Milnacipran Hydrochloride

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Milnacipran hydrochloride 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 milnacipran hydrochloride 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. Milnacipran hydrochloride is not approved for use in the treatment of major depressive disorder. Milnacipran hydrochloride 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 ). • Milnacipran hydrochloride is not approved for use in pediatric patients ( 1 , 8.4 ).

5 WARNINGS AND PRECAUTIONS • Suicidality : Monitor for worsening of depressive symptoms and suicide risk ( 5.1 ). • Serotonin Syndrome : Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue milnacipran hydrochloride and any other serotonergic agents, and initiate supportive treatment ( 5.2 ). • Elevated Blood Pressure and Heart Rate : Milnacipran hydrochloride may increase blood pressure and heart rate. Measure blood pressure and heart rate prior to initiating treatment with milnacipran hydrochloride and monitor periodically throughout treatment ( 5.3 , 5.4 ). • Seizures : Cases have been reported with milnacipran hydrochloride therapy. Prescribe milnacipran hydrochloride with care in patients with a history of seizure disorder ( 5.5 ). • Hepatotoxicity : milnacipran hydrochloride may cause elevations of ALT and AST. Avoid concomitant use of milnacipran hydrochloride in patients with substantial alcohol use or chronic liver disease ( 5.6 ). • Discontinuation : Withdrawal symptoms have been reported in patients when discontinuing treatment with milnacipran hydrochloride. A gradual dose reduction is recommended ( 5.7 ). • Increased Risk of Bleeding : Milnacipran hydrochloride may increase the risk of bleeding events. Caution patients about the risk of bleeding associated with the concomitant use of milnacipran hydrochloride and NSAIDs, aspirin, or other drugs that affect coagulation ( 5.9 ). • History of Dysuria : Male patients with a history of obstructive uropathies may experience higher rates of genitourinary adverse events ( 5.11 ). • Sexual Dysfunction : Milnacipran hydrochloride use may cause symptoms of sexual dysfunction ( 5.12 ). 5.1 Suicide Risk Milnacipran hydrochloride 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 milnacipran hydrochloride 100 mg/day, and 1.3% in patients treated with milnacipran hydrochloride 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 non-psychiatric. 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 ), 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 milnacipran hydrochloride 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 Selective-serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), including milnacipran hydrochloride, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, tramadol, meperidine, methadone, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin i.e., MAOIs [see Contraindications ( 4 ), Drug Interactions ( 7 )] . Serotonin syndrome can also occur when these drugs are used alone. 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). The concomitant use of milnacipran hydrochloride with MAOIs is contraindicated. In addition, do not initiate milnacipran hydrochloride in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking milnacipran hydrochloride, discontinue milnacipran hydrochloride before initiating treatment with the MAOI [see Contraindications ( 4.1 ), Dosage and Administration ( 2.5 , 2.6 ), Drug Interactions ( 7.1 )] . Monitor all patients taking milnacipran hydrochloride for the emergence of serotonin syndrome. Discontinue treatment with milnacipran hydrochloride and any concomitant serotonergic agents immediately if the above events occur and initiate supportive symptomatic treatment. If concomitant use of milnacipran hydrochloride with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 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 milnacipran hydrochloride-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 milnacipran hydrochloride-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 milnacipran hydrochloride-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 milnacipran hydrochloride 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 milnacipran hydrochloride 100 mg BID for two weeks, the mean increase from baseline in SBP and DBP was 6 mmHg. Similar elevations occurred in milnacipran hydrochloride-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) 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) *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 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 milnacipran hydrochloride 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 milnacipran hydrochloride on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. milnacipran hydrochloride should be used with caution in these patients. Measure blood pressure prior to initiating treatment and periodically monitor blood pressure throughout milnacipran hydrochloride treatment. Treat pre-existing hypertension and other cardiovascular disease