This information is not for clinical use. These highlights do not include all the information needed to use Savella safely and effectively. Before taking Savella please consult with your doctor. See full prescribing information for Savella.

Warning

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS 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. 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 [see Indications and Usage (1), Warnings and Precautions (5.1), Use in Specific Populations (8.4)]. WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS See full prescribing information for complete boxed warning. Increased risk of suicidal ideation, thinking, and behavior in children, adolescents, and young adults taking antidepressants for major depressive disorder (MDD) and other psychiatric disorders (5.1). Savella is not approved for use in pediatric patients (1, 8.4).

Indications And Usage

Savella is indicated for the management of fibromyalgia. Savella is not approved for use in pediatric patients [see Use in Specific Populations (8.4)]. Savella® is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the management of fibromyalgia (1). Savella is not approved for use in pediatric patients (1).

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Dosage Forms And Strengths

Film-coated, immediate-release tablets in four strengths: 12.5 mg, 25 mg, 50 mg, and 100 mg of milnacipran hydrochloride. 12.5 mg tablets are round, blue, "F" on one side, "L" on the reverse; 25 mg tablets are round, white, "FL" on one side, "25" on the reverse; 50 mg tablets are oval, white, "FL" on one side, "50" on the reverse; 100 mg tablets are oval, pink, "FL" on one side, "100" on the reverse [see Description (11) and How Supplied/ Storage and Handling (16)]. Tablets: 12.5 mg, 25 mg, 50 mg, 100 mg (3)

Contraindications

Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with Savella or within 5 days of stopping treatment with Savella. Do not use Savella within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start Savella in a patient who is being treated with linezolid or intravenous methylene blue (4.1, 5.2). 4.1 Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with Savella or within 5 days of stopping treatment with Savella is contraindicated because of an increased risk of serotonin syndrome. The use of Savella within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.5), Warnings and Precautions (5.2)]. Starting Savella in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.6), Warnings and Precautions (5.2)].

Warning and Cautions

Suicidality: Monitor for worsening of depressive symptoms and suicide risk (5.1). Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including Savella, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines and St. John's Wort). If such symptoms occur, discontinue Savella and initiate supportive treatment. If concomitant use of Savella with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment and dose increases (5.2). Elevated blood pressure and heart rate: Savella may increase blood pressure and heart rate. In an ambulatory blood pressure monitoring study, a substantially higher proportion of Savella-treated patients experienced clinically significant blood pressure and heart rate elevations as compared with placebo-treated patients. Measure blood pressure and heart rate prior to initiating treatment with Savella and monitor periodically throughout treatment (5.3, 5.4). Seizures: Cases have been reported with Savella therapy. Prescribe Savella with care in patients with a history of seizure disorder (5.5). 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 (5.6). Discontinuation: Withdrawal symptoms have been reported in patients when discontinuing treatment with Savella. A gradual dose reduction is recommended (5.7). 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 (5.9). Male patients with a history of obstructive uropathies may experience higher rates of genitourinary adverse events (5.11). 5.1 Suicide Risk 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 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated < 18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 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 (2.1, 2.4), and Warnings and Precautions (5.7)]. 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. 5.2 Serotonin Syndrome 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, amphetamines, 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 methylene blue). 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 (4.1), Dosage and Administration (2.5, 2.6)]. If concomitant use of Savella with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, 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. 5.3 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 Savella-treated 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 Savella-treated 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) *Blood pressure measurements made after 3 weeks of milnacipran 50mg BID ^Blood pressure measurements made after 2 weeks of milnacipran 100mg BID Normotensive Hypertensive n Systolic Diastolic n Systolic Diastolic Placebo 39 0(2) -1(1) 50 0(2) 0(2) 50 mg BID* 92 5(1) 5(1) 84 5(2) 4(1) Placebo 37 0(2) -1(1) 47 -1(2) 0(1) 100 mg BID^ 82 6(1) 6(1) 80 5(2) 4(1) 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 controlled trials Milnacipran 50 mg BID Milnacipran 100 mg BID Placebo FM patients normotensive at baseline who became hypertensive (defined as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg on three consecutive post-baseline visits) 20% 17% 7% FM patients with sustained increases in SBP (increase of ≥ 15 mmHg on three consecutive post-baseline visits) 9% 6% 2% FM patients with sustained increases in DBP (increase of ≥ 10 mmHg on three consecutive post-baseline visits) 13% 10 % 4% FM patients hypertensive at baseline who had increases in SBP ≥ 15 mmHg at end of study 10% 7% 4% FM patients hypertensive at baseline who had increases in DBP ≥ 10 mmHg at end of study 8% 6% 3% 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 (7)]. 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. 5.4 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 Warnings and Precautions (5.3)]. 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 (6.1)]. 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 placebo arm). 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. 5.5 Seizures 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. 5.6 Hepatotoxicity 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. 5.7 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 and Administration (2.4)]. 5.8 Hyponatremia 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 (8.5)]. Discontinuation of Savella should be considered in patients with symptomatic hyponatremia. 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. 5.9 Abnormal Bleeding 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. 5.10 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. 5.11 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 ejaculation disorders. 5.12 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. 5.13 Concomitant Use with Alcohol In clinical trials, more patients treated with Savella developed elevated transaminases than did placebo treated patients [see Warnings and Precautions (5.6)]. 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.

