Savella Tapering Guide
milnacipran
Boxed Warning
Suicidality risk in children, adolescents, and young adults under 25 during initial treatment.
Overview
Milnacipran is a serotonin-norepinephrine reuptake inhibitor (SNRI) approved in the US for fibromyalgia management. It has a roughly 3:1 selectivity for norepinephrine over serotonin reuptake inhibition.
12.5mg, 25mg, 50mg, 100mg
Tablets: 12.5mg, 25mg, 50mg, 100mg; Titration pack: 12.5mg and 25mg tablets
Category C (risk cannot be ruled out)
Mechanism of Action
Dual reuptake inhibitor of serotonin and norepinephrine with preferential activity at the norepinephrine transporter (NET > SERT, approximately 3:1 ratio).
Taper Notes
SNRI approved for fibromyalgia (not depression in the US). Short half-life (6–8 hours) requires BID dosing and produces a discontinuation syndrome similar to other SNRIs on abrupt cessation. Taper gradually with proportional reductions.
Maudsley Deprescribing Guidance
Reduce dose gradually over at least 1–2 weeks; transition to proportional ~10% reductions at lower doses. Short half-life means withdrawal symptoms can emerge within 24 hours of a missed dose — emphasize dosing consistency.
Common Withdrawal Symptoms
Interactions & Safety
Drug Interactions
- MAOIs — contraindicated (risk of serotonin syndrome)
- Serotonergic drugs increase serotonin syndrome risk
- Epinephrine and norepinephrine — enhanced pressor effects
Food Interactions
- Food does not significantly affect overall absorption (AUC unchanged)
- No specific food contraindications
Contraindications
- MAOIs within 14 days
- Uncontrolled narrow-angle glaucoma
- Known hypersensitivity to milnacipran
Toxicity
Serotonin syndrome risk. Hypertension and tachycardia. Hepatotoxicity reported rarely.
Pharmacokinetics
ADME Profile
Well absorbed (85–90% bioavailability). Tmax ~2–4 hours. Food does not affect AUC but delays Tmax.
~400 L
Hepatic — primarily conjugation (glucuronidation), not significantly CYP-mediated. Active desethyl metabolite.
Renal (55% unchanged, 24% as glucuronide conjugate).
13%
~60 L/hr
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