Last updated: October 29, 2014

Trade Names: Savella

Drug Class: Antidepressant, serotononin/norepinephrine reuptake inhibitor (SNRI)

Preparations: 12.5-, 25-, 50-, 75-, 100-mg tablets

Dose: Administration with food and a slow  flexible dose escalation over several weeks  may reduce nausea and improve tolerability. For example, initially,  12.5 mg daily for 3 days, 12.5 mg twice daily for 4  days, 25 mg twice daily for 7 days,  37.5 mg twice daily  for 7 days and then 50 mg twice daily thereafter. Maximum dose is 200 mg a  day.

Indications: Fibromyalgia

Mechanism of Action: Increases synaptic concentrations of serotonin and  norepinephrine

Contraindications: Hypersensitivity.  Avoid for at least 14 days after patient has received an MAOI. Avoid in patients with uncontrolled narrow-angle glaucoma.

Precautions: May increase suicidality, particularly in children and adolescents. Risk of serotonin syndrome. Seizures reported. Avoid  with hepatic  disease.  May elevate blood pressure and heart rate.  If discontinuing, reduce dose gradually over weeks or months to prevent withdrawal symptoms.  Can exacerbate prostatism.

Pregnancy Risk: C

Adverse Effects
Common: Nausea, constipation, headache,  hot flashes, sweating, dizziness, palpitations, tachycardia, insomnia, difficulty with urination, dry mouth, weight loss
Less common: Hypertension, mild increase in LFTs, withdrawal syndrome with abrupt discontinuation (nausea, vomiting, diarrhea, anxiety, dizziness, sleep disturbances),seizures
Rarely: Inappropriate ADH, hyponatremia, increased  bleeding, fulminant hepatitis

Drug Interactions
Alcohol: Increased risk of elevated LFTs
MAOIs and serotonergic drugs: Risk of serotonin syndrome with concomitant use 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 such as MAOIs and linezolid and methylene blue.
Catecholamines: Increased risk of arrhythmia and hypertension
Clonidine: Antihypertensive effect is attenuated

Patient Instructions: Avoid alcohol use. Increased risk of suicide; contact  physician for suicidal thoughts or change in behavior. Patients should be advised of the risk factors for serotonin syndrome and symptoms that may include mental changes (e.g., agitation, hallucinations, delirium), increased heart rate and labile blood pressure, dizziness, sweating, flushing, fever, tremor, rigidity, nausea, vomiting, diarrhea. Monitor blood pressure.  Slow taper for discontinuation to prevent withdrawal symptoms.

Comments: Modestly more effective than placebo in fibromyalgia clinical  trials;  more patients receiving milnacipran  than placebo had a 30% or greater reduction in pain  (44.6% vs. 30.6%)  or a 50% or greater reduction in pain (27.7% vs. 18.1%).  Withdrawal for adverse effects was more common with milnacipran than placebo (17.8% vs. 13.9%).

Clinical Pharmacology: Well absorbed, 55% excreted  unchanged in urine, half-life 8 hours

Cost: $$$

Arnold LM, Gendreau RM, Palmer RH, et al. Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010;62:2745-56.  PMID:20496365.

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