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 γ-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.

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

• 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.

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.

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

• Suicidality: 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. See package insert for complete information.