Adverse Reactions

The most frequently occurring adverse reactions (≥ 5% and greater than placebo) were nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth, and hypertension (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Patient Exposure Savella was evaluated in three double-blind placebo-controlled trials involving 2209 fibromyalgia patients (1557 patients treated with Savella and 652 patients treated with placebo) for a treatment period up to 29 weeks. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Adverse Reactions Leading to Discontinuation In placebo-controlled trials in patients with fibromyalgia, 23% of patients treated with Savella 100 mg/day, 26% of patients treated with Savella 200 mg/day discontinued prematurely due to adverse reactions, compared to 12% of patients treated with placebo. The adverse reactions that led to withdrawal in ≥ 1% of patients in the Savella treatment group and with an incidence rate greater than that in the placebo treatment group were nausea (milnacipran 6%, placebo 1%), palpitations (milnacipran 3%, placebo 1%), headache (milnacipran 2%, placebo 0%), constipation (milnacipran 1%, placebo 0%), heart rate increased (milnacipran 1%, placebo 0%), hyperhidrosis (milnacipran 1%, placebo 0%), vomiting (milnacipran 1%, placebo 0%), and dizziness (milnacipran 1% and placebo 0.5%). Discontinuation due to adverse reactions was generally more common among patients treated with Savella 200 mg/day compared to Savella 100 mg/day. Most Common Adverse Reactions in Placebo Controlled Trials In the placebo-controlled fibromyalgia patient trials, the most frequently occurring adverse reaction in clinical trials was nausea. The most common adverse reactions (incidence ≥ 5% and twice placebo) in patients treated with Savella were constipation, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth, and hypertension. Table 4 lists all adverse reactions that occurred in at least 2% of patients treated with Savella at either 100 or 200 mg/day and at an incidence greater than that of placebo. Table 4: Treatment-Emergent Adverse Reaction Incidence in Placebo Controlled Trials in Fibromyalgia Patients (Events Occurring in at Least 2% of All Savella-Treated Patients and Occurring More Frequently in Either Savella Treatment Group Than in the Placebo Treatment Group) System Organ Class– Preferred Term Savella 100 mg/day (n = 623) % Savella 200 mg/day (n = 934) % All Savella (n = 1557) % Placebo (n = 652) % Cardiac Disorders Palpitations 8 7 7 2 Tachycardia 3 2 2 1 Eye Disorders Vision blurred 1 2 2 1 Gastrointestinal Disorders Nausea 35 39 37 20 Constipation 16 15 16 4 Vomiting 6 7 7 2 Dry mouth 5 5 5 2 Abdominal pain 3 3 3 2 General Disorders Chest pain 3 2 2 2 Chills 1 2 2 0 Chest discomfort 2 1 1 1 Infections Upper respiratory tract infection 7 6 6 6 Investigations Heart rate increased 5 6 6 1 Blood pressure increased 3 3 3 1 Metabolism and Nutrition Disorders Decreased appetite 1 2 2 0 Nervous System Disorders Headache 19 17 18 14 Dizziness 11 10 10 6 Migraine 6 4 5 3 Paresthesia 2 3 2 2 Tremor 2 2 2 1 Hypoesthesia 1 2 1 1 Tension headache 2 1 1 1 Psychiatric Disorders Insomnia 12 12 12 10 Anxiety 5 3 4 4 Respiratory Disorders Dyspnea 2 2 2 1 Skin Disorders Hyperhidrosis 8 9 9 2 Rash 3 4 3 2 Pruritus 3 2 2 2 Vascular Disorders Hot flush 11 12 12 2 Hypertension 7 4 5 2 Flushing 2 3 3 1 Weight Changes In placebo-controlled fibromyalgia clinical trials, patients treated with Savella for up to 3 months experienced a mean weight loss of approximately 0.8 kg in both the Savella 100 mg/day and the Savella 200 mg/day treatment groups, compared with a mean weight loss of approximately 0.2 kg in placebo-treated patients. Genitourinary Adverse Reactions in Males In the placebo-controlled fibromyalgia studies, the following treatment-emergent adverse reactions related to the genitourinary 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. Other Adverse Reactions Observed During Clinical Trials of Savella in Fibromyalgia Following is a list of frequent (those occurring on one or more occasions in at least 1/100 patients) treatment-emergent adverse reactions reported from 1824 fibromyalgia patients treated with Savella for periods up to 68 weeks. The listing does not include those events already listed in Table 4 , those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening. Adverse reactions are categorized by body system and listed in order of decreasing frequency. Adverse reactions of major clinical importance are described in the Warnings and Precautions section (5). Gastrointestinal Disorders — diarrhea, dyspepsia, gastroesophageal reflux disease, flatulence, abdominal distension General Disorders — fatigue, peripheral edema, irritability, pyrexia Infections — urinary tract infection, cystitis Injury, Poisoning, and Procedural Complications — contusion, fall Investigations — weight decreased or increased Metabolism and Nutrition Disorders — hypercholesterolemia Nervous System Disorders — somnolence, dysgeusia Psychiatric Disorders — depression, stress Skin Disorders — night sweats 6.2 Postmarketing Experience The following additional adverse reactions have been identified from spontaneous reports of Savella received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to Savella. However, because these adverse reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events include: Blood and Lymphatic System Disorders — leukopenia, neutropenia, thrombocytopenia Cardiac Disorders — supraventricular tachycardia, Takotsubo cardiomyopathy Eye Disorders — accommodation disorder Endocrine Disorders — hyperprolactinemia Gastrointestinal Disorders — acute pancreatitis Hepatobiliary Disorders — hepatitis Metabolism and Nutrition Disorders — anorexia, hyponatremia Musculoskeletal and Connective Tissue Disorders — rhabdomyolysis Nervous System Disorders — convulsions (including grand mal), loss of consciousness, Parkinsonism Psychiatric Disorders — aggression, anger, delirium, hallucination, homicidal ideation Renal and Urinary Disorders — acute renal failure Reproductive System and Breast Disorders — galactorrhea Skin Disorders — erythema multiforme, Stevens Johnson syndrome Vascular Disorders — hypertensive crisis

