Side Effects of Savella (milnacipran)

Does Savella (milnacipran) cause side effects?

Savella (milnacipran) is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) used to treat pain associated with fibromyalgia. Savella affects neurotransmitters, chemicals nerves within the brain make and release in order to communicate with one another. 

Neurotransmitters either travel across the space between nerves, attach to receptors on the surface of nearby nerves, or they attach to receptors on the surface of the nerves that produced them. The neurotransmitters may be taken up by the nerve and released again (re-uptake). 

Savella prevents the reuptake of the neurotransmitters serotonin and epinephrine by nerves after they have been released. Since uptake is an important mechanism for removing released neurotransmitters and terminating their actions on adjacent nerves, the reduced uptake caused by Savella increases the effect of serotonin and norepinephrine in the brain. 

The mechanism responsible for its effectiveness for treating fibromyalgia is not known but Savella’s action is thought to involve its effects on serotonin and norepinephrine in the brain.

Common side effects of Savella include

Serious side effects of Savella include

Drug interactions of Savella include monoamine oxidase inhibitors (MAOIs) because it may lead to serious, sometimes fatal, reactions including very high body temperature, rigidity, rapid fluctuations of heart rate and blood pressure, extreme agitation progressing to delirium and coma.

  • Similar reactions may occur if Savella is combined with antipsychotics, tricyclic antidepressants or other drugs that affect serotonin in the brain (for example, tryptophan and sumatriptan).
  • Combining Savella with epinephrine or norepinephrine may lead to high blood pressure and abnormal heart beats because Savella increases epinephrine and norepinephrine.
  • Combining Savella with aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, or other drugs that are associated with bleeding may increase the risk of bleeding, because Savella is associated with bleeding. 

Taking Savella during pregnancy may cause serious lung problems or other complications in the baby. Tell your doctor right away if you become pregnant.  If you are pregnant, you may be listed on a pregnancy registry to track the effects of Savella on the baby.

Savella is excreted in human breast milk. The effect of Savella on nursing infants is not known. Breastfeeding should probably be avoided while taking Savella.

What are the important side effects of Savella (milnacipran)?

The most frequent side effects include:

Other side effects include:

  • seizures,
  • hypertensive crisis,
  • abnormal bleeding,
  • low blood sodium (hyponatremia), and
  • withdrawal syndrome.

Antidepressants may increase the risk of suicidal thinking and behavior in children and adolescents with depression. Patients who are started on milnacipran or another antidepressant should be observed closely for clinical worsening, suicidal thinking and behavior, or unusual behavior.

Savella (milnacipran) side effects list for healthcare professionals

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

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 TermSavella 100 mg/day
(n = 623) %
Savella 200 mg/day
(n = 934) %
All Savella
(n = 1557) %
(n = 652) %
Cardiac Disorders
Eye Disorders
  Vision blurred1221
Gastrointestinal Disorders
  Constipation 1615164
  Dry mouth5552
  Abdominal pain3332
General Disorders
  Chest pain3222
  Chest discomfort2111
  Upper respiratory tract infection 7666
  Heart rate increased5661
  Blood pressure increased3331
Metabolism and Nutrition Disorders
  Decreased appetite1220
Nervous System Disorders 
  Tension headache2111
Psychiatric Disorders
Respiratory Disorders
Skin Disorders
Vascular Disorders
  Hot flush1112122

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:

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 labeling information.

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 Experience

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, Parkinsonism

Psychiatric Disorders - aggression, anger, delirium, hallucination, homicidal ideation

Renal and Urinary Disorders - acute renal failure

Reproductive System and Breast Disorders - galactorrhea

Skin Disorders - erythema multiforme, Stevens Johnson syndrome

Vascular Disorders - hypertensive crisis

What drugs interact with Savella (milnacipran)?

Milnacipran undergoes minimal CYP450 related metabolism, with the majority of the dose excreted unchanged in urine (55%), and has a low binding to plasma proteins (13%). In vitro and in vivo studies showed that Savella is unlikely to be involved in clinically significant pharmacokinetic drug interactions.

Monoamine Oxidase Inhibitors (MAOIs)

See prescribing information.

Serotonergic Drugs

See prescribing information.


There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Savella with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.


Savella inhibits the reuptake of norepinephrine. Therefore concomitant use of Savella with epinephrine and norepinephrine may be associated with paroxysmal hypertension and possible arrhythmia.

CNS-active drugs

Given the primary CNS effects of Savella, caution should be used when it is taken in combination with other centrally acting drugs, including those with a similar mechanism of action.

Clomipramine: In a drug-drug interaction study, an increase in euphoria and postural hypotension was observed in patients who switched from clomipramine to Savella.

Clinically Important Interactions With Select Cardiovascular Agents

Digoxin: Use of Savella concomitantly with digoxin may be associated with potentiation of adverse hemodynamic effects. Postural hypotension and tachycardia have been reported in combination therapy with intravenously administered digoxin (1 mg). Co-administration of Savella and intravenous digoxin should be avoided.

Clonidine: Because Savella inhibits norepinephrine reuptake, co-administration with clonidine may inhibit clonidine's anti-hypertensive effect.

Does Savella (milnacipran) cause addiction or withdrawal symptoms?

Drug Abuse And Dependence

Controlled Substance

Milnacipran is not a controlled substance.


Milnacipran did not produce behavioral signs indicative of abuse potential in animal or human studies.


Milnacipran produces physical dependence, as evidenced by the emergence of withdrawal symptoms following drug discontinuation, similar to other SNRIs and SSRIs. These withdrawal symptoms can be severe. Thus, Savella should be tapered and not abruptly discontinued after extended use.


Savella (milnacipran) is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) used to treat pain associated with fibromyalgia. Common side effects of Savella include nausea, headache, constipation, dizziness, insomnia, flushing, excessive sweating, vomiting, palpitations, increased heart rate, dