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Milnacipran Hydrochloride

FDA Drug Information • Also known as: Milnacipran Hydrochloride, Savella

Brand Names
Milnacipran Hydrochloride, Savella
Dosage Form
POWDER
Product Type
BULK INGREDIENT

⚠ Boxed Warning (Black Box)

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS SAVELLA is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of such drugs in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on SAVELLA should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. SAVELLA is not approved for use in the treatment of major depressive disorder. SAVELLA is not approved for use in pediatric patients [see Indications and Usage ( 1 ), Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.4 )]. WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS See full prescribing information for complete boxed warning.

  • Increased risk of suicidal ideation, thinking, and behavior in children, adolescents, and young adults taking antidepressants for major depressive disorder (MDD) and other psychiatric disorders ( 5.1 ).
  • SAVELLA is not approved for use in pediatric patients ( 1 , 8.4 ).

    • Description

    11 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. The structural formula is: 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 C15H23ClN2O 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. The film coat contains the following additional inactive ingredients: 12.5 mg: FD&C Blue #2 Aluminum Lake, polyvinyl alcohol, polyethylene glycol, titanium dioxide 25 mg: Polyvinyl alcohol, polyethylene glycol, titanium dioxide 50 mg: Polyvinyl alcohol, polyethylene glycol, titanium dioxide 100 mg: FD&C Red #40 Aluminum Lake, polyvinyl alcohol, polyethylene glycol, titanium dioxide The structural formula is 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.

    What Is Milnacipran Hydrochloride Used For?

    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 )] .

  • SAVELLA ® is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the management of fibromyalgia ( 1 ).
  • SAVELLA is not approved for use in pediatric patients ( 1 ).

    • Dosage and Administration

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

  • Administer SAVELLA in two divided doses per day ( 2.1 ).
  • Based on efficacy and tolerability, dosing may be titrated according to the following schedule ( 2.1 ): 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 ( 2.1 ).
  • May be increased to 200 mg/day based on individual patient response ( 2.1 ).
  • Adjust dose in patients with severe renal impairment ( 2.2 ). 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. Taper SAVELLA and do not abruptly discontinue after extended use [see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.7 )] . 2.2 Patients with Renal Insufficiency No dosage adjustment is necessary in patients with mild renal impairment. Use SAVELLA 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), reduce the maintenance dose 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, exercise caution 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). Monitor patients for these symptoms when discontinuing treatment. Taper SAVELLA and do not abruptly discontinue after extended use [see Warnings and Precautions ( 5.7 )] . 2.5 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 SAVELLA. Conversely, allow at least 5 days after stopping SAVELLA before starting a MAOI intended to treat psychiatric disorders [see Contraindications ( 4.1 )] . 2.6 Use of SAVELLA with other MAOIs such as Linezolid or Methylene Blue Do not start SAVELLA in a patient being treated with linezolid or intravenous methylene blue because there is increased...

    • Side Effects (Adverse Reactions)

    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 AbbVie at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Patient Exposure SAVELLA was evaluated in three double-blind placebo-controlled trials involving 2209 fibromyalgia patients (1557 patients treated with SAVELLA and 652 patients treated with placebo) for a treatment period up to 29 weeks. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Adverse Reactions Leading to Discontinuation In placebo-controlled trials in patients with fibromyalgia, 23% of patients treated with SAVELLA 100 mg/day, 26% of patients treated with SAVELLA 200 mg/day discontinued prematurely due to adverse reactions, compared to 12% of patients treated with placebo. The adverse reactions that led to withdrawal in ≥ 1% of patients in the SAVELLA treatment group and with an incidence rate greater than that in the placebo treatment group were nausea (milnacipran 6%, placebo 1%), palpitations (milnacipran 3%, placebo 1%), headache (milnacipran 2%, placebo 0%), constipation (milnacipran 1%, placebo 0%), heart rate increased (milnacipran 1%, placebo 0%), hyperhidrosis (milnacipran 1%, placebo 0%), vomiting (milnacipran 1%, placebo 0%), and dizziness (milnacipran 1% and placebo 0.5%). Discontinuation due to adverse reactions was generally more common among patients treated with SAVELLA 200 mg/day compared to SAVELLA 100 mg/day. Most Common Adverse Reactions in Placebo Controlled Trials In the placebo-controlled fibromyalgia patient trials, the most frequently occurring adverse reaction in clinical trials was nausea. The most common adverse reactions (incidence ≥ 5% and twice placebo) in patients treated with SAVELLA were constipation, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth, and hypertension. Table 4 lists all adverse reactions that occurred in at least 2% of patients treated with SAVELLA at either 100 or 200 mg/day and at an incidence greater than that of placebo. Table 4: Treatment-Emergent Adverse Reaction Incidence in Placebo Controlled Trials in Fibromyalgia Patients (Events Occurring in at Least 2% of All SAVELLA-Treated Patients and Occurring More Frequently in Either SAVELLA Treatment Group Than in the Placebo Treatment Group) System Organ Class– Preferred Term SAVELLA 100 mg/day (n = 623) % SAVELLA 200 mg/day (n = 934) % All SAVELLA (n = 1557) % Placebo (n = 652) % Cardiac Disorders Palpitations 8 7 7 2 Tachycardia 3 2 2 1 Eye Disorders Vision blurred 1 2 2 1 Gastrointestinal Disorders Nausea 35 39 37 20 Constipation 16 15 16 4 Vomiting 6 7 7 2 Dry mouth 5 5 5 2 Abdominal pain 3 3 3 2 General Disorders Chest pain 3 2 2 2 Chills 1 2 2 0 Chest discomfort 2 1 1 1 Infections Upper respiratory tract infection 7 6 6 6 Investigations Heart rate increased 5 6 6 1 Blood pressure increased 3 3 3 1 Metabolism and Nutrition Disorders Decreased appetite 1 2 2 0 Nervous System Disorders Headache 19 17 18 14 Dizziness 11 10 10 6 Migraine 6 4 5 3 Paresthesia 2 3 2 2 Tremor 2 2 2 1 Hypoesthesia 1 2 1 1 Tension headache 2 1 1 1 Psychiatric Disorders Insomnia 12 12 12 10 Anxiety 5 3 4 4 Respiratory Disorders Dyspnea 2 2 2 1 Skin Disorders...