before starting therapy with milnacipran hydrochloride. For patients who experience a sustained increase in blood pressure while receiving milnacipran hydrochloride, either reduce the dose or discontinue treatment with milnacipran hydrochloride 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 milnacipran hydrochloride 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 milnacipran hydrochloride 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 milnacipran hydrochloride 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 milnacipran hydrochloride-treated patients when compared to placebo (8% in the milnacipran hydrochloride 50 mg BID and 100 mg BID treatment arms versus 0.3% in the placebo arm). Milnacipran hydrochloride 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 milnacipran hydrochloride treatment. Treat pre-existing tachyarrhythmias and other cardiac disease before starting therapy with milnacipran hydrochloride. For patients who experience a sustained increase in heart rate while receiving milnacipran hydrochloride, either reduce the dose or discontinue treatment with milnacipran hydrochloride if clinically warranted. 5.5 Seizures Milnacipran hydrochloride has not been systematically evaluated in patients with a seizure disorder. In clinical trials evaluating milnacipran hydrochloride in patients with fibromyalgia, seizures/convulsions have not been reported. However, seizures have been reported infrequently in patients treated with milnacipran hydrochloride for disorders other than fibromyalgia. milnacipran hydrochloride 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 milnacipran hydrochloride 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 milnacipran hydrochloride 100 mg/day (6%) and milnacipran hydrochloride 200 mg/day (7%), compared to the patients treated with placebo (3%). One patient receiving milnacipran hydrochloride 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 milnacipran hydrochloride 100 mg/day (3%) and milnacipran hydrochloride 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. Discontinue milnacipran hydrochloride in patients who develop jaundice or other evidence of liver dysfunction. Treatment with milnacipran hydrochloride should not be resumed unless another cause can be established. Milnacipran hydrochloride should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. 5.7 Discontinuation of Treatment with Milnacipran hydrochloride 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. Monitor patients for these symptoms when discontinuing treatment with milnacipran hydrochloride. Milnacipran hydrochloride should be tapered after extended use. Do not abruptly discontinue. 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 milnacipran hydrochloride. 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 milnacipran hydrochloride. Also, patients taking diuretics or who are otherwise volume-depleted may be at greater risk [see Geriatric Use ( 8.5 )] . Consider discontinuation of milnacipran hydrochloride 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 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake, including milnacipran hydrochloride, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants 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. Based on data from published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations ( 8.1 )]. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding associated with the concomitant use of milnacipran hydrochloride and NSAIDs, aspirin, or other drugs that affect coagulation [see Drug Interactions ( 7.7 )] . 5.10 Activation of Mania No activation of mania or hypomania was reported in the clinical trials evaluating effects of milnacipran hydrochloride 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, use milnacipran hydrochloride cautiously in patients with a history of mania. 5.11 Patients with a History of Dysuria Because of their noradrenergic effect, SNRIs including milnacipran hydrochloride, can affect urethral resistance and micturition. In the controlled fibromyalgia trials, dysuria occurred more frequently in patients treated with milnacipran hydrochloride (1%) than in placebo-treated patients (0.5%). Caution is advised in use of milnacipran hydrochloride 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 Sexual Dysfunction Use of SNRIs, including milnacipran hydrochloride, may cause symptoms of sexual dysfunction [see Adverse Reactions ( 6.1 , 6.2 )] . In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of milnacipran hydrochloride and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment. 5.13 Angle Closure Glaucoma The pupillary dilation that occurs following use of SNRI drugs including milnacipran hydrochloride may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.14 Concomitant Use with Alcohol In clinical trials, more patients treated with milnacipran hydrochloride 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, milnacipran hydrochloride should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

