Toledomin

Toledomin is indicated for the management of fibromyalgia. Toledomin is not approved for use in pediatric patients.

Toledomin is given orally with or without food. Taking Toledomin with food may improve the tolerability of the drug.

Recommended Dosing

The recommended dose of Toledomin is 100 mg/day (50 mg twice daily).

Based on efficacy and tolerability dosing may be titrated according to the following schedule:

Day 1: 12.5 mg once

Days 2-3: 25 mg/day (12.5 mg twice daily)

Days 4-7: 50 mg/day (25 mg twice daily)

After Day 7: 100 mg/day (50 mg twice daily)

Based on individual patient response, the dose may be increased to 200 mg/day (100 mg twice daily).

Doses above 200 mg/day have not been studied.

Toledomin should be tapered and not abruptly discontinued after extended use.

Patients With Renal Insufficiency

No dosage adjustment is necessary in patients with mild renal impairment.

Toledomin should be used with caution in patients with moderate renal impairment.

For patients with severe renal impairment (indicated by an estimated creatinine clearance of 5-29 mL/min), the maintenance dose should be reduced by 50% to 50 mg/day (25 mg twice daily).

Based on individual patient response, the dose may be increased to 100 mg/day (50 mg twice daily).

Toledomin is not recommended for patients with end-stage renal disease.

Patients With Hepatic Insufficiency

No dosage adjustment is necessary for patients with hepatic impairment. As with any drug, caution should be exercised in patients with severe hepatic impairment.

Discontinuing Toledomin

Withdrawal symptoms have been observed in clinical trials following discontinuation of milnacipran, as with other serotonin and norepinephrine re-uptake inhibitors (SNRIs) and selective serotonin re-uptake inhibitors (SSRIs). Patients should be monitored for these symptoms when discontinuing treatment. Toledomin should be tapered and not abruptly discontinued after extended use.

Switching A Patient To Or From A Monoamine Oxidase Inhibitor (MAOI) Intended To Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of a MAOI intended to treat psychiatric disorders and initiation of therapy with Toledomin. Conversely, at least 5 days should be allowed after stopping Toledomin before starting a MAOI intended to treat psychiatric disorders.

Use Of Toledomin With Other MAOIs Such As Linezolid Or Methylene Blue

Do not start Toledomin in a patient being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.

In some cases, a patient already receiving Toledomin therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Toledomin should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Toledomin may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Toledomin is unclear. The clinician should nevertheless be aware of the possibility of emergent symptoms of serotonin syndrome with such use.

Monoamine Oxidase Inhibitors (MAOIs)

The use of MAOIs intended to treat psychiatric disorders with Toledomin or within 5 days of stopping treatment with Toledomin is contraindicated because of an increased risk of serotonin syndrome. The use of Toledomin within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.

Starting Toledomin 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.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Suicide Risk

Toledomin 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 Toledomin 100 mg/day, and 1.3% in patients treated with Toledomin 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

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.

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 Toledomin should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Toledomin, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous 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 Toledomin with MAOIs intended to treat psychiatric disorders is contraindicated. Toledomin 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 Toledomin. Toledomin should be discontinued before initiating treatment with the MAOI.

If concomitant use of Toledomin with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with Toledomin and any concomitant serotonergic agents should be discontinued immediately if the above events occur, and supportive symptomatic treatment should be initiated.

Elevated Blood Pressure

A double-blind, placebo-controlled ambulatory blood pressure monitoring (ABPM) study was conducted to evaluate the effects of milnacipran (up to 200 mg/day) on blood pressure in 321 fibromyalgia patients. Among fibromyalgia patients who were normotensive at baseline, an analysis of the blood pressure findings demonstrated a substantially higher proportion of Toledomintreated 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 Toledomintreated 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 Toledomin-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 Toledomin 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 Toledomin 100 mg BID for two weeks, the mean increase from baseline in SBP and DBP was 6 mmHg. Similar elevations occurred in Toledomin-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)

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

Sustained increases in blood pressure may have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported.

Concomitant use of Toledomin with drugs that increase blood pressure and heart rate has not been evaluated and such combinations should be used with caution.

Effects of Toledomin on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. Toledomin should be used with caution in these patients.

