Included as part of the PRECAUTIONS section.
Savella is a selective serotonin and norepinephrine
re-uptake inhibitor (SNRI), similar to some drugs used for the treatment of
depression and other psychiatric disorders.
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. 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
fibromyalgia, 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
treated with Savella 200 mg/day. No suicides occurred in the short-term or
longer-term (up to 1 year) fibromyalgia 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 major depressive disorder (MDD)
and other psychiatric disorders. Short-term studies did not show an increase in
the risk of suicidality with these drugs compared to placebo in adults beyond
age 24; there was a reduction in suicidality risk with antidepressants compared
to placebo in adults age 65 and older.
The pooled analyses of placebo-controlled trials in
children and adolescents with MDD, obsessive compulsive disorder (OCD), or
other psychiatric disorders included a total of 24 short-term trials of 9 drugs
used to treat depression in over 4400 patients. 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 over 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 of differences (drug versus placebo), however, were relatively stable
within age strata and across indications. These risk differences (drug-placebo
difference in the number of cases of suicidality per 1000 patients treated) are
provided in Table 1.
Table 1: Risk Differences (Drug – Placebo) in the
number of Cases of Suicidality, per 1000 patients treated
||Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
| < 18
||14 additional cases
||5 additional cases
||Decreases Compared to Placebo
||1 fewer case
| ≥ 65
||6 fewer cases
No suicides occurred in any of the pediatric trials.
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, i.e., beyond several months.
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.
The following symptoms, anxiety, agitation, panic
attacks, insomnia, irritability, hostility, aggressiveness, impulsivity,
akathisia (psychomotor restlessness), hypomania, mania, have been reported in
adult and pediatric patients being treated with drugs inhibiting the reuptake
of norepinephrine and/or serotonin for major depressive disorder as well as for
other indications, both psychiatric and nonpsychiatric. 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.
If the decision has been made to discontinue treatment
due to worsening depressive symptoms or emergent suicidality, medication should
be tapered, as rapidly as is feasible, but with recognition that abrupt
discontinuation can produce withdrawal symptoms [see DOSAGE AND
ADMINISTRATION, and Discontinuation of Treatment with Savella].
Families and caregivers of patients being treated with
drugs inhibiting the reuptake of norepinephrine and/or serotonin for major
depressive disorder 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. 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.
The development of a potentially life-threatening
serotonin syndrome has been reported with SNRIs and SSRIs, including Savella,
alone but particularly with concomitant use of other serotonergic drugs
(including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol,
tryptophan, buspirone, and St. John's Wort) and with drugs that impair
metabolism of serotonin (in particular MAOIs, both those intended to treat
psychiatric disorders and also others, such as linezolid and intravenous
Serotonin syndrome symptoms may include mental status
changes (e.g., agitation, hallucinations, delirium, and coma), autonomic
instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis,
flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity,
myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal
symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for
the emergence of serotonin syndrome.
The concomitant use of Savella with MAOIs intended to
treat psychiatric disorders is contraindicated. Savella should also not be
started in a patient who is being treated with MAOIs such as linezolid or
intravenous methylene blue. All reports with methylene blue that provided
information on the route of administration involved intravenous administration
in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration
of methylene blue by other routes (such as oral tablets or local tissue injection)
or at lower doses. There may be circumstances when it is necessary to initiate
treatment with an MAOI such as linezolid or intravenous methylene blue in a
patient taking Savella. Savella should be discontinued before initiating
treatment with the MAOI [see CONTRAINDICATIONS, DOSAGE AND
If concomitant use of Savella with other serotonergic
drugs including triptans, tricyclic antidepressants, fentanyl, lithium,
tramadol, buspirone, tryptophan and St. John's Wort is clinically warranted,
patients should be made aware of a potential increased risk for serotonin
syndrome, particularly during treatment initiation and dose increases.
Treatment with Savella and any concomitant serotonergic
agents should be discontinued immediately if the above events occur, and
supportive symptomatic treatment should be initiated.
Elevated Blood Pressure
A double-blind, placebo-controlled ambulatory blood
pressure monitoring (ABPM) study was conducted to evaluate the effects of
milnacipran (up to 200 mg/day) on blood pressure in 321 fibromyalgia patients.
Among fibromyalgia patients who were normotensive at baseline, an analysis of
the blood pressure findings demonstrated a substantially higher proportion of
Savellatreated patients had a hypertensive blood pressure measurement at the
Week 4, 50 mg BID steady state visit (17.7% [n=21/119]) and the Week 7, 100 mg
BID steady state visit (14.3% [n=15/105]) as compared to placebo-treated
patients (3.7% [n=2/54] and 0% [0/49] at the Week 4 and Week 7 visits,
respectively). Hypertension was defined as mean systolic blood pressure (SBP)
≥ 140 mmHg and change from baseline in mean SBP ≥ 10 mmHg or mean
diastolic blood pressure (DBP) ≥ 90 mmHg and change from baseline in mean
DBP ≥ 5 mmHg for the 12-hour period post AM study drug measurement at that
visit. Furthermore, 1.9% (4/210) of Savellatreated and 0.9% (1/111) of placebo
patients discontinued treatment for increases in blood pressure.
The increased risk of blood pressure measurements in the
hypertensive range in Savella-treated patients is supported by substantial
increases in mean SBP and DBP measurements observed in the ABPM study. Table 2 shows
that, following treatment with Savella 50 mg BID for three weeks in patients
who were normotensive at baseline, the mean increase from baseline was 5 mmHg
in systolic blood pressure (SBP) and diastolic blood pressure (DBP). After
further treatment with Savella 100 mg BID for two weeks, the mean increase from
baseline in SBP and DBP was 6 mmHg. Similar elevations occurred in
Savella-treated patients who were hypertensive at baseline.
Table 2: Mean (Standard Error) Change from Baseline in
Mean 24-hour Systolic and Diastolic Blood Pressure (mmHg) of Milnacipran or
Placebo following 4 Weeks of Treatment (50mg BID) and a Subsequent 2 Weeks of
Treatment (100mg BID)
|50 mg BID*
|100 mg BID^
|*Blood pressure measurements made after 3 weeks of
milnacipran 50mg BID
^Blood pressure measurements made after 2 weeks of milnacipran 100mg BID
Similar patterns of treatment-emergent blood pressure
elevations were observed in Phase 3 and clinical pharmacology studies as
manifested by an increased risk of new onset hypertension or substantial
increases in end of study blood pressure measurements in patients with
hypertension at baseline (Table 3).
Table 3: Blood pressure changes in Phase 3 randomized
||Milnacipran 50 mg BID
||Milnacipran 100 mg BID
|FM patients normotensive at baseline who became hypertensive (defined as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg on three consecutive post-baseline visits)
|FM patients with sustained increases in SBP (increase of ≥ 15 mmHg on three consecutive post-baseline visits)
|FM patients with sustained increases in DBP (increase of ≥ 10 mmHg on three consecutive post-baseline visits)
|FM patients hypertensive at baseline who had increases in SBP ≥ 15 mmHg at end of study
|FM patients hypertensive at baseline who had increases in DBP ≥ 10 mmHg at end of study
Sustained increases in blood pressure may have adverse
consequences. Cases of elevated blood pressure requiring immediate treatment
have been reported.
Concomitant use of Savella with drugs that increase blood
pressure and heart rate has not been evaluated and such combinations should be
used with caution [see DRUG INTERACTIONS].
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.
Measure blood pressure prior to initiating treatment and
periodically monitor blood pressure throughout Savella treatment. Treat
pre-existing hypertension and other cardiovascular disease before starting
therapy with Savella. For patients who experience a sustained increase in blood
pressure while receiving Savella, either reduce the dose or discontinue
treatment with Savella if clinically warranted.
Elevated Heart Rate
A double-blind, placebo-controlled ABPM study was
conducted to evaluate the effects of milnacipran (up to 200 mg/day) on blood
pressure in 321 fibromyalgia patients [see Elevated Blood Pressure].
Information on heart rate was also collected. Following treatment with Savella
50mg BID for three weeks in patients who were normotensive at baseline, the
mean increase in mean 24-hour heart rate from baseline was 13 beats per minute.