<table ID="_RefID0EQWAG" width="100%"><caption>Table 1: Risk Differences (Drug &#x2013; Placebo) in the number of Cases of Suicidality, per 1000 patients treated</caption><col width="17%"/><col width="83%"/><tbody><tr><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Age Range</content></paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph>&lt; 18</paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph>14 additional cases</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph>18-24</paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph>5 additional cases</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Decreases Compared to Placebo</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph>25-64</paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1 fewer case</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>&#x2265; 65</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>6 fewer cases</paragraph></td></tr></tbody></table>

<table ID="_RefID0EE3AG" width="100%"><caption>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)</caption><col width="23%"/><col width="11%"/><col width="13%"/><col width="14%"/><col width="12%"/><col width="14%"/><col width="14%"/><tbody><tr><td styleCode="Lrule Toprule " valign="top"/><td align="center" colspan="3" styleCode="Toprule " valign="top"><paragraph>Normotensive</paragraph></td><td align="center" colspan="3" styleCode="Rrule Toprule " valign="top"><paragraph>Hypertensive</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"/><td align="center" styleCode="Toprule " valign="top"><paragraph>n</paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph>Systolic</paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph>Diastolic</paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph>n</paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph>Systolic</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="top"><paragraph>Diastolic</paragraph></td></tr><tr><td align="center" styleCode="Lrule Toprule " valign="top"><paragraph>Placebo</paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph>39</paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph>0(2)</paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph>-1(1)</paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph>50</paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph>0(2)</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="top"><paragraph>0(2)</paragraph></td></tr><tr><td align="center" styleCode="Lrule " valign="top"><paragraph>50 mg BID^*</paragraph></td><td align="center" valign="top"><paragraph>92</paragraph></td><td align="center" valign="top"><paragraph>5(1)</paragraph></td><td align="center" valign="top"><paragraph>5(1)</paragraph></td><td align="center" valign="top"><paragraph>84</paragraph></td><td align="center" valign="top"><paragraph>5(2)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4(1)</paragraph></td></tr><tr><td align="center" styleCode="Lrule " valign="top"><paragraph> </paragraph></td><td align="center" valign="top"><paragraph> </paragraph></td><td align="center" valign="top"><paragraph> </paragraph></td><td align="center" valign="top"><paragraph> </paragraph></td><td align="center" valign="top"><paragraph> </paragraph></td><td align="center" valign="top"><paragraph> </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph> </paragraph></td></tr><tr><td align="center" styleCode="Lrule " valign="top"><paragraph>Placebo</paragraph></td><td align="center" valign="top"><paragraph>37</paragraph></td><td align="center" valign="top"><paragraph>0(2)</paragraph></td><td align="center" valign="top"><paragraph>-1(1)</paragraph></td><td align="center" valign="top"><paragraph>47</paragraph></td><td align="center" valign="top"><paragraph>-1(2)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>0(1)</paragraph></td></tr><tr><td align="center" styleCode="Botrule Lrule " valign="top"><paragraph>100 mg BID^{^}</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>82</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6(1)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>6(1)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>80</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>5(2)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4(1)</paragraph></td></tr></tbody></table>

<table ID="_RefID0E3ABG" width="100%"><caption>Table 3: Blood pressure changes in Phase 3 randomized controlled trials</caption><col width="38%"/><col width="21%"/><col width="21%"/><col width="20%"/><tbody><tr><td styleCode="Rrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Milnacipran</content> <content styleCode="bold">50 mg BID</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Milnacipran</content> <content styleCode="bold">100 mg BID</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph>FM patients normotensive at baseline who became hypertensive (defined as SBP &#x2265; 140 mmHg or DBP &#x2265; 90 mmHg on three consecutive post-baseline visits)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>20%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>17%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>7% </paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph>FM patients with sustained increases in SBP (increase of &#x2265; 15 mmHg on three consecutive post-baseline visits)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>9%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph>FM patients with sustained increases in DBP (increase of &#x2265; 10 mmHg on three consecutive post-baseline visits)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>10 %</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td align="center" colspan="4" styleCode="Rrule Lrule Toprule " valign="top"><paragraph> </paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph>FM patients hypertensive at baseline who had increases in SBP &#x2265; 15 mmHg at end of study</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>FM patients hypertensive at baseline who had increases in DBP &#x2265; 10 mmHg at end of study</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>3%</paragraph></td></tr></tbody></table>

