A double-blind, placebo-controlled ambulatory blood pressure monitoring (ABPM) study was conducted to evaluate the effects of milnacipran (up to 200 mg/day) on blood pressure in 321 fibromyalgia patients. Among fibromyalgia patients who were normotensive at baseline, an analysis of the blood pressure findings demonstrated a substantially higher proportion of milnacipran hydrochloride-treated patients had a hypertensive blood pressure measurement at the Week 4, 50 mg BID steady-state visit (17.7% [n=21/119]) and the Week 7, 100 mg BID steady-state visit (14.3% [n=15/105]) as compared to placebo-treated patients (3.7% [n=2/54] and 0% [0/49] at the Week 4 and Week 7 visits, respectively). Hypertension was defined as mean systolic blood pressure (SBP) ≥ 140 mmHg and change from baseline in mean SBP ≥ 10 mmHg or mean diastolic blood pressure (DBP) ≥ 90 mmHg and change from baseline in mean DBP ≥ 5 mmHg for the 12-hour period post AM study drug measurement at that visit. Furthermore, 1.9% (4/210) of milnacipran hydrochloride-treated and 0.9% (1/111) of placebo patients discontinued treatment for increases in blood pressure. 

The increased risk of blood pressure measurements in the hypertensive range in milnacipran hydrochloride-treated patients is supported by substantial increases in mean SBP and DBP measurements observed in the ABPM study. Table 2 shows that, following treatment with milnacipran hydrochloride 50 mg BID for three weeks in patients who were normotensive at baseline, the mean increase from baseline was 5 mmHg in systolic blood pressure (SBP) and diastolic blood pressure (DBP). After further treatment with milnacipran hydrochloride 100 mg BID for two weeks, the mean increase from baseline in SBP and DBP was 6 mmHg. Similar elevations occurred in milnacipran hydrochloride-treated patients who were hypertensive at baseline.

Table 2: Mean (Standard Error) Change from Baseline in Mean 24-hour Systolic and Diastolic Blood Pressure (mmHg) of Milnacipran or Placebo following 4 Weeks of Treatment (50mg BID) and a Subsequent 2 Weeks of Treatment (100mg BID)

Similar patterns of treatment-emergent blood pressure elevations were observed in Phase 3 and clinical pharmacology studies as manifested by an increased risk of new onset hypertension or substantial increases in end of study blood pressure measurements in patients with hypertension at baseline (Table 3).

Table 3: Blood pressure changes in Phase 3 randomized controlled trials

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

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

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

Measure blood pressure prior to initiating treatment and periodically monitor blood pressure throughout milnacipran hydrochloride treatment. Treat pre-existing hypertension and other cardiovascular disease before starting therapy with milnacipran hydrochloride. For patients who experience a sustained increase in blood pressure while receiving milnacipran hydrochloride, either reduce the dose or discontinue treatment with milnacipran hydrochloride if clinically warranted.