After further treatment with Savella 100 mg BID for two weeks, the mean increase
from baseline in heart rate was 13 beats per minute.
Similar trends were observed in the clinical trials where
Savella treatment was associated with mean increases in heart rate of
approximately 7 to 8 beats per minute [see ADVERSE REACTIONS].
Increases in heart rate ≥ 20 beats per minute
occurred more frequently in Savella-treated patients when compared to placebo
(8% in the Savella 50 mg BID and 100 mg BID treatment arms versus 0.3% in the
Savella has not been systematically evaluated in patients
with a cardiac rhythm disorder.
Measure heart rate prior to initiating treatment and
periodically monitor the heart rate throughout Savella treatment. Treat
pre-existing tachyarrhythmias and other cardiac disease before starting therapy
with Savella. For patients who experience a sustained increase in heart rate
while receiving Savella, either reduce the dose or discontinue treatment with
Savella if clinically warranted.
Savella has not been systematically evaluated in patients
with a seizure disorder. In clinical trials evaluating Savella in patients with
fibromyalgia, seizures/convulsions have not been reported. However, seizures
have been reported infrequently in patients treated with Savella for disorders
other than fibromyalgia. Savella should be prescribed with care in patients
with a history of a seizure disorder.
In the placebo-controlled fibromyalgia trials, increases
in the number of patients treated with Savella with mild elevations of ALT or
AST (1-3 times the upper limit of normal, ULN) were observed. Increases in ALT
were more frequently observed in the patients treated with Savella 100 mg/day
(6%) and Savella 200 mg/day (7%), compared to the patients treated with placebo
(3%). One patient receiving Savella 100 mg/day (0.2%) had an increase in ALT
greater than 5 times the upper limit of normal but did not exceed 10 times the
upper limit of normal. Increases in AST were more frequently observed in the
patients treated with Savella 100 mg/day (3%) and Savella 200 mg/day (5%)
compared to the patients treated with placebo (2%).
The increases of bilirubin observed in the fibromyalgia
clinical trials were not clinically significant.
No case met the criteria of elevated ALT > 3x ULN and
associated with an increase in bilirubin ≥ 2x ULN.
There have been cases of increased liver enzymes and
reports of severe liver injury, including fulminant hepatitis with milnacipran
from foreign postmarketing experience. 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. Treatment with Savella should
not be resumed unless another cause can be established.
Savella should ordinarily not be prescribed to patients
with substantial alcohol use or evidence of chronic liver disease.
Discontinuation Of Treatment With Savella
Withdrawal symptoms have been observed in clinical trials
following discontinuation of milnacipran, as with other SNRIs and SSRIs.
During marketing of milnacipran, and other SNRIs and
SSRIs, there have been spontaneous reports of adverse events indicative of
withdrawal and physical dependence occurring upon discontinuation of these
drugs, particularly when discontinuation is abrupt. The adverse events include
the following: dysphoric mood, irritability, agitation, dizziness, sensory
disturbances (e.g., 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. 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 [see DOSAGE
Hyponatremia may occur as a result of treatment with
SSRIs and SNRIs, including Savella. In many cases, this hyponatremia appears to
be the result of the syndrome of inappropriate antidiuretic hormone secretion
(SIADH). Cases with serum sodium lower 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 [see Geriatric Use].
Discontinuation of Savella should be considered in patients with symptomatic
Signs and symptoms of hyponatremia include headache,
difficulty concentrating, memory impairment, confusion, weakness, and
unsteadiness, which may lead to falls. Signs and symptoms associated with more
severe and/or acute cases have included hallucination, syncope, seizure, coma,
respiratory arrest, and death.
SSRIs and SNRIs, including Savella, may increase the risk
of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory
drugs (NSAIDs), warfarin, and other anti-coagulants may add to this risk. Case
reports and epidemiological 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 SSRIs and SNRIs use have ranged from ecchymoses, hematomas,
epistaxis, and petechiae to life-threatening 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.
Activation Of Mania
No activation of mania or hypomania was reported in the
clinical trials evaluating effects of Savella in patients with fibromyalgia.