6 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 Glenmark Pharmaceuticals Inc., USA at 1-888-721-7115 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 Milnacipran hydrochloride was evaluated in three double-blind placebo-controlled trials involving 2209 fibromyalgia patients (1557 patients treated with milnacipran hydrochloride 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 milnacipran hydrochloride 100 mg/day, 26% of patients treated with milnacipran hydrochloride 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 milnacipran hydrochloride 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 milnacipran hydrochloride 200 mg/day compared to milnacipran hydrochloride 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 milnacipran hydrochloride 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 milnacipran hydrochloride 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 Milnacipran hydrochloride-Treated Patients and Occurring More Frequently in Either Milnacipran hydrochloride Treatment Group Than in the Placebo Treatment Group) System Organ Class– Preferred Term Milnacipran hydrochloride 100 mg/day (n = 623) % Milnacipran hydrochloride 200 mg/day (n = 934) % All Milnacipran hydrochloride (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 milnacipran hydrochloride for up to 3 months experienced a mean weight loss of approximately 0.8 kg in both the milnacipran hydrochloride 100 mg/day and the milnacipran hydrochloride 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 milnacipran hydrochloride, 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 Milnacipran hydrochloride 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 milnacipran hydrochloride 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 milnacipran hydrochloride received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to milnacipran hydrochloride. 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 ― anosmia, convulsions (including grand mal), hyposmia, 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, decreased libido, delayed or absent orgasm Skin Disorders ― erythema multiforme, Stevens Johnson syndrome Vascular Disorders ― hypertensive crisis

<table ID="_RefID0EURBG" width="100%"><caption>Table 4: Treatment-Emergent Adverse Reaction Incidence in Placebo Controlled Trials in Fibromyalgia Patients (Events Occurring in at Least 2% of All Milnacipran hydrochloride-Treated Patients and Occurring More Frequently in Either Milnacipran hydrochloride Treatment Group Than in the Placebo Treatment Group)</caption><col width="30%"/><col width="18%"/><col width="18%"/><col width="18%"/><col width="16%"/><tbody><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">System Organ Class&#x2013; </content> <content styleCode="bold">Preferred Term </content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Milnacipran hydrochloride</content> <content styleCode="bold">100 mg/day</content> <content styleCode="bold">(n = 623) %</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Milnacipran hydrochloride</content> <content styleCode="bold">200 mg/day</content> <content styleCode="bold"> (n = 934) %</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">All</content> <content styleCode="bold">Milnacipran hydrochloride </content> <content styleCode="bold">(n = 1557) %</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo </content> <content styleCode="bold">(n = 652) %</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cardiac Disorders</content></paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Palpitations </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Tachycardia </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Eye Disorders</content></paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Vision blurred </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Nausea </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>35</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>39</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>37</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>20</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Constipation </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Vomiting </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Dry mouth </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Abdominal pain </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">General Disorders </content></paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Chest pain </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Chills </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Chest discomfort </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Infections</content></paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Upper respiratory tract infection </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Investigations</content></paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Heart rate increased </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Blood pressure increased </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Metabolism and Nutrition Disorders</content></paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Decreased appetite </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Headache </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>19</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>14</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Dizziness </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Migraine </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Paresthesia </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Tremor </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Hypoesthesia </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Tension headache </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Psychiatric Disorders</content></paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Insomnia </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>10</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Anxiety </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Respiratory Disorders</content></paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph>Dyspnea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Skin Disorders</content></paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Hyperhidrosis </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>8 </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>9 </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>9 </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Rash</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Pruritus </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Vascular Disorders</content></paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Hot flush </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>11</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph> Hypertension </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>7 </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>4 </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>5 </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph> Flushing</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td></tr></tbody></table>