Savella

SAVELLA- milnacipran hydrochloride tablet, film coated
Lake Erie Medical & Surgical Supply DBA Quality Care Products LLC

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS

Savella is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of such drugs in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on Savella should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Savella is not approved for use in the treatment of major depressive disorder. Savella is not approved for use in pediatric patients [see Warnings and Precautions (5.1), Use in Specific Populations (8.4)].

1 INDICATIONS AND USAGE

Savella is indicated for the management of fibromyalgia.

Savella is not approved for use in pediatric patients [see Use in Specific Populations (8.4)].

2 DOSAGE AND ADMINISTRATION

Savella is given orally with or without food.

Taking Savella with food may improve the tolerability of the drug.

2.1 Recommended Dosing

The recommended dose of Savella 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.

Savella should be tapered and not abruptly discontinued after extended use [see Discontinuing Savella (2.4) and Warnings and Precautions (5.7)]

2.2 Patients with Renal Insufficiency

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

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

2.3 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.

2.4 Discontinuing Savella

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. Savella should be tapered and not abruptly discontinued after extended use [see Warnings and Precautions (5.7)].

2.5 Switching patients to or from a Monoamine Oxidase Inhibitor (MAOI)

At least 14 days should elapse between discontinuation of a MAOI and initiation of therapy with Savella. In addition, at least 5 days should be allowed after stopping Savella before starting a MAOI [see Contraindications (4.1)].

3 DOSAGE FORMS AND STRENGTHS

Film-coated, immediate-release tablets in four strengths: 12.5 mg, 25 mg, 50 mg, and 100 mg of milnacipran hydrochloride.

12.5 mg tablets are round, blue, “F” on one side, “L” on the reverse;
25 mg tablets are round, white, “FL” on one side, “25″ on the reverse;
50 mg tablets are oval, white, “FL” on one side, “50″ on the reverse;
100 mg tablets are oval, pink, “FL” on one side, “100″ on the reverse[see Description (11) and How Supplied/ Storage and Handling (16)].

4 CONTRAINDICATIONS

4.1 Monoamine Oxidase Inhibitors

Concomitant use of Savella in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated. In patients receiving a serotonin reuptake inhibitor in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. The effects of combined use of Savella and MAOIs have not been evaluated in humans. Therefore, it is recommended that Savella should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 5 days should be allowed after stopping Savella before starting an MAOI [see Dosage and Administration (2.5), Warnings and Precautions (5.2)].

4.2 Uncontrolled Narrow-Angle Glaucoma

In clinical trials, Savella was associated with an increased risk of mydriasis. Mydriasis has been reported with other dual reuptake inhibitors of norepinephrine and serotonin; therefore, do not use Savella in patients with uncontrolled narrow-angle glaucoma.

5 WARNINGS AND PRECAUTIONS

5.1 Suicide Risk

Savella is a selective serotonin and norepinephrine re-uptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders.

Patients, both adult and pediatric, with depression or other psychiatric disorders may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking these medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants, including drugs that inhibit the reuptake of norepinephrine and/or serotonin, may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

In the placebo-controlled clinical trials of adults with fibromyalgia, among the patients who had a history of depression at treatment initiation, the incidence of suicidal ideation was 0.5% in patients treated with placebo, 0% in patients treated with Savella 100 mg/day, and 1.3% in patients treated with Savella 200 mg/day. No suicides occurred in the short-term or longer-term (up to 1 year) fibromyalgia trials.

Pooled analyses of short-term placebo-controlled trials of drugs used to treat depression (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with these drugs compared to placebo in adults beyond age 24; there was a reduction in suicidality risk with antidepressants compared to placebo in adults age 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 drugs used to treat depression in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1. Risk Differences (Drug — Placebo) in the number of Cases of Suicidality, per 1000 patients treated
Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
< 18 14 additional cases
18-24 5 additional cases
Decreases Compared to Placebo
25-64 1 fewer case
≥ 65 6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, have been reported in adult and pediatric patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who may experience worsening depressive symptoms, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe or abrupt in onset, or were not part of the patient’s presenting symptoms.

If the decision has been made to discontinue treatment due to worsening depressive symptoms or emergent suicidality, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can produce withdrawal symptoms [see Dosage and Administration (2.1, 2.4), and Warnings and Precautions (5.7)].

Families and caregivers of patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Savella should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

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