Drug Interactions

Milnacipran undergoes minimal CYP450 related metabolism, with the majority of the dose excreted unchanged in urine (55%), and has a low binding to plasma proteins (13%). In vitro and in vivo studies showed that Savella is unlikely to be involved in clinically significant pharmacokinetic drug interactions [see Pharmacokinetics in Special Populations (12.3)]. Savella is unlikely to be involved in clinically significant pharmacokinetic drug interactions (7). Pharmacodynamic interactions of Savella with other drugs can occur (7). 7.1 Monoamine Oxidase Inhibitors (MAOIs) [See Dosage and Administration (2.5 and 2.6), Contraindications (4.1), Warnings and Precautions (5.2)]. 7.2 Serotonergic Drugs [See Dosage and Administration (2.5 and 2.6), Contraindications (4.1), Warnings and Precautions (5.2)]. 7.3 Triptans There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Savella with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions (5.2)]. 7.4 Catecholamines Savella inhibits the reuptake of norepinephrine. Therefore concomitant use of Savella with epinephrine and norepinephrine may be associated with paroxysmal hypertension and possible arrhythmia [see Warnings and Precautions (5.3, 5.4)]. 7.5 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. Clomipramine: In a drug-drug interaction study, an increase in euphoria and postural hypotension was observed in patients who switched from clomipramine to Savella. 7.6 Clinically Important Interactions with Select Cardiovascular Agents Digoxin: Use of Savella concomitantly with digoxin may be associated with potentiation of adverse hemodynamic effects. Postural hypotension and tachycardia have been reported in combination therapy with intravenously administered digoxin (1 mg). Co-administration of Savella and intravenous digoxin should be avoided [see Warnings and Precautions (5.3, 5.4)]. Clonidine: Because Savella inhibits norepinephrine reuptake, co-administration with clonidine may inhibit clonidine's anti-hypertensive effect.

Use In Specific Populations

Pregnancy: Based on animal data, may cause fetal harm (8.1). 8.1 Pregnancy Pregnancy Category C Risk Summary 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. Pregnancy Registry 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. Clinical Consideration 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 (5.2)]. Animal Data 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). 8.3 Nursing Mothers 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. 8.4 Pediatric Use 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 (1), and Warnings and Precautions (5.1)]. The use of Savella is not recommended in pediatric patients. 8.5 Geriatric Use 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 (2.2)]. 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 (5.8)].