Measure blood pressure prior to initiating treatment and periodically monitor blood pressure throughout Toledomin treatment. Treat pre-existing hypertension and other cardiovascular disease before starting therapy with Toledomin. For patients who experience a sustained increase in blood pressure while receiving Toledomin, either reduce the dose or discontinue treatment with Toledomin if clinically warranted.

Elevated Heart Rate

A double-blind, placebo-controlled ABPM study was conducted to evaluate the effects of milnacipran (up to 200 mg/day) on blood pressure in 321 fibromyalgia patients. Information on heart rate was also collected. Following treatment with Toledomin 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 Toledomin 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 Toledomin treatment was associated with mean increases in heart rate of approximately 7 to 8 beats per minute.

Increases in heart rate ≥ 20 beats per minute occurred more frequently in Toledomin-treated patients when compared to placebo (8% in the Toledomin 50 mg BID and 100 mg BID treatment arms versus 0.3% in the placebo arm).

Toledomin 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 Toledomin treatment. Treat pre-existing tachyarrhythmias and other cardiac disease before starting therapy with Toledomin. For patients who experience a sustained increase in heart rate while receiving Toledomin, either reduce the dose or discontinue treatment with Toledomin if clinically warranted.

Seizures

Toledomin has not been systematically evaluated in patients with a seizure disorder. In clinical trials evaluating Toledomin in patients with fibromyalgia, seizures/convulsions have not been reported. However, seizures have been reported infrequently in patients treated with Toledomin for disorders other than fibromyalgia. Toledomin should be prescribed with care in patients with a history of a seizure disorder.

Hepatotoxicity

In the placebo-controlled fibromyalgia trials, increases in the number of patients treated with Toledomin 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 Toledomin 100 mg/day (6%) and Toledomin 200 mg/day (7%), compared to the patients treated with placebo (3%). One patient receiving Toledomin 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 Toledomin 100 mg/day (3%) and Toledomin 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.

Toledomin should be discontinued in patients who develop jaundice or other evidence of liver dysfunction. Treatment with Toledomin should not be resumed unless another cause can be established.

Toledomin should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

Discontinuation Of Treatment With Toledomin

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 Toledomin. Toledomin should be tapered and not abruptly discontinued after extended use. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Toledomin. 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 Toledomin. Also, patients taking diuretics or who are otherwise volume-depleted may be at greater risk. Discontinuation of Toledomin 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.

Abnormal Bleeding

SSRIs and SNRIs, including Toledomin, 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 Toledomin and NSAIDs, aspirin, or other drugs that affect coagulation.

Activation Of Mania

No activation of mania or hypomania was reported in the clinical trials evaluating effects of Toledomin 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, Toledomin should be used cautiously in patients with a history of mania.

Patients With A History Of Dysuria

Because of their noradrenergic effect, SNRIs including Toledomin, can affect urethral resistance and micturition. In the controlled fibromyalgia trials, dysuria occurred more frequently in patients treated with Toledomin (1%) than in placebo-treated patients (0.5%). Caution is advised in use of Toledomin 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.

Angle Closure Glaucoma

The pupillary dilation that occurs following use of SNRI drugs including Toledomin may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Concomitant Use With Alcohol

In clinical trials, more patients treated with Toledomin developed elevated transaminases than did placebo treated patients. Because it is possible that milnacipran may aggravate pre-existing liver disease, Toledomin should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

Patient Counseling Information

See Medication Guide

Information For Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Toledomin and should counsel them in its appropriate use. A patient Medication Guide is available for Toledomin. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Toledomin:

Clinical Worsening And Suicide Risk

Patients and their families and caregivers should be advised that Toledomin is a selective norepinephrine and serotonin reuptake inhibitor and therefore belongs to the same class of drugs as antidepressants. Patients, their families, and their caregivers should be advised that patients with depression may be at increased risk for clinical worsening and/or suicidal ideation if they stop taking anti-depressant medication, change the dose, or start a new medication.

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, or other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during treatment with Toledomin or other drugs that inhibit the reuptake of norepinephrine and/or serotonin, and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Serotonin Syndrome

Patients should be cautioned about the risk of serotonin syndrome with concomitant use of Toledomin with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John's Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid).

Patients should be advised of the signs and symptoms associated with serotonin syndrome that may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be cautioned to seek medical care immediately if they experience these symptoms.