    Drug Interactions

    7 DRUG INTERACTIONS Milnacipran undergoes minimal CYP450 related metabolism, with the majority of the dose excreted unchanged in urine (55%) and has a low binding to plasma proteins (13%). In vitro and in vivo studies showed that SAVELLA is unlikely to be involved in clinically significant pharmacokinetic drug interactions [see Pharmacokinetics in Special Populations ( 12.3 )] .

  • SAVELLA is unlikely to be involved in clinically significant pharmacokinetic drug interactions ( 7 ).
  • Pharmacodynamic interactions of SAVELLA with other drugs can occur ( 7 ). 7.1 Monoamine Oxidase Inhibitors (MAOIs) The concomitant use of SSRIs and SNRIs, including SAVELLA, with MAOIs increases the risk of serotonin syndrome. The use of MAOIs intended to treat psychiatric disorders with SAVELLA or within 5 days of stopping treatment with SAVELLA is contraindicated. The use of SAVELLA within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. In addition, do not initiate SAVELLA 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 a MAOI such as linezolid or intravenous methylene blue in a patient taking SAVELLA, discontinue SAVELLA before initiating treatment with the MAOI [see Dosage and Administration ( 2.5 , 2.6 ), Contraindications ( 4 ), Drug Interactions ( 7.1 )] . 7.2 Serotonergic Drugs Serotonin syndrome can occur with use of SAVELLA and other serotonergic drugs (other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort), or with drugs that impair metabolism of serotonin (i.e., monoamine oxidase inhibitors). Advise patients of the signs and symptoms associated with serotonin syndrome and to seek medical care immediately if they experience these symptoms [see Dosage and Administration ( 2.5 , 2.6 ), Warnings and Precautions ( 5.2 )] . 7.3 Triptans There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of SAVELLA with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions ( 5.2 )] . 7.4 Catecholamines SAVELLA inhibits the reuptake of norepinephrine. Therefore, concomitant use of SAVELLA with epinephrine and norepinephrine may be associated with paroxysmal hypertension and possible arrhythmia [see Warnings and Precautions ( 5.3 , 5.4 )] . 7.5 CNS-active drugs Given the primary CNS effects of SAVELLA, use caution when it is taken in combination with other centrally acting drugs, including those with a similar mechanism of action. Clomipramine: In a drug-drug interaction study, an increase in euphoria and postural hypotension was observed in patients who...

    • Contraindications

    4 CONTRAINDICATIONS

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

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary 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 Warnings and Precautions ( 5.2 )] . The available data on SAVELLA use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks associated with exposure to serotonin and norepinephrine reuptake inhibitors (SNRIs) and selective-serotonin reuptake inhibitors (SSRIs), including SAVELLA, during pregnancy (see Clinical Considerations). Animal reproduction studies have been performed in rats, rabbits and mice. Milnacipran was shown to increase embryofetal 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/m 2 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/m 2 basis (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Clinical Consideration Maternal adverse reactions Use of SAVELLA in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.9 )]. Fetal/Neonatal adverse reactions Neonates exposed to SNRIs or SSRIs, including SAVELLA, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise...

    Overdosage

    10 OVERDOSAGE Clinical Presentation There is limited clinical experience with SAVELLA 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 SAVELLA 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 SAVELLA, 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. Ensure adequate airway, oxygenation, and ventilation and monitor cardiac rhythm and vital signs. 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 SAVELLA, consider symptomatic care and treatment with gastric lavage and activated charcoal as soon as possible for patients who experience a SAVELLA 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, consider the possibility of multiple drug involvement. 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).

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING 50-mg tablets: White, oval-shaped, film-coated tablets, debossed with “FL” on one side and “50” on the reverse side Bottles of approximately 1920 film-coated tablets, NDC 55154-4626-8 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] .

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.