What is the recommended dosing and titration schedule for Savella (milnacipran) in fibromyalgia, and how should the dose be adjusted in patients with mild hepatic impairment (Child‑Pugh A), renal impairment (creatinine clearance 30‑50 mL/min), and elderly patients (≥65 years)?

Savella (Milnacipran) Dosing for Fibromyalgia

Standard Dosing and Titration Schedule

Savella should be initiated at 12.5 mg once daily on day 1, then 12.5 mg twice daily on days 2–3, followed by 25 mg twice daily on days 4–7, and finally increased to the recommended target dose of 50 mg twice daily (100 mg/day total) starting on day 8. 1, 2, 3

Titration Algorithm

• Day 1: 12.5 mg once daily 1
• Days 2–3: 12.5 mg twice daily (25 mg/day total) 1
• Days 4–7: 25 mg twice daily (50 mg/day total) 1
• Day 8 onward: 50 mg twice daily (100 mg/day total) 1, 2

The target maintenance dose is 100 mg/day (50 mg twice daily), though some patients may benefit from escalation to 200 mg/day (100 mg twice daily) if tolerated. 4, 2, 3 In clinical trials, 84% of patients successfully escalated to the highest dose of 200 mg/day without tolerability issues. 2

Dose Adjustments for Special Populations

Severe Renal Impairment (CrCl <30 mL/min)

Patients with severe renal impairment (creatinine clearance <30 mL/min) should receive a reduced maintenance dose of 50 mg/day (25 mg twice daily). 1 No dosage recommendation can be provided for patients with end-stage renal disease. 1

Moderate Renal Impairment (CrCl 30–50 mL/min)

For moderate renal impairment (creatinine clearance 30–50 mL/min), reduce the maintenance dose to 50 mg twice daily (100 mg/day total) and monitor closely for adverse effects. 1 Consider further dose reduction to 25 mg twice daily if tolerability issues emerge. 1

Mild Hepatic Impairment (Child-Pugh A)

No dose adjustment is required for patients with mild hepatic impairment (Child-Pugh Class A). 1 Milnacipran undergoes minimal hepatic metabolism, making it relatively safe in this population. 1

Elderly Patients (≥65 Years)

No specific dose adjustment is required based solely on age ≥65 years; however, elderly patients should be monitored more closely for cardiovascular effects (tachycardia, hypertension) and may benefit from slower titration. 1, 3 Because elderly patients are more likely to have decreased renal function, assess creatinine clearance and adjust dosing accordingly if CrCl <50 mL/min. 1

Clinical Efficacy Expectations

Approximately 40% of patients treated with milnacipran 100–200 mg/day achieve at least 30% pain reduction, compared to 30% with placebo (NNT 6–10). 4 Using stricter responder criteria (at least 50% pain reduction), about 37% of milnacipran-treated patients respond versus 14% with placebo. 2

Beyond pain relief, milnacipran significantly improves fatigue, cognitive dysfunction, and global fibromyalgia symptoms, though it does not substantially affect sleep disturbance. 1, 5, 3

Common Adverse Effects and Management

The most common adverse events are nausea (NNH 5.7), constipation (NNH 13), and headache (NNH 29), which are typically mild to moderate and transient. 4, 2 Nausea occurs most frequently during dose escalation and usually resolves within the first week. 2

Cardiovascular effects including tachycardia and both hypertension and hypotension can occur; monitor heart rate and blood pressure, especially in elderly patients and those with pre-existing cardiovascular disease. 1, 3

Milnacipran increases bleeding risk, particularly when combined with NSAIDs, aspirin, or anticoagulants; avoid concomitant use when possible. 1

Discontinuation Rates

Adverse event withdrawals occur in approximately 14% of patients on 100 mg/day (NNH 14) and 7% on 200 mg/day (NNH 7.0), compared to placebo. 4 Overall withdrawals for any reason are more common with 200 mg (NNH 9) than 100 mg (NNH 23). 4

Critical Warnings

Milnacipran carries a black box warning for increased risk of suicidal thinking and behavior in patients under 24 years of age; monitor all patients closely for unusual changes in mood, behavior, or suicidal ideation, especially during initial treatment and dose changes. 1

Do not use milnacipran within 14 days of monoamine oxidase inhibitor (MAOI) therapy due to risk of serotonin syndrome. 1

Practical Implementation Tips

Start with the lowest dose (12.5 mg once daily) and follow the week-long titration schedule strictly to minimize nausea and other gastrointestinal side effects. 1, 2 Taking milnacipran with food may reduce nausea. 1

If a patient cannot tolerate 100 mg/day, maintain treatment at 50 mg/day (25 mg twice daily) rather than discontinuing, as some patients still derive benefit at this lower dose. 4

Milnacipran works best as part of a comprehensive treatment plan that includes aerobic and resistance exercise, patient education, and behavioral therapies. 1, 5