Elevated Blood Pressure And Heart Rate

Patients should be advised that Toledomin may increase their blood pressure and heart rate and that they should have their blood pressure and heart rate monitored at regular intervals when receiving treatment with Toledomin.

Abnormal Bleeding

Patients should be cautioned about the concomitant use of Toledomin and NSAIDs, aspirin, or other drugs that affect coagulation, since the combined use of agents that interfere with serotonin reuptake and these agents has been associated with an increased risk of abnormal bleeding.

Angle Closure Glaucoma

Patients should be advised that taking Toledomin can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

Ability To Drive And Use Machinery

Toledomin might diminish mental and physical capacities necessary to perform certain tasks such as operating machinery, including motor vehicles. Patients should be cautioned about operating machinery or driving motor vehicles until they are reasonably certain that Toledomin treatment does not affect their ability to engage in such activities.

Alcohol

Patients should talk to their healthcare provider about their alcohol intake prior to initiating treatment with Toledomin.

Discontinuation

Patients should be advised that withdrawal symptoms can occur when discontinuing treatment with Toledomin, particularly when discontinuation is abrupt.

Missing a Dose

Patients should be advised that if they miss a dose, they should skip the missed dose and take the next dose at their regular time.

Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during Toledomin therapy.

Patients should be encouraged to enroll in the Toledomin Pregnancy Registry if they become pregnant, preferably before any prenatal testing is done. This registry is collecting information about the safety of milnacipran during pregnancy. To enroll, patients or their healthcare providers may call the toll-free number 1-877-643-3010 , download data forms from our website, www.Toledominpregnancyregistry.com, or email the registry for further information at [email protected]

Nursing

Advise patients to notify their physician if they are breast feeding.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Dietary administration of milnacipran to rats at doses of 50 mg/kg/day (2 times the MRHD on a mg/m² basis) for 2 years caused a statistically significant increase in the incidence of thyroid C-cell adenomas and combined adenomas and carcinomas in males. A carcinogenicity study was conducted in Tg.rasH2 mice for 6 months at oral gavage doses of up to 125 mg/kg/day.

Milnacipran did not induce tumors in Tg.rasH2 mice at any dose tested.

Mutagenesis

Milnacipran was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) or in the L5178Y TK +/-mouse lymphoma forward mutation assay. Milnacipran was also not clastogenic in an in vitro chromosomal aberration test in human lymphocytes or in the in vivo mouse micronucleus assay.

Impairment of Fertility

Although administration of milnacipran to male and female rats had no statistically significant effect on mating or fertility at doses up to 80 mg/kg/day (4 times the MRHD on an mg/m² basis), there was an apparent dose-related decrease in the fertility index at clinically relevant doses based on body surface area.

Use In Specific Populations

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 Toledomin), 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, Toledomin 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 Toledomin enroll in the Toledomin 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.Toledominpregnancyregistry.com.

Clinical Consideration

Neonates exp

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

Toledomin was evaluated in three double-blind placebo-controlled trials involving 2209 fibromyalgia patients (1557 patients treated with Toledomin 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 Toledomin

100 mg/day, 26% of patients treated with Toledomin 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 Toledomin 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 Toledomin 200 mg/day compared to Toledomin 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 Toledomin 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 Toledomin 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 Toledomin-Treated Patients and Occurring More Frequently in Either Toledomin Treatment Group Than in the Placebo Treatment Group)

Weight Changes

In placebo-controlled fibromyalgia clinical trials, patients treated with Toledomin for up to 3 months experienced a mean weight loss of approximately 0.8 kg in both the Toledomin 100 mg/day and the Toledomin 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 Toledomin, 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 Toledomin 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 Toledomin 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.

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

Postmarketing Experience

The following additional adverse reactions have been identified from spontaneous reports of Toledomin received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to Toledomin. 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

Eye Disorders - accommodation disorder

Endocrine Disorders - hyperprolactinemia

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

There is limited clinical experience with Toledomin overdose in humans. In clinical trials, cases of acute ingestions up to 1000 mg, alone or in combination with other drugs, were reported with none being fatal.

