Savella (Page 2 of 7)

5.2 Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Savella, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of Savella with MAOIs intended to treat psychiatric disorders is contraindicated. Savella should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Savella. Savella should be discontinued before initiating treatment with the MAOI [see Contraindications (4.1), Dosage and Administration (2.5, 2.6)].

If concomitant use of Savella with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with Savella and any concomitant serotonergic agents should be discontinued immediately if the above events occur, and supportive symptomatic treatment should be initiated.

5.3 Elevated Blood Pressure

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 Savella-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 Savella-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 Savella-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 Savella 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 Savella 100 mg BID for two weeks, the mean increase from baseline in SBP and DBP was 6 mmHg. Similar elevations occurred in Savella-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)

*Blood pressure measurements made after 3 weeks of milnacipran 50mg BID

^Blood pressure measurements made after 2 weeks of milnacipran 100mg BID

Normotensive Hypertensive
n Systolic Diastolic n Systolic Diastolic
Placebo 39 0(2) -1(1) 50 0(2) 0(2)
50 mg BID* 92 5(1) 5(1) 84 5(2) 4(1)
Placebo 37 0(2) -1(1) 47 -1(2) 0(1)
100 mg BID^ 82 6(1) 6(1) 80 5(2) 4(1)

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
Milnacipran
50 mg BID
Milnacipran
100 mg BID
Placebo
FM patients normotensive at baseline who became hypertensive (defined as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg on three consecutive post-baseline visits) 20% 17%
7%
FM patients with sustained increases in SBP (increase of ≥ 15 mmHg on three consecutive post-baseline visits) 9% 6% 2%
FM patients with sustained increases in DBP (increase of ≥ 10 mmHg on three consecutive post-baseline visits) 13% 10 % 4%
FM patients hypertensive at baseline who had increases in SBP ≥ 15 mmHg at end of study 10% 7% 4%
FM patients hypertensive at baseline who had increases in DBP ≥ 10 mmHg at end of study 8% 6% 3%

Sustained increases in blood pressure may 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 heart rate 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.

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

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