SAVELLA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SAVELLA (SAVELLA).
Selective serotonin and norepinephrine reuptake inhibitor (SNRI); also weakly inhibits dopamine reuptake. Binds to serotonin and norepinephrine transporters, increasing their extracellular concentrations.
| Metabolism | Primarily metabolized by CYP3A4 and CYP2D6; also undergoes N-demethylation and glucuronide conjugation. |
| Excretion | Renal excretion of unchanged drug and metabolites accounts for approximately 51-58% of the dose. Fecal excretion accounts for about 19-22%. The remainder is eliminated via other routes (e.g., oxidative metabolism and subsequent conjugation). |
| Half-life | Approximately 11 hours for milnacipran (SAVELLA). In the context of twice-daily dosing, steady state is reached within 2-3 days. |
| Protein binding | Approximately 13% bound to plasma proteins, primarily albumin. Binding is low and not concentration-dependent. |
| Volume of Distribution | Mean Vd is approximately 400 L (about 5.7 L/kg for a 70 kg person). This large Vd indicates extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 85-90%, with peak plasma concentrations achieved 2-4 hours after dosing. |
| Onset of Action | Oral administration: Clinical effects such as pain relief in fibromyalgia may be observed within 1-2 weeks, but full therapeutic benefit may take 3-4 weeks. |
| Duration of Action | With twice-daily dosing, plasma concentrations remain within the therapeutic range over the dosing interval. The duration of clinical effect is sustained with regular dosing. |
| Molecular Weight | 486.62 |
100 mg orally twice daily; may initiate at 50 mg twice daily and increase to 100 mg twice daily after 1 week.
| Dosage form | TABLET |
| Renal impairment | For GFR 30-59 mL/min: limit dose to 50 mg twice daily. For GFR <30 mL/min: not recommended. |
| Liver impairment | Child-Pugh Class A or B: limit dose to 50 mg twice daily. Child-Pugh Class C: not recommended. |
| Pediatric use | Not approved for use in pediatric patients under 18 years of age. |
| Geriatric use | No specific dose adjustment required, but use caution due to potential increased sensitivity; consider lower starting dose of 50 mg twice daily. |
| 1st trimester | Limited human data; animal studies show increased risk of fetal vascular malformations at high doses. Use only if benefit outweighs risk. |
| 2nd trimester | May cause fetal harm based on animal data; no adequate human studies. Avoid unless necessary. |
| 3rd trimester | Risk of neonatal withdrawal syndrome (e.g., irritability, feeding difficulties) if used near term. Consider tapering prior to delivery. |
Clinical note
Comprehensive clinical and safety monograph for SAVELLA (SAVELLA).
| Placental transfer | Crosses placenta in animal models; molecular weight low enough for transfer. Human data limited but likely crosses. |
| Breastfeeding | Excreted into human milk in low amounts; infant exposure estimated at 1-3% of maternal weight-adjusted dose. Monitor infant for somnolence, poor feeding, or irritability. Use caution, especially in preterm or ill infants. |
■ FDA Black Box Warning
Increased risk of suicidal ideation and behavior in children, adolescents, and young adults taking antidepressants. Monitor for worsening and emergence of suicidal thoughts and behaviors.
| Serious Effects |
Concomitant use with MAOIs (risk of serotonin syndrome)Severe hepatic impairment (Child-Pugh C)Uncontrolled narrow-angle glaucomaEnd-stage renal disease (CrCl <15 mL/min)
| Precautions | Suicidality: Monitor for clinical worsening and suicide risk., Serotonin syndrome: Risk with concomitant serotonergic drugs., Elevated blood pressure: Dose-dependent; monitor blood pressure regularly., Hepatic impairment: Not recommended in severe hepatic impairment., Discontinuation syndrome: Taper dose gradually., Angle-closure glaucoma: May precipitate mydriasis., Seizures: Use with caution in patients with seizure disorders. |
| Food/Dietary | No specific food interactions documented. However, taking with food can minimize gastrointestinal upset. Avoid alcohol due to additive CNS depression and potential worsening of hypotension. |
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| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | Pregnancy Category C. In animal studies, increased fetal skeletal and visceral malformations were observed at doses 2-5 times the maximum recommended human dose. In humans, insufficient data are available; risk cannot be ruled out. Avoid use in first trimester unless benefit outweighs risk. |
| Fetal Monitoring | Monitor for development of serotonin syndrome, especially if co-administered with other serotonergic drugs. Assess maternal vital signs, mood, and suicidal ideation. In third trimester, observe neonate for serotonergic toxidrome (agitation, hypertonia, tachypnea) and poor adaptation syndrome. |
| Fertility Effects | In animal studies, no impairment of fertility at clinically relevant doses. Human data insufficient. Potential for transient sexual dysfunction in both sexes; impact on fertility unknown. |
| Clinical Pearls | Savella (milnacipran) is a serotonin-norepinephrine reuptake inhibitor (SNRI) indicated for fibromyalgia. Unlike other SNRIs, it does not significantly inhibit CYP450 enzymes, reducing drug-drug interactions. Baseline blood pressure monitoring is essential due to dose-dependent hypertension. Titrate slowly to minimize gastrointestinal side effects; start at 12.5 mg once daily and increase gradually. Efficacy may take several weeks; avoid abrupt discontinuation to prevent withdrawal symptoms. |
| Patient Advice | Take Savella with food to reduce nausea. · Do not stop suddenly; taper under medical supervision. · Avoid alcohol, which can increase CNS depression. · Report signs of elevated blood pressure, such as severe headache or blurred vision. · Warn about the risk of serotonin syndrome if combined with other serotonergic drugs. |