Savella® (milnacipran HCl) Tablets

Warnings

(description)

Clinical pharmacology

Indications and usage

Contraindications

Precautions

Adverse reactions

Dosage and administration

How supplied

Reference

Warnings

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, Use in Specific Populations]

(description)

Initial U.S. Approval: 2009
DESCRIPTION
Milnacipran hydrochloride is a selective norepinephrine and serotonin reuptake inhibitor; it inhibits norepinephrine uptake with greater potency than serotonin. It is a racemic mixture with the chemical name: (±)-[1R(S),2S(R)]-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide hydrochloride.

Milnacipran hydrochloride is a white to off-white crystalline powder with a melting point of 179°C. It is freely soluble in water, methanol, ethanol, chloroform, and methylene chloride and sparingly soluble in diethyl ether. It has an empirical formula of C15H23CIN20 and a molecular weight of 282.8 g/mol.

Savella is available for oral administration as film-coated tablets containing 12.5 mg, 25 mg, 50 mg, and 100 mg milnacipran hydrochloride. Each tablet also contains dibasic calcium phosphate, povidone, carboxymethylcellulose calcium, colloidal silicon dioxide, magnesium stearate, and talc as inactive ingredients. Additionally, the following inactive ingredients are also present as components of the film coat:

12.5 mg:
FD&C Blue #2 Aluminum Lake, hypromellose, polyethylene glycol, titanium dioxide

25 mg:
Hypromellose, polyethylene glycol, titanium dioxide

50 mg:
Hypromellose, polyethylene glycol, titanium dioxide

100 mg:
FD&C Red #40 Aluminum Lake, hypromellose, polyethylene glycol, titanium dioxide

Clinical pharmacology

CLINICAL PHARMACOLOGY
Mechanism of Action
The exact mechanism of the central pain inhibitory action of milnacipran and its ability to improve the symptoms of fibromyalgia in humans are unknown. Preclinical studies have shown that milnacipran is a potent inhibitor of neuronal norepinephrine and serotonin reuptake; milnacipran inhibits norepinephrine uptake with approximately 3-fold higher potency in vitro than serotonin without directly affecting the uptake of dopamine or other neurotransmitters. Milnacipran has no significant affinity for serotonergic (5-HT1-7), α- and β-adrenergic, muscarinic (M1-5), histamine (H1-4), dopamine (D1-5), opiate, benzodiazepine, and ?-aminobutyric acid (GABA) receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Milnacipran has no significant affinity for Ca++, K+, Na+ and Cl- channels and does not inhibit the activity of human monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase.

Indications and usage

INDICATIONS AND USAGE
Savella is indicated for the management of fibromyalgia.
Savella is not approved for use in pediatric patients.

DRUG INTERACTIONS
Savella is unlikely to be involved in clinically significant pharmacokinetic drug interactions.
Pharmacodynamic interactions of Savella with other drugs can occur.

USE IN SPECIFIC POPULATIONS
Pregnancy and nursing mothers: Use only if the potential benefit justifies the potential risk to the fetus or child.
To enroll in the Savella Pregnancy Registry call 1-877-643-3010 (toll free) or download data forms from the registry website: www.savellapregnancyregistry.com (8.1).

Contraindications

CONTRAINDICATIONS
Use of monoamine oxidase inhibitors concomitantly or in close temporal proximity.
Use in patients with uncontrolled narrow-angle glaucoma.

Precautions

WARNINGS AND PRECAUTIONS

Suicidally: Monitor for worsening of depressive symptoms and suicide risk
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions: Serotonin syndrome or NMS-like reactions have been reported with SNRIs and SSRIs. Discontinue Savella and initiate supportive treatment
Elevated blood pressure and heart rate: Cases have been reported with Savella. Monitor blood pressure and heart rate prior to initiating treatment with Savella and periodically throughout treatment
Seizures: Cases have been reported with Savella therapy. Prescribe Savella with care in patients with a history of seizure disorder
Hepatotoxicity: More patients treated with Savella than with placebo experienced mild elevations of ALT and AST. Rarely, fulminant hepatitis has been reported in patients treated with Savella. Avoid concomitant use of Savella in patients with substantial alcohol use or chronic liver disease
Discontinuation: Withdrawal symptoms have been reported in patients when discontinuing treatment with Savella. A gradual dose reduction is recommended
Abnormal Bleeding: Savella may increase the risk of bleeding events. Caution patients about the risk of bleeding associated with the concomitant use of Savella and NSAIDs, aspirin, or other drugs that affect coagulation
Male patients with a history of obstructive uropathies may experience higher rates of genitourinary adverse events

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.

To report SUSPECTED ADVERSE REACTIONS, contact Forest Pharmaceuticals, Inc., at (800) 678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dosage and administration

DOSAGE AND ADMINISTRATION - SUMMARY
Administer Savella in two divided doses per day.
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)

Recommended dose is 100 mg/day.
May be increased to 200 mg/day based on individual patient response.
Dose should be adjusted in patients with severe renal impairment.

DOSAGE AND ADMINISTRATION
Savella is given orally with or without food.
Taking Savella with food may improve the tolerability of the drug.

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 and Warnings and Precautions]

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.

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 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].

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].

How supplied

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

Storage
Store at 25°C (77°F); excursions permitted between 15°C and 30°C (between 59°F and 86°F) [See USP Controlled Room Temperature].

Reference

Package Insert data:
Revised: January 2009

Manufactured for:
Forest Pharmaceuticals, Inc.
Manufactured by:
Forest Laboratories, Inc.

Licensed from Pierre Fabre Medicament and Cypress Bioscience, Inc.

PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - 12.5 MG LABEL
Rx Only
NDC 0456-1512-60
Savella®
(milnacipran HCl)Tablets
12.5 mg
60 Tablets

Reference(s)

National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
Provides access to the latest drug monographs submitted to the Food and Drug Administration (FDA). Please review the latest applicable package insert for additional information and possible updates. A local search option of this data can be found here.