustained increase in heart rate
while receiving Savella, either dose
reduction or discontinuation should
be considered.
Seizures
Savella has not been systematically evaluated in patients with a seizure disorder.41 In clinical trials evaluating Savella
16
n
in patients with FM, seizures/convulsions have not been reported. However,
seizures have been reported infrequently in patients treated with Savella for
disorders other than FM. Savella should
be prescribed with care in patients with
a history of a seizure disorder.
Hepatotoxicity
In the placebo-controlled FM trials,
increases in the number of patients
treated with Savella with mild elevations of alanine aminotransferase
(ALT) or aspartate aminotransferase
(AST) (1-3 times the upper limit of normal [ULN]) were observed.41 Increases
in ALT were more frequently observed
in the patients treated with Savella
100 mg/day (6%) and Savella 200 mg/
day (7%), compared with the patients
treated with placebo (3%). One patient
receiving Savella 100 mg/day (0.2%) had
an increase in ALT greater than 5 times
ULN but did not exceed 10 times ULN.
Increases in AST were more frequently
observed in the patients treated with
Savella 100 mg/day (3%) and Savella 200
mg/day (5%), compared with patients
treated with placebo (2%).
The increases of bilirubin observed in
the FM clinical trials were not clinically
significant.41 No case met the criteria of
elevated ALT greater than 3 times ULN
and associated with an increase in bilirubin at least 2 times ULN.
There have been cases of increased
liver enzymes and reports of severe
liver injury, including fulminant hepatitis, with Savella from foreign postmarketing experience.41 In the cases
of severe liver injury, there were significant underlying clinical conditions
and/or the use of multiple concomitant
medications. Because of underreporting, it is impossible to provide an accurate estimate of the true incidence of
these reactions.
Savella should be discontinued in
patients who develop jaundice or
other evidence of liver dysfunction.41
Treatment with Savella should not be
resumed unless another cause can be
established.
Savella should ordinarily not be prescribed to patients with substantial alco-
hol use or evidence of chronic liver
disease.41
Discontinuation of Treatment
with Savella
Withdrawal symptoms have been
observed in clinical trials following discontinuation of Savella, as with other
SNRIs and SSRIs.41
During marketing of Savella, and
other SNRIs and SSRIs, there have been
spontaneous reports of AEs indicative
of withdrawal and physical dependence occurring upon discontinuation of these drugs, particularly when
discontinuation is abrupt.41 The AEs
include the following: dysphoric mood,
irritability, agitation, dizziness, sensory
distur­bances (eg, paresthesias such as
electric shock sensations), anxiety, confusion, headache, lethargy, emotional
lability, insomnia, hypomania, tinnitus,
and seizures. Although these events are
generally self-limiting, some have been
reported to be severe.
Patients should be monitored for
these symptoms when discontinuing
treatment with Savella.41 Savella should
be tapered and not abruptly discontinued after extended use. If intolerable
symptoms occur following a decrease
in the dose or upon discontinuation of
treatment, then resuming the previously
prescribed dose may be considered.
Subsequently, the physician may continue decreasing the dose but at a more
gradual rate.
Hyponatremia
Hyponatremia may occur as a result
of treatment with SSRIs and SNRIs,
including Savella.41 In many cases,
this hyponatremia appears to be the
result of the syndrome of inappropriate antidiuretic hormone secretion.
Cases with serum sodium less than 110
mmol/L have been reported. Elderly
patients may be at greater risk of
developing hyponatremia with SNRIs,
SSRIs, or Savella. Also, patients taking diuretics, or who are otherwise
volume-depleted, may be at greater
risk. Discontinuation of Savella should
be considered in patients with symptomatic hyponatremia.
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
Signs and symptoms of hyponatremia
include headache, difficulty concentrating, memory impairment, confusion,
weakness, and unsteadiness, which may
lead to falls.41 Signs and symptoms associated with more severe and/or acute
cases have included hallucination, syncope, seizure, coma, respiratory arrest,
and death.
use of Savella in patients with a history
of dysuria, notably in male patients with
prostatic hypertrophy, prostatitis, and
other lower urinary tract obstructive
disorders. Male patients are more prone
to genitourinary adverse effects, such
as dysuria or urinary retention, and may
experience testicular pain or ejaculation
disorders.
