Savella (Page 3 of 7)

5.4 Elevated Heart Rate

A double-blind, placebo-controlled ABPM study was conducted to evaluate the effects of milnacipran (up to 200 mg/day) on blood pressure in 321 fibromyalgia patients [see Warnings and Precautions (5.3)]. Information on heart rate was also collected. Following treatment with Savella 50mg BID for three weeks in patients who were normotensive at baseline, the mean increase in mean 24-hour heart rate from baseline was 13 beats per minute. After further treatment with Savella 100 mg BID for two weeks, the mean increase from baseline in heart rate was 13 beats per minute.

Similar trends were observed in the clinical trials where Savella treatment was associated with mean increases in heart rate of approximately 7 to 8 beats per minute [see Adverse Reactions (6.1].

Increases in heart rate ≥ 20 beats per minute occurred more frequently in Savella-treated patients when compared to placebo (8% in the Savella 50 mg BID and 100 mg BID treatment arms versus 0.3% in the placebo arm).

Savella has not been systematically evaluated in patients with a cardiac rhythm disorder.

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

5.5 Seizures

Savella has not been systematically evaluated in patients with a seizure disorder. In clinical trials evaluating Savella in patients with fibromyalgia, seizures/convulsions have not been reported. However, seizures have been reported infrequently in patients treated with Savella for disorders other than fibromyalgia. Savella should be prescribed with care in patients with a history of a seizure disorder.

5.6 Hepatotoxicity

In the placebo-controlled fibromyalgia trials, increases in the number of patients treated with Savella with mild elevations of ALT or AST (1-3 times the upper limit of normal, ULN) were observed. Increases in ALT were more frequently observed in the patients treated with Savella 100 mg/day (6%) and Savella 200 mg/day (7%), compared to the patients treated with placebo (3%). One patient receiving Savella 100 mg/day (0.2%) had an increase in ALT greater than 5 times the upper limit of normal but did not exceed 10 times the upper limit of normal. Increases in AST were more frequently observed in the patients treated with Savella 100 mg/day (3%) and Savella 200 mg/day (5%) compared to the patients treated with placebo (2%).

The increases of bilirubin observed in the fibromyalgia clinical trials were not clinically significant.

No case met the criteria of elevated ALT > 3x ULN and associated with an increase in bilirubin ≥ 2x ULN.

There have been cases of increased liver enzymes and reports of severe liver injury, including fulminant hepatitis with milnacipran from foreign postmarketing experience. In the cases of severe liver injury, there were significant underlying clinical conditions and/or the use of multiple concomitant medications. Because of underreporting, it is impossible to provide an accurate estimate of the true incidence of these reactions.

Savella should be discontinued in patients who develop jaundice or other evidence of liver dysfunction. Treatment with Savella should not be resumed unless another cause can be established.

Savella should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

5.7 Discontinuation of Treatment with Savella

Withdrawal symptoms have been observed in clinical trials following discontinuation of milnacipran, as with other SNRIs and SSRIs.

During marketing of milnacipran, and other SNRIs and SSRIs, there have been spontaneous reports of adverse events indicative of withdrawal and physical dependence occurring upon discontinuation of these drugs, particularly when discontinuation is abrupt. The adverse events include the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.

Patients should be monitored for these symptoms when discontinuing treatment with Savella. Savella should be tapered and not abruptly discontinued after extended use. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration (2.4)].

5.8 Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Savella. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SNRIs, SSRIs, or Savella. Also, patients taking diuretics or who are otherwise volume-depleted may be at greater risk [see Geriatric Use (8.5)]. Discontinuation of Savella should be considered in patients with symptomatic hyponatremia.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.9 Abnormal Bleeding

SSRIs and SNRIs, including Savella, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of Savella and NSAIDs, aspirin, or other drugs that affect coagulation.

5.10 Activation of Mania

No activation of mania or hypomania was reported in the clinical trials evaluating effects of Savella in patients with fibromyalgia. However those clinical trials excluded patients with current major depressive episode. Activation of mania and hypomania have been reported in patients with mood disorders who were treated with other similar drugs for major depressive disorder. As with these other agents, Savella should be used cautiously in patients with a history of mania.

5.11 Patients with a History of Dysuria

Because of their noradrenergic effect, SNRIs including Savella, can affect urethral resistance and micturition. In the controlled fibromyalgia trials, dysuria occurred more frequently in patients treated with Savella (1%) than in placebo-treated patients (0.5%). Caution is advised in use of Savella in patients with a history of dysuria, notably in male patients with prostatic hypertrophy, prostatitis, and other lower urinary tract obstructive disorders. Male patients are more prone to genitourinary adverse effects, such as dysuria or urinary retention, and may experience testicular pain or ejaculation disorders.

5.12 Angle Closure Glaucoma

The pupillary dilation that occurs following use of SNRI drugs including Savella may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.13 Concomitant Use with Alcohol

In clinical trials, more patients treated with Savella developed elevated transaminases than did placebo treated patients [see Warnings and Precautions (5.6)]. Because it is possible that milnacipran may aggravate pre-existing liver disease, Savella should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Patient Exposure

Savella was evaluated in three double-blind placebo-controlled trials involving 2209 fibromyalgia patients (1557 patients treated with Savella and 652 patients treated with placebo) for a treatment period up to 29 weeks.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Adverse Reactions Leading to Discontinuation

In placebo-controlled trials in patients with fibromyalgia, 23% of patients treated with Savella

100 mg/day, 26% of patients treated with Savella 200 mg/day discontinued prematurely due to adverse reactions, compared to 12% of patients treated with placebo. The adverse reactions that led to withdrawal in ≥ 1% of patients in the Savella treatment group and with an incidence rate greater than that in the placebo treatment group were nausea (milnacipran 6%, placebo 1%), palpitations (milnacipran 3%, placebo 1%), headache (milnacipran 2%, placebo 0%), constipation (milnacipran 1%, placebo 0%), heart rate increased (milnacipran 1%, placebo 0%), hyperhidrosis (milnacipran 1%, placebo 0%), vomiting (milnacipran 1%, placebo 0%), and dizziness (milnacipran 1% and placebo 0.5%). Discontinuation due to adverse reactions was generally more common among patients treated with Savella 200 mg/day compared to Savella 100 mg/day.

Most Common Adverse Reactions in Placebo Controlled Trials

In the placebo-controlled fibromyalgia patient trials, the most frequently occurring adverse reaction in clinical trials was nausea. The most common adverse reactions (incidence ≥ 5% and twice placebo) in patients treated with Savella were constipation, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth, and hypertension.

Table 4 lists all adverse reactions that occurred in at least 2% of patients treated with Savella at either 100 or 200 mg/day and at an incidence greater than that of placebo.

Table 4: Treatment-Emergent Adverse Reaction Incidence in Placebo Controlled Trials in Fibromyalgia Patients (Events Occurring in at Least 2% of All Savella-Treated Patients and Occurring More Frequently in Either Savella Treatment Group Than in the Placebo Treatment Group)
System Organ Class–
Preferred Term
Savella
100 mg/day
(n = 623) %
Savella
200 mg/day
(n = 934) %
All Savella
(n = 1557) %
Placebo
(n = 652) %
Cardiac Disorders
Palpitations 8 7 7 2
Tachycardia 3 2 2 1
Eye Disorders
Vision blurred 1 2 2 1
Gastrointestinal Disorders
Nausea 35 39 37 20
Constipation 16 15 16 4
Vomiting 6 7 7 2
Dry mouth 5 5 5 2
Abdominal pain 3 3 3 2
General Disorders
Chest pain 3 2 2 2
Chills 1 2 2 0
Chest discomfort 2 1 1 1
Infections
Upper respiratory tract infection 7 6 6 6
Investigations
Heart rate increased 5 6 6 1
Blood pressure increased 3 3 3 1
Metabolism and Nutrition Disorders
Decreased appetite 1 2 2 0
Nervous System Disorders
Headache 19 17 18 14
Dizziness 11 10 10 6
Migraine 6 4 5 3
Paresthesia 2 3 2 2
Tremor 2 2 2 1
Hypoesthesia 1 2 1 1
Tension headache 2 1 1 1
Psychiatric Disorders
Insomnia 12 12 12 10
Anxiety 5 3 4 4
Respiratory Disorders
Dyspnea 2 2 2 1
Skin Disorders
Hyperhidrosis 8 9 9 2
Rash 3 4 3 2
Pruritus 3 2 2 2
Vascular Disorders
Hot flush 11 12 12 2
Hypertension 7 4 5 2
Flushing 2 3 3 1

Weight Changes

In placebo-controlled fibromyalgia clinical trials, patients treated with Savella for up to 3 months experienced a mean weight loss of approximately 0.8 kg in both the Savella 100 mg/day and the Savella 200 mg/day treatment groups, compared with a mean weight loss of approximately 0.2 kg in placebo-treated patients.

Genitourinary Adverse Reactions in Males

In the placebo-controlled fibromyalgia studies, the following treatment-emergent adverse reactions related to the genitourinary system were observed in at least 2% of male patients treated with Savella, and occurred at a rate greater than in placebo-treated male patients: dysuria, ejaculation disorder, erectile dysfunction, ejaculation failure, libido decreased, prostatitis, scrotal pain, testicular pain, testicular swelling, urinary hesitation, urinary retention, urethral pain, and urine flow decreased.

Other Adverse Reactions Observed During Clinical Trials of Savella in Fibromyalgia

Following is a list of frequent (those occurring on one or more occasions in at least 1/100 patients) treatment-emergent adverse reactions reported from 1824 fibromyalgia patients treated with Savella for periods up to 68 weeks. The listing does not include those events already listed in Table 4, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening.

Adverse reactions are categorized by body system and listed in order of decreasing frequency. Adverse reactions of major clinical importance are described in the Warnings and Precautions section (5).

Gastrointestinal Disorders — diarrhea, dyspepsia, gastroesophageal reflux disease, flatulence, abdominal distension

General Disorders — fatigue, peripheral edema, irritability, pyrexia

Infections — urinary tract infection, cystitis

Injury, Poisoning, and Procedural Complications — contusion, fall

Investigations — weight decreased or increased

Metabolism and Nutrition Disorders — hypercholesterolemia

Nervous System Disorders — somnolence, dysgeusia

Psychiatric Disorders — depression, stress

Skin Disorders — night sweats

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