Inhibition of the reuptake of norepinephrine (NE) and serotonin (5-HT) can lead to cardiovascular effects. SNRIs, including Savella, have been associated with reports of increase in blood pressure.

In a double-blind, placebo-controlled clinical pharmacology study in healthy subjects designed to evaluate the effects of milnacipran on various parameters, including blood pressure at supratherapeutic doses, there was evidence of mean increases in supine blood pressure at doses up to 300 mg twice daily (600 mg/day). At the highest 300 mg twice daily dose, the mean increase in systolic blood pressure was up to 8.1 mm Hg for the placebo group and up to 10.0 mm Hg for the Savella treated group over the 12 hour steady state dosing interval. The corresponding mean increase in diastolic blood pressure over this interval was up to 4.6 mm Hg for placebo and up to 11.5 mm Hg for the Savella treated group.

In the 3-month placebo-controlled fibromyalgia clinical trials, Savella treatment was associated with mean increases of up to 3.1 mm Hg in systolic blood pressure (SBP) and diastolic blood pressure (DBP) [see Adverse Reactions (6.3)].

In the placebo-controlled trials, among fibromyalgia patients who were non-hypertensive at baseline, approximately twice as many patients in the Savella treatment arms became hypertensive at the end of the study (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg) compared with the placebo patients: 7.2% of patients in the placebo arm versus 19.5% of patients treated with Savella 100 mg/day and 16.6% of patients treated with Savella 200 mg/day. Among patients who met systolic criteria for pre-hypertension at baseline (SBP 120-139 mmHg), more patients became hypertensive at the end of the study in the Savella treatment arms than placebo: 9% of patients in the placebo arm versus 14% in both the Savella 100 mg/day and the Savella 200 mg/day treatment arms.

Among fibromyalgia patients who were hypertensive at baseline, more patients in the Savella treatment arms had a >15 mmHg increase in SBP than placebo at the end of the study: 1% of patients in the placebo arm versus 7% in the Savella 100 mg/day and 2% in the Savella 200 mg/day treatment arms. Similarly, more patients who were hypertensive at baseline and were treated with Savella had DBP increases > 10 mmHg than placebo at the end of study: 3% of patients in the placebo arm versus 8% in the Savella 100 mg/day and 6% in the Savella 200 mg/day treatment arms.

Sustained increases in SBP (increase of ≥ 15 mmHg on three consecutive post-baseline visits) occurred in 2% of placebo patients versus 9% of patients receiving Savella 100 mg/day and 6% of patients receiving Savella 200 mg/day. Sustained increases in DBP (increase of ≥ 10 mmHg on 3 consecutive post-baseline visits) occurred in 4% of patients receiving placebo versus 13% of patients receiving Savella 100 mg/day and 10% of patients receiving Savella 200 mg/day.

Sustained increases in blood pressure could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported.

Concomitant use of Savella with drugs that increase blood pressure and pulse has not been evaluated and such combinations should be used with caution [see Drug Interactions (7)].

Effects of Savella on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. Savella should be used with caution in these patients.

Blood pressure should be measured prior to initiating treatment and periodically measured throughout Savella treatment. Pre-existing hypertension and other cardiovascular disease should be treated before starting therapy with Savella. For patients who experience a sustained increase in blood pressure while receiving Savella, either dose reduction or discontinuation should be considered.