Abnormal Bleeding
Controlled Narrow-Angle
Glaucoma
SSRIs and SNRIs, including Savella,
may increase the risk of bleeding
events.41 Concomitant use of aspirin,
nonsteroidal anti-inflammatory drugs
(NSAIDs), warfarin, and other anticoagulants may add to this risk. Case
reports and epidemiologic studies
(case-control and cohort design) have
demonstrated an association between
use of drugs that interfere with serotonin reuptake and the occurrence
of gastrointestinal bleeding. Bleeding
events related to SSRI and SNRI use
have ranged from ecchymoses, hematomas, epistaxis, and petechiae to lifethreatening hemorrhages.
Patients should be cautioned about
the risk of bleeding associated with the
concomitant use of Savella and NSAIDs,
aspirin, or other drugs that affect coagulation.41
Activation of Mania
No activation of mania or hypomania
was reported in the clinical trials evaluating effects of Savella in patients with
FM.41 However, those clinical trials
excluded patients with current major
depressive episode. Activation of mania
and hypomania has been reported in
patients with mood disorders who
were treated with other similar drugs
for MDD. As with these other agents,
Savella should be used cautiously in
patients with a history of mania.
Patients with a History of Dysuria
Because of their noradrenergic effect,
SNRIs, including Savella, can affect urethral resistance and micturition.41 In the
controlled FM trials, dysuria occurred
more frequently in patients treated with
Savella (1%) than in placebo-treated
patients (0.5%). Caution is advised in
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Mydriasis has been reported in association with SNRIs and Savella; therefore, Savella should be used cautiously
in patients with controlled narrowangle glaucoma.41 Do not use Savella
in patients with uncontrolled narrowangle glaucoma.
Concomitant Use with Alcohol
In clinical trials, more patients treated with Savella developed elevated
transaminases than did placebo-treated patients.41 Because it is possible
that Savella may aggravate preexisting
liver disease, Savella should not be
prescribed to patients with substantial
alcohol use or evidence of chronic liver
disease.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, and
Impairment of Fertility
Carcinogenesis
Dietary administration of milnacipran
to rats at doses of 50 mg/kg/day (2
times the maximum recommended
human dose [MRHD] on an mg/m2
basis) for 2 years caused a statistically
significant increase in the incidence of
thyroid C-cell adenomas and combined
adenomas and carcinomas in males.41
A carcinogenicity study was conducted in Tg.rasH2 mice for 6 months at
oral gavage doses of up to 125 mg/kg/
day. Savella did not induce tumors in
Tg.rasH2 mice at any dose tested.
Mutagenesis
Milnacipran was not mutagenic in the
in vitro bacterial reverse mutation
assay (Ames test) or in the L5178Y TK
+/- mouse lymphoma forward mutation
assay.41 Milnacipran was also not clasto-
genic in an in vitro chromosomal aberration test in human lymphocytes or in
the in vivo mouse micronucleus assay.
Impairment of Fertility
Although administration of milnacipran to male and female rats had no
statistically significant effect on mating or fertility at doses up to 80 mg/
kg/day (4 times the MRHD on an mg/
m2 basis), there was an apparent doserelated decrease in the fertility index at
clinically relevant doses based on body
surface area.41
Animal Toxicology and
Pharmacology
Hepatic Effects
Chronic administration (2 years) of milnacipran to rats at 15 mg/kg (0.6 times
the MRHD on an mg/m2 basis) and higher doses showed increased incidences
of centrilobular vacuolation of the liver
in male rats and eosinophilic foci in
male and female rats in the absence of
any change in hepatic enzymes.41 The
clinical significance of the finding is not
known. Chronic (1-year) administration
in the primate at doses up to 25 mg/kg
(2 times the MRHD on an mg/m2 basis)
did not demonstrate similar evidence of
hepatic changes.
Ocular Effects
Chronic (2-year) administration of milnacipran to rats at 15 mg/kg (0.6 times
the MRHD on an mg/m2 basis) and higher doses showed increased incidence of
keratitis of the eye.41 One-year studies
in the rat and primate did not show this
response.
Use in Specific Populations
Pregnancy
Pregnancy Category C
Milnacipran increased the incidence
of dead fetuses in utero in rats at
doses of 5 mg/kg/day (0.25 times
the MRHD on an mg/m 2 basis). 41
Administration of milnacipran to
mice and rabbits during the period
of organogenesis did not result in
embryotoxicity or teratogenicity at
doses up to 125 mg/kg/day in mice
(3 times the MRHD of 200 mg/day
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
on an mg/m2 basis) and up to 60 mg/
kg/day in rabbits (6 times the MRHD
of 200 mg/day on an mg/m2 basis).
In rabbits, the incidence of the skeletal variation, extra single rib, was
increased following administration
of Savella at 15 mg/kg/day during the
period of organogenesis.
There are no adequate and wellcontrolled studies in pregnant women.
Savella should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.41
Nonteratogenic Effects
Neonates exposed to dual reuptake
inhibitors of serotonin and norepinephrine or SSRIs late in the third trimester
have developed complications requiring
prolonged hospitalization, respiratory
support, and tube feeding.41 Such complications can arise immediately upon
delivery. Reported clinical findings have
included respiratory distress, cyanosis,
apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability,
and constant crying. These features are
consistent with either a direct toxic
effect of these classes of drugs or, possibly, a drug discontinuation syndrome.
It should be noted that, in some cases,
the clinical picture is consistent with
serotonin syndrome.
In rats, a decrease in pup body weight
and viability on postpartum day 4 were
observed when milnacipran, at a dose
of 5 mg/kg/day (approximately 0.2
times the MRHD on a mg/m2 basis),
was administered orally to rats during
late gestation.41 The no-effect dose for
maternal and offspring toxicity was 2.5
mg/kg/day (approximately 0.1 times the
MRHD on a mg/m2 basis).
is not known if Savella is excreted in
human milk. Studies in animals have
shown that milnacipran or its metabolites are excreted in breast milk.
Because many drugs are excreted in
human milk and because of the potential for serious adverse reactions in
nursing infants from Savella, a decision
should be made whether to discontinue the drug, taking into account the
importance of the drug to the mother.
Because the safety of Savella in infants
is not known, nursing while on Savella
is not recommended.
daily)
• After day 7: 100 mg/day (50 mg twice
daily)
Based on individual patient response, the
physician may reduce or maintain the current dose until the patient is able to reach
the recommended 100 mg daily dose (50
mg twice daily).
Based on individual patient response,
the dose may be increased to 200 mg/day
(100 mg twice daily).41 Doses above 200
mg/day have not been studied. Savella
should be tapered and not abruptly discontinued after extended use.
Pediatric Use
Safety and effectiveness of Savella in an
FM pediatric population below the age
of 17 have not been established.41 The
use of Savella is not recommended in
pediatric patients.
Patients with Renal
Insufficiency
Geriatric Use
In controlled clinical studies of Savella,
402 patients were 60 years of age or
older, and no overall differences in safety and efficacy were observed between
these patients and younger patients.41
In view of the predominant excretion
of unchanged Savella via kidneys and
the expected decrease in renal function with age, renal function should be
considered prior to use of Savella in the
elderly.
SNRIs, SSRIs, and Savella have been
associated with cases of clinically significant hyponatremia in elderly patients,
who may be at greater risk for this
AE.41
Nursing Mothers
There are no adequate and well-controlled studies in nursing mothers.41 It
18
n
Patients with Hepatic
Insufficiency
No dosage adjustment is necessary for
patients with hepatic impairment.41 As
with any drug, caution should be exercised in patients with severe hepatic
impairment.
Dosage and Administration
Discontinuing Savella
Savella is given orally with or without
food. Taking Savella with a meal may
improve the tolerability of the drug.41
Withdrawal symptoms have been
observed in clinical trials following
discontinuation of Savella, as with
other SNRIs and SSRIs.41 Patients
should be monitored for these symptoms when discontinuing treatment.
Savella should be tapered and not
abruptly discontinued after extended use.
Recommended Dosing
Labor and Delivery
The effect of milnacipran on labor
and delivery is unknown.41 The use of
Savella during labor and delivery is not
recommended.
No dosage adjustment is necessary in
patients with mild renal impairment.41
Savella should be used with caution in
patients with moderate renal impairment. For patients with severe renal
impairment (indicated by an estimated
CLcr of 5-29 mL/min), the maintenance
dose should be reduced by 50% to 50
mg/day (25 mg twice daily).
Based on individual patient response,
the dose may be increased to 100 mg/
day (50 mg twice daily).41 Savella is not
recommended for patients with endstage renal disease.