However those clinical trials excluded patients with current major depressive
episode. Activation of mania and hypomania have been reported in patients with
mood disorders who were treated with other similar drugs for major depressive
disorder. 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. In the controlled
fibromyalgia trials, dysuria occurred more frequently in patients treated with
Savella (1%) than in placebo-treated patients (0.5%). Caution is advised in 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
Angle Closure Glaucoma
The pupillary dilation that occurs following use of SNRI
drugs including Savella may trigger an angle closure attack in a patient with
anatomically narrow angles who does not have a patent iridectomy.
Concomitant Use With Alcohol
In clinical trials, more patients treated with Savella
developed elevated transaminases than did placebo treated patients [see Hepatotoxicity]. Because it is possible that milnacipran may aggravate
pre-existing liver disease, Savella should not be prescribed to patients with
substantial alcohol use or evidence of chronic liver disease.
Patient Counseling Information
See Medication Guide
Information For Patients
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. 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. The complete text of the Medication Guide is reprinted at the
end of this document.
Patients should be advised of the following issues and
asked to alert their prescriber if these occur while taking Savella:
Clinical Worsening And Suicide 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 anti-depressant 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 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 [see
BOXED WARNING and WARNINGS AND PRECAUTIONS].
Patients should be cautioned about the risk of serotonin
syndrome with concomitant use of Savella with other serotonergic drugs
including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol,
tryptophan, buspirone and St. John's Wort, and with drugs that impair
metabolism of serotonin (in particular MAOIs, both those intended to treat
psychiatric disorders and also others, such as linezolid) [see WARNINGS AND
Patients should be advised of the signs and symptoms
associated with serotonin syndrome that may include mental status changes
(e.g., agitation, hallucinations, delirium, and coma), autonomic instability
(e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing,
hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia,
incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea,
vomiting, diarrhea). Patients should be cautioned to seek medical care
immediately if they experience these symptoms.
Elevated Blood Pressure And Heart Rate
Patients should be advised that Savella may increase
their blood pressure and heart rate and that they should have their blood
pressure and heart rate monitored at regular intervals when receiving treatment
with Savella [see WARNINGS AND PRECAUTIONS].
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 [see WARNINGS
Angle Closure Glaucoma
Patients should be advised that taking Savella can cause
mild pupillary dilation, which in susceptible individuals, can lead to an
episode of angle closure glaucoma. Pre-existing glaucoma is almost always
open-angle glaucoma because angle closure glaucoma, when diagnosed, can be
treated definitively with iridectomy. Open-angle glaucoma is not a risk factor
for angle closure glaucoma. Patients may wish to be examined to determine
whether they are susceptible to angle closure, and have a prophylactic
procedure (e.g., iridectomy), if they are susceptible [see WARNINGS AND
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.
Patients should talk to their healthcare provider about
their alcohol intake prior to initiating treatment with Savella [see WARNINGS
Patients should be advised that withdrawal symptoms can
occur when discontinuing treatment with Savella, particularly when
discontinuation is abrupt [see WARNINGS AND PRECAUTIONS].
Missing a Dose
Patients should be advised that if they miss a dose, they
should skip the missed dose and take the next dose at their regular time.
Patients should be advised to notify their physician if
they become pregnant or intend to become pregnant during Savella therapy [see Use
in Specific Populations].
Patients should be encouraged to enroll in the Savella
Pregnancy Registry if they become pregnant, preferably before any prenatal
testing is done. This registry is collecting information about the safety of
milnacipran during pregnancy. To enroll, patients or their healthcare providers
may call the toll-free number 1-877-643-3010 [see Use In Specific
Populations], download data forms from our website,
www.savellapregnancyregistry.com, or email the registry for further information
at [email protected]
Advise patients to notify their physician if they are
breast feeding [see Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Dietary administration of milnacipran to rats at doses of
50 mg/kg/day (2 times the MRHD on a 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. A carcinogenicity study was
conducted in Tg.rasH2 mice for 6 months at oral gavage doses of up to 125
Milnacipran did not induce tumors in Tg.rasH2 mice at any
Milnacipran was not mutagenic in the in vitro bacterial
reverse mutation assay (Ames test) or in the L5178Y TK +/-mouse lymphoma
forward mutation assay. Milnacipran was also not clastogenic in an in vitro
chromosomal aberration test in human lymphocytes or in the in vivo mouse
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
dose-related decrease in the fertility index at clinically relevant doses based
on body surface area.