In postmarketing experience, fatal outcomes have been reported for acute overdoses primarily involving multiple drugs but also with Toledomin only. The most common signs and symptoms included increased blood pressure, cardio-respiratory arrest, changes in the level of consciousness (ranging from somnolence to coma), confusional state, dizziness, and increased hepatic enzymes.

Management of Overdose

There is no specific antidote to Toledomin, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug.

An adequate airway, oxygenation, and ventilation should be assured and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Because there is no specific antidote for Toledomin, symptomatic care and treatment with gastric lavage and activated charcoal should be considered as soon as possible for patients who experience a Toledomin overdose.

Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial.

In managing overdose, the possibility of multiple drug involvement should be considered. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR).

Cardiovascular Electrophysiology

The effect of Toledomin on the QTcF interval was measured in a double-blind placebo-and positive-controlled parallel study in 88 healthy subjects using 600 mg/day Toledomin (3 to 6 times the recommended therapeutic dose for fibromyalgia). After baseline and placebo adjustment, the maximum mean QTcF change was 8 ms (2-sided 90% CI, 3-12 ms). This increase is not considered to be clinically significant.

Milnacipran is well absorbed after oral administration with an absolute bioavailability of approximately 85% to 90%. The exposure to milnacipran increased proportionally within the therapeutic dose range. It is excreted predominantly unchanged in urine (55%) and has a terminal elimination half-life of about 6 to 8 hours. Steady-state levels are reached within 36 to 48 hours and can be predicted from single-dose data. The active enantiomer, d-milnacipran, has a longer elimination half-life (8-10 hours) than the l-enantiomer (4-6 hours). There is no interconversion between the enantiomers.

Absorption and Distribution

Toledomin is absorbed following oral administration with maximum concentrations (Cmax) reached within 2 to 4 hours post dose. Absorption of Toledomin is not affected by food. The absolute bioavailability is approximately 85% to 90%. The mean volume of distribution of milnacipran following a single intravenous dose to healthy subjects is approximately 400 L.

Plasma protein binding is 13%.

Metabolism and Elimination

Milnacipran and its metabolites are eliminated primarily by renal excretion. Following oral administration of ¹⁴C-milnacipran hydrochloride, approximately 55% of the dose was excreted in urine as unchanged milnacipran (24% as l-milnacipran and 31% as d-milnacipran). The lmilnacipran carbamoyl-O-glucuronide was the major metabolite excreted in urine and accounted for approximately 17% of the dose; approximately 2% of the dose was excreted in urine as dmilnacipran carbamoyl-O-glucuronide. Approximately 8% of the dose was excreted in urine as the N-desethyl milnacipran metabolite.

Pharmacokinetics in Special Populations

Renal Impairment: Milnacipran pharmacokinetics were evaluated following single oral administration of 50 mg Toledomin to subjects with mild (creatinine clearance [CLcr] 50-80 mL/min), moderate (CLcr 30-49 mL/min), and severe (CLcr 5-29 mL/min) renal impairment and to healthy subjects (CLcr > 80 mL/min). The mean AUC0-∞ increased by 16%, 52%, and 199%, and terminal elimination half-life increased by 38%, 41%, and 122% in subjects with mild, moderate, and severe renal impairment, respectively, compared with healthy subjects.

No dosage adjustment is necessary for patients with mild renal impairment. Caution should be exercised in patients with moderate renal impairment. Dose adjustment is necessary in severe renal impairment patients.

Hepatic Impairment: Milnacipran pharmacokinetics were evaluated following single oral administration of 50 mg Toledomin to subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment and to healthy subjects. AUC0-∞ and T½ were similar in healthy subjects and subjects with mild and moderate hepatic impairment. However, subjects with severe hepatic impairment had a 31% higher AUC0-∞ and a 55% higher T½ than healthy subjects. Caution should be exercised in patients with severe hepatic impairment.

Elderly: Cmax and AUC parameters of milnacipran were about 30% higher in elderly ( > 65 years) subjects compared with young subjects due to age-related decreases in renal function.

No dosage adjustment is necessary based on age unless renal function is severely impaired.

Gender: Cmax and AUC parameters of milnacipran were about 20% higher in female subjects compared with male subjects. Dosage adjustment based on gender is not necessary.

Lactation study: 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 Toledomin, caution should be exercised when Toledomin is administered to a nursing woman.