The recommended dose of Savella is
100 mg/day (50 mg twice daily).41
Based on efficacy and tolerability,
dosing may be titrated according to the
following schedule41:
• Day 1: 12.5 mg once
• Days 2-3: 25 mg/day (12.5 mg twice
daily)
• Days 4-7: 50 mg/day (25 mg twice
Switching Patients to or from an
MAOI
At least 14 days should elapse between
discontinuation of an MAOI and initia-
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
Table 6
Savella Strengths and Package Configurations41
Strength
Package Configuration
Tablet Color
Tablet Shape
12.5-mg tablets
Bottle of 60
Blue
Round
25-mg tablets
Bottle of 60
White
Round
50-mg tablets
Bottle of 60
White
Oval
100-mg tablets
Bottle of 60
Pink
Oval
4-week Titration Pack:
5 x 12.5-mg tablets
8 x 25-mg tablets
42 x 50-mg tablets
Blister package of
55 tablets
Milnacipran is not a controlled substance.41
comes have been reported for acute overdoses primarily involving multiple drugs
but also with Savella only.41 The most
common signs and symptoms included
increased blood pressure, cardiorespiratory arrest, changes in the level of consciousness (ranging from somnolence to
coma), confusional state, dizziness, and
increased hepatic enzymes.
Abuse
Management of Overdose
Milnacipran did not produce behavioral
signs indicative of abuse potential in
animal or human studies.41
There is no specific antidote to Savella,
but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control)
may be considered.41 In case of acute
overdose, treatment should consist of
those general measures employed in
the management of overdose with any
drug.
An adequate airway, oxygenation,
and ventilation should be assured,
and cardiac rhythm and vital signs
should be monitored.41 Induction of
emesis is not recommended. Gastric
lavage with a large-bore orogastric
tube with appropriate airway protection, if needed, may be indicated if
performed soon after ingestion or in
symptomatic patients. Because there
is no specific antidote for Savella,
symptomatic care and treatment with
gastric lavage and activated charcoal
should be considered as soon as possible for patients who experience a
Savella overdose.
tion of therapy with Savella.41 In addition, at least 5 days should be allowed
after stopping Savella before starting
an MAOI.
Drug Abuse and Dependence
Controlled Substance
Dependence
Milnacipran produces physical dependence, as evidenced by the emergence
of withdrawal symptoms following
drug discontinuation, similar to other
SNRIs and SSRIs.41 These withdrawal
symptoms can be severe. Thus, Savella
should be tapered and not abruptly discontinued after extended use. (Please
refer to Section 5.7, “Discontinuation
of Treatment with Savella,” in the Full
Prescribing Information.)
Overdosage
There is limited clinical experience with
Savella overdose in humans.41 In clinical
trials, cases of acute ingestions up to
1000 mg, alone or in combination with
other drugs, were reported with none
being fatal.
In postmarketing experience, fatal out-
www.PharmacyTimes.com
Because of the large volume of distribution of this drug, forced diuresis,
dialysis, hemoperfusion, and exchange
transfusion are unlikely to be beneficial.41
In managing overdose, the possibility of multiple drug involvement should
be considered.41 The physician should
consider contacting a poison control
center for additional information on the
treatment of any overdose. Telephone
numbers for certified poison control
centers are listed in the Physicians’
Desk Reference.
How Supplied/Storage
AND HAndling
Savella is available for oral administration as film-coated tablets containing
12.5 mg, 25 mg, 50 mg, and 100 mg
milnacipran hydrochloride.41 Each tablet also contains dibasic calcium phosphate, povidone, carboxymethylcellulose calcium, colloidal silicon dioxide,
magnesium stearate, and talc as inactive
ingredients.
Additionally, the following inactive
ingredients are also present as components of the film coat41: 12.5 mg: FD&C
Blue #2 Aluminum Lake, hypromellose, polyethylene glycol, titanium
dioxide; 25 mg: Hypromellose, polyethylene glycol, titanium dioxide; 50
mg: Hypromellose, polyethylene glycol,
titanium dioxide; 100 mg: FD&C Red
#40 Aluminum Lake, hypromellose,
polyethylene glycol, titanium dioxide.
Savella is available in both bottle and
Titration Pack configurations.41 Table
6 lists the strengths and package configurations for Savella.41
Storage
Savella should be stored at 25°C (77°F);
excursions are permitted between 15°C
and 30°C (between 59°F and 86°F). (See
USP Controlled Room Temperature.)41
A Quick Reference guide for Savella
is located at the end of the monograph.