Use In Specific Populations
Pregnancy Category C
There are no adequate or well-controlled studies in
pregnant women. Neonates exposed to dual reuptake inhibitors of serotonin and
norepinephrine (such as Savella), or selective serotonin reuptake inhibitors
late in the third trimester have developed complications that can arise
immediately upon delivery. Reproduction studies have been performed in rats,
rabbits and mice. Milnacipran was shown to increase embryo fetal and perinatal
lethality in rats and the incidence of a minor skeletal variation in rabbits at
doses below (rat) or approximately equal to (rabbit) the maximum recommended
human dose (MRHD) of 200 mg/day on a mg/m² basis. No effects were seen in mice
when treated with milnacipran during the period of organogenesis at doses up to
3 times the MHRD on a mg/m² basis. Because animal reproduction studies are not
always predictive of human response, Savella should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.
Physicians are advised to recommend that pregnant
patients taking Savella enroll in the Savella Pregnancy Registry. Enrollment is
voluntary and may be initiated by pregnant patients or their healthcare
providers by contacting the registry at 1-877-643-3010 or by email at [email protected]
Data forms may also be downloaded from the registry website at www.savellapregnancyregistry.com.
Neonates exposed to dual reuptake inhibitors of serotonin
and norepinephrine, or selective serotonin reuptake inhibitors late in the
third trimester have developed complications that can arise immediately upon
delivery and require prolonged hospitalization, respiratory support, and tube
feeding. Such complications can arise immediately upon delivery. Monitor
neonates for reported clinical findings such as 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 [see WARNINGS AND PRECAUTIONS].
Studies were conducted in rats, rabbits and mice with
dosing of milnacipran during the period of organogenesis. In rats, milnacipran
was shown to increase embryo fetal lethality at doses of 5 mg/kg/day (0.25
times the MRHD on a mg/m² basis). In rabbits, dose-dependent increases in the incidence
of the skeletal variation of an extra single rib were observed in several pups
from multiple litters in the absence of maternal toxicity at 15 mg/kg/day (1.5
times the MRHD on a mg/m² basis). The clinical significance of this finding is
unknown. In mice, no embryotoxic or teratogenic effects were seen at doses up
to 125 mg/kg/day (3 times the MHRD on a mg/m² basis).
With peri-and postnatal exposure to oral milnacipran in
rats, decreases in viability and body weight were observed on Postpartum Day 4
at a dose of 5 mg/kg/day (approximately 0.25 times the MRHD on a mg/m² basis).
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).
Milnacipran is present in the milk of lactating women
treated with Savella. In a pharmacokinetic study, a single, oral dose of 50 mg
milnacipran HCl tablet was administered to 8 lactating women who were at least
12 weeks postpartum and weaning their infants. The maximum estimated daily
infant dose for milnacipran from breast milk (assuming mean milk consumption of
150 mL/kg/day) was 5% of the maternal dose based on peak plasma concentrations.
In most patients, peak concentrations of milnacipran in breast milk were seen
within 4 hours after the maternal dose. Because of the limited data regarding
infant exposure to Savella, caution should be exercised when Savella is
administered to a nursing woman.
Safety and effectiveness of Savella in a fibromyalgia
pediatric population below the age of 18 have not been established [see BOXED
WARNING, INDICATIONS AND USAGE, and WARNINGS AND PRECAUTIONS].
The use of Savella is not recommended in pediatric patients.
In controlled clinical studies of Savella, 402 patients
were 60 years or older, and no overall differences in safety and efficacy were
observed between these patients and younger patients.
In view of the predominant excretion of unchanged
milnacipran via kidneys and the expected decrease in renal function with age,
renal function should be considered prior to use of Savella in the elderly [see
DOSAGE AND ADMINISTRATION].
SNRIs, SSRIs, and Savella, have been associated with
cases of clinically significant hyponatremia in elderly patients, who may be at
greater risk for this adverse event [see WARNINGS AND PRECAUTIONS].