ADVERSE REACTIONS
Clinical Trial Data Sources
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.
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.
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%), and 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 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 2 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 2. 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 1, 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
Postmarketing Spontaneous Reports
The following additional adverse reactions have been identified from spontaneous reports of Savella received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to Savella. However, because these adverse reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events include:
Blood and Lymphatic System Disorders - leukopenia, neutropenia, thrombocytopenia
Cardiac Disorders - supraventricular tachycardia
Eye Disorders - accommodation disorder
Endocrine Disorders - hyperprolactinemia
Hepatobiliary Disorders - hepatitis
Metabolism and Nutrition Disorders - anorexia, hyponatremia
Musculoskeletal and Connective Tissue Disorders - rhabdomyolysis
Nervous System Disorders - convulsions (including grand mal), loss of consciousness, neuroleptic malignant syndrome, Parkinsonism, serotonin syndrome
Psychiatric Disorders - delirium, hallucination
Renal and Urinary Disorders - acute renal failure
Reproductive System and Breast Disorders - galactorrhea
Skin Disorders - erythema multiforme, Stevens Johnson syndrome
Vascular Disorders - hypertensive crisis
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