Pharmacy Times | 10.10
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
SECTION 3. The Role of the Pharmacist
Pharmacists educated about FM are in a
better position to identify possible cases
of FM and help patients get proper treatment. Pharmacists can also assist physicians with information about treatments
for FM and possible interactions with
the other prescription drugs. Moreover,
pharmacists can help patients with FM
who have questions or incomplete information about their role in managing this
unique condition. The APS guidelines
recommend adequate patient education
as an initial step in FM treatment.7,39
However, the education a patient gets in
the clinician’s office may be limited by
the patient’s hesitancy to ask questions
or the clinician’s lack of time. The community pharmacist can fill many gaps
in the patient’s understanding of the
condition and thereby help optimize the
chances of treatment success.
Identifying FM
Pharmacists are made aware of FM in
several ways. Some patients with FM
may confide their diagnosis to their
pharmacist and ask questions about the
condition. Others might be undiagnosed
but wonder about their symptoms, comparing their condition to news stories
or advertising they have encountered.
Some undiagnosed patients may purchase several different prescription and
OTC medications that may signal the
possibility of FM. It is appropriate to
ask patients about the nature of their
pain and other symptoms and functional
impairment, using a list of common FM
symptoms, and to refer patients to their
physician when symptoms suggest FM.
Assisting the Clinician with FM
Treatment
Pharmacists can expect to see several different prescriptions, which may
change over time, for FM and various
comorbidities in diagnosed and undiagnosed patients. The pharmacist’s principal task is to help the clinician and
patient by ensuring that the treatment
regimen is rational and safe, and assist
with adherence.15
20
n
Consultation with the prescriber may
be advisable if:
• A new prescription duplicates the main
effects of an ongoing prescription.
• A new prescription increases the risk
of AEs associated with an ongoing
prescription.
• A new agent could produce drug interactions with an ongoing prescription.
The pharmacist may know something
patient-specific that the prescriber may
not know and that could affect treatment with this prescription (eg, herbal
supplements purchased or mentioned by
the patient, prescriptions for scheduled
drugs from another prescriber, or treatment by another prescriber for cardiac
or renal conditions).
Conversations with the prescriber
can reveal how well the prescriber is
informed about the recent FDA approval
of drugs for FM. The pharmacist can
serve as a valuable resource about the
effects of the various drugs and inform
the prescriber if a prescription for an
FDA-approved agent might be appro­
priate.
Assisting the Patient with FM
Treatment
When patients confide that their new
prescription is for FM, the pharmacist
should take advantage of this opportunity for patient education. The pharmacist might explain that FM is a multisymptom condition, and that it cannot
be cured, but it can be managed. FM
is not the same as other conditions
with similar symptoms (eg, rheumatoid
arthritis, chronic fatigue syndrome). The
pharmacist may help the patient understand altered pain processing in FM.
Patient education should also include
information about major FM symptoms,
triggers and stressors, and pharmacologic and nonpharmacologic treatment
options. For more information, direct
the patient to other re­sources, including
educational materials and support and
advocacy groups (see “FM resources,”
page 21).
A pharmacist should ask patients to
list all their prescriptions and any known
drug allergies to prevent drug interactions
or other serious AEs. Inform patients in
advance about potential AEs associated
with their prescription drug. Because
patients’ symptoms can be affected by
external stressors, level of activity, and
other factors, emphasize that taking the
drug exactly as prescribed is essential,
especially for the first month. Inadequate
adherence will not only inhibit efficacy,
it will make it more difficult to ascertain
the cause if something feels worse. Let
patients know that you are available,
if needed, to discuss changes in their
symptoms or overall well-being. If they
call, take the opportunity to encourage
medication adherence.
When discussing FM prescriptions
with patients, it can be helpful to ask
about nonpharmacologic therapies that
the clinician recommended. This will
help patients understand how different
elements of treatment work together to
reduce symptoms and improve function.
Emphasize managing stress, limiting
exposure to cold or damp, and avoiding
overexertion.24 In particular, overexertion may have a delayed effect, resulting
in a flare-up hours to days later. Advise
patients that they may need to moderate
physical activities even if their stamina
does not seem impaired. Conversely, if
prescribed treatment includes an exercise plan, stress its importance. The
patients’ physical energy should be
directed toward rehabilitative exercise
before other physical exertion.
The pharmacist can expect that the
initial conversation about FM will not
be the last, nor should it be. Prescription
refills offer an opportunity for a quick
update on patients’ progress. It is appropriate to follow up in this way, because
management is complex and various
reminders may be useful. FM management requires a high level of engagement and responsibility on the part of
patients.14 Patients need counseling to
understand (1) how they can manage
their symptoms with positive attitudes
and actions and coping strategies,
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Please see Important Safety Information, including Boxed Warning, on pages 13-19.
FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
and (2) the importance of medication
adherence. Pharmacists should ask
patients if their symptoms are getting
better, if they have improved function
and level of physical activity, and if any
new symptoms have emerged (whether
from FM, a new comorbidity, or AEs
from the drug). They should also ask
patients how they are managing stressors, and whether they have added
or changed other prescriptions, OTC
medications, or dietary supplements.
Counseling patients, or, in some cases,
contacting the prescriber, can facilitate
necessary “course corrections.”
Because of the subjective nature of
FM, clear and sufficient communication
can be a challenge. Discussions with a
patient with a complex case of FM—even
listening to the many symptoms and
complaints—can be time-consuming and
therefore difficult for the busy pharmacist. However, many patients with FM
receive inadequate support from skeptical friends and family; thus, empathy
and assistance from their most frequently
visited health care professional, the community pharmacist, may be crucial to
treatment success. Even when they have
a diagnosis from their physician, many
patients with FM still feel judged, misunderstood, or stigmatized. It is important
for patients to remain positive and focus
on improving function rather than dwelling on symptoms. Pharmacists should
avoid comments or a tone that might
imply personal failure on the part of the
patient.
FM Resources: In addition to counseling and discussions about the mechanisms and treatments for FM, pharmacists can assist with patient education
by offering printed materials and/or
directions to other resources, which
include:
• FibroTogether: www.fibrotogether.
com (FibroTogether.com is a Web site
developed and sponsored by Forest
Laboratories, Inc. and Cypress
Bioscience, Inc.)
• National Fibromyalgia Association:
www.fmaware.org
• National Fibromyalgia Partnership:
www.fmpartnership.org
www.PharmacyTimes.com
Patient Counseling Tips
Managing Nausea Associated with Savella Therapy
As with any drug therapy, pharmacists should ask patients with FM how they feel
and how they are doing with their prescription medication. In particular, patients new
to using Savella may experience nausea, the most common side effect associated
with Savella. If patients disclose nausea, they should be referred to their physician.
Pharmacists should reassure patients that the AE of nausea does not mean the medication is not working and they should not stop taking Savella until they speak to their
doctor. Over this time period, the sensation of nausea may disappear as the body
becomes accustomed to the medication.
Taking Savella with a meal or snack may improve tolerability. Although not specifically studied with the nausea associated with Savella, generally, patients may be
able to reduce a feeling of nausea through dietary adjustments, including60:
• Eating several light meals and snacks daily instead of 3 large meals
• Eating and drinking slowly
• Avoiding spicy, fried, and acidic foods and juices
• Avoiding coffee, caffeinated tea, and alcohol
• Drinking herbal teas or carbonated beverages, especially ginger ale
• Fibromyalgia Network:
www.fmnetnews.com
• American Pain Foundation:
www.painfoundation.org
• American College of Rheumatology
pa­­­tient information: www.rheuma
tology.org/practice/clinical/patients/
diseases_and_conditions/fibromyal
gia.asp
• Arthritis Foundation FM information:
www.arthritis.org/disease-center.
php?disease+id=10
• National Institute of Arthritis and
Musculoskeletal Diseases FM information: www.niams.nih.gov/Health_Info/
Fibromyalgia/default.asp
• National Chronic Fatigue Syndrome
and Fibromyalgia Association: www.
ncfsfa.org
Counseling Patients Using Savella
Information in Medication Guide
Prescribers or other health professionals should inform patients, their families,
and their caregivers about the benefits
and risks associated with treatment with
Savella and should counsel them in its
appropriate use.41 A patient Medication
Guide is available for Savella. The prescriber or health professional should
instruct patients, their families, and
their caregivers to read the Medication
Guide and should assist them in understanding its contents. Patients should
be given the opportunity to discuss the
contents of the Medication Guide and
to obtain answers to any questions they
may have.
Patients should be advised of the following issues and asked to alert their
prescriber if these occur while taking
Savella41:
• S
uicide risk. Patients and their families and caregivers should be advised
that Savella is a selective norepinephrine and serotonin reuptake inhibitor
and therefore belongs to the same
class of drugs as antidepressants.
Patients, their families, and their
caregivers should be advised that
patients with depression may be at
increased risk for clinical worsening
and/or suicidal ideation if they stop
taking antidepressant medication,
change the dose, or start a new medication. Patients, their families, and
their caregivers should be encouraged to be alert to the emergence
of anxiety, agitation, panic attacks,
insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania
or other unusual changes in behavior,
worsening of depression, and suicidal
ideation, especially early during treatment with Savella or other drugs that
inhibit the reuptake of norepinephrine and/or serotonin, and when the
dose is adjusted up or down. Families
and caregivers of patients should be
advised to observe for the emergence
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
of such symptoms on a day-to-day
basis, since changes may be abrupt.
Such symptoms should be reported to
the patient’s prescriber or health professional, especially if they are severe,
abrupt in onset, or were not part of
the patient’s presenting symptoms.
• S erotonin syndrome. Patients
should be cautioned about the risk of
serotonin syndrome with concomitant
use of Savella and triptans, tramadol,
or other serotonergic agents.
• Effect on blood pressure and pulse.
Patients should be advised that their
blood pressure and pulse should be
monitored at regular intervals when
receiving treatment with Savella.
• Abnormal bleeding. Patients should
be cautioned about the concomitant
use of Savella and NSAIDs, aspirin, or
other drugs that affect coagulation,
since the combined use of agents that
interfere with serotonin reuptake and
these agents has been associated with
an increased risk of abnormal bleeding.
• Ability to drive and use machinery.
Savella might diminish mental and physical capacities necessary to perform
certain tasks such as operating machinery, including motor vehicles. Patients
should be cautioned about operating
machinery or driving motor vehicles
until they are reasonably certain that
Savella treatment does not affect their
ability to engage in such activities.
• Alcohol. Patients should be advised
to avoid consumption of alcohol while
taking Savella.
• Discontinuation. Patients should be
advised that withdrawal symptoms
can occur when discontinuing treatment with Savella, particularly when
discontinuation is abrupt.
• Pregnancy. Patients should be
advised to notify their physician if they
become pregnant or intend to become
pregnant during Savella therapy.
• Nursing. Patients should be advised
to notify their physician if they are
breastfeeding.
Conclusion
Patients with FM may require high levels of external support to manage their
condition. The informed, empathetic
22
n
Patient Counseling Tips
Adherence to FM Medications
The community pharmacist can help fill
gaps in patient education and motivation, becoming an ally in the patient’s
battle against FM symptoms. The
pharmacist can educate patients about
potential AEs and remain available to
discuss these effects or other problems in adherence as they emerge.
Patient adherence to treatment with
prescription medications is a problem
in most chronic disorders, and FM is no
exception. Adherence to FM therapy
may be as low as 53%.14 A 2004 study
of adherence in 127 hospitalized and
outpatient women with FM and their
rheumatologists found that 60 patients
(47%) were nonadherent to medication over a period of 2 weeks (defined
as sometimes forgetting to take medication, being careless about taking
medication, or intentionally stopping
the medication because of feeling better or worse).14 Of those, 20 patients
(33%) were intentionally nonadherent,
24 patients (40%) were unintentionally nonadherent, and the rest of the
patients were both.14 Greater disagreement between patients and physicians
on their perception about the exchange
of health-related information with each
other (communication and satisfaction) predicted non-adherence. These
findings suggest that the therapeutic
relationship between patients and their
providers may influence adherence, as
may treatment by less specialized physicians in community settings.
community pharmacist can play a critical role in the successful treatment of
the patient with FM and can assist in
many ways, some of which are common
in daily pharmacy practice and some
unique to those patients with FM. These
services can include:
Provision of clinical information
regarding FM. For both diagnosed
and undiagnosed patients with FM,
the pharmacist remains an accessible
health care provider who can educate
patients about their condition. In addition, through these discussions, if FM is
suspected, the pharmacist can refer the
patient to a physician for further care.
Consultation to physicians. When
patients are actively being treated for
FM, the pharmacist can offer counsel to the prescribing physician about
other medications patients are taking
(which can be numerous and from
many individual prescribers), as well
as any nonprescription drugs and
nutritional supplements. In addition,
monitoring the patient’s drug profile
helps prevent drug interactions when
new prescriptions are ordered from
the treating physician or other practitioners. Lastly, the pharmacist can
also assist in monitoring efficacy of the
regimen and monitor for side effects
through regular discussions with the
patients, which can then be reported
back to the physician.
Patient education and counseling
on drug therapies. The pharmacists’
role, in addition to dispensing medications, is to educate patients on the
proper use of their medications, including instructions for optimizing dosing
and minimizing AEs (eg, taking with a
meal to improve tolerability), education
about AEs and how to manage (or seek
care), as well as encouraging adherence
to prescribed regimens (since some
regimens can take up to 1 month to
become effective). Overall, by managing
patients’ expectations about their prescriptions, experiences and outcomes
can be improved.
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FIBROMYALGIA AND SAVELLA (milnacipran HCl): An Overview for THE PHARMACIST
Savella Quick Reference41
What it is
Milnacipran, an FDA-approved medication for the management of fibromyalgia
How it works
A dual reuptake inhibitor that blocks the uptake of norepinephrine over serotonin with approximately 3 times greater potency in vitroa
What it does
Savella delivers simultaneous improvements on 3 measures of fibromyalgia: pain reduction, improvement in patient global
fibromyalgia assessment, and improvement in physical function.
Indication
Indicated for the management of fibromyalgia in adults
How supplied
Film-coated tablets:
12.5-mg (blue) round tablets in bottles of 60
25-mg (white) round tablets in bottles of 60
50-mg (white) oval-shaped tablets in bottles of 60
100-mg (pink) oval-shaped tablets in bottles of 60
4-week Titration Pack:
Blister package containing 5 x 12.5-mg tablets, 8 x 25-mg tablets, and 42 x 50-mg tablets
Dosing
Take in 2 divided doses per day, with a meal (to improve tolerability) or without a meal
Based on efficacy and tolerability, dosing may be titrated according to the following schedule:
Day 1: 12.5 mg once
Days 2-3: 25 mg/day (12.5 mg twice daily)
Days 4-7: 50 mg/day (25 mg twice daily)
After Day 7: 100 mg/day (50 mg twice daily)
Recommended dose is 100 mg/day; may be increased to 200 mg/day based on individual patient response. Dose should be adjusted
in patients with severe renal impairment. Savella should be tapered and should not be abruptly discontinued after extended use.
Most common
adverse events
Nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhidrosis, vomiting, palpitations, increased heart rate, dry
mouth, hypertension
Contraindications
Do not use with MAOIs concomitantly or in close temporal proximity. Do not use in patients with uncontrolled narrow-angle glaucoma.
Warnings and
precautions
• Suicidality: Monitor for worsening of depressive symptoms and suicide risk
• Serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions: Serotonin syndrome or NMS-like reactions have
been reported with SNRIs and SSRIs. Discontinue Savella and initiate supportive treatment
• Elevated blood pressure and heart rate: Cases have been reported with Savella. Monitor blood pressure and heart rate prior to
initiating treatment with Savella and periodically throughout treatment
• Seizures: Cases have been reported with Savella therapy. Prescribe Savella with care in patients with a history of seizure disorder
• Hepatotoxicity: More patients treated with Savella than with placebo experienced mild elevations of ALT and AST. Rarely, fulminant hepatitis has been reported in patients treated with Savella. Avoid concomitant use of Savella in patients with substantial
alcohol use or chronic liver disease
• Discontinuation: Withdrawal symptoms have been reported in patients when discontinuing treatment with Savella. A gradual dose
reduction is recommended
• Abnormal bleeding: Savella may increase the risk of bleeding events. Caution patients about the risk of bleeding associated with
the concomitant use of Savella and NSAIDs, aspirin, or other drugs that affect coagulation
• Male patients with a history of obstructive uropathies may experience higher rates of genitourinary adverse events
Drug interactions
Clinically important interactions may occur with MAOIs, serotonergic drugs (including other SSRIs, SNRIs, lithium, tryptophan,
antipsychotics, and dopamine antagonists), triptans, catecholamines (epinephrine and norepinephrine), CNS-active drugs (including clomipramine), and select cardiovascular agents (digoxin and clonidine).
Use in pregnancy
and nursing
Use only when potential benefit justifies potential risk to the fetus or child
Use in geriatric and
pediatric patients
Not approved for use in pediatric patients. No dosage adjustment required for patients ≥60 years of age, but dosage adjustment is
required for those with severe renal impairment.
The clinical significance of in vitro data is unknown. ALT = alanine aminotransferase; AST = aspartate aminotransferase; CNS = central nervous system; FDA = US Food and Drug
Administration; MAOIs = monoamine oxidase inhibitors; NSAIDs = nonsteroidal anti-inflammatory drugs; SNRIs = serotonin-norepinephrine reuptake inhibitor; SSRIs = selective serotonin
reuptake inhibitor.
a
Please see Full Prescribing Information at http://www.frx.com/pi/Savella_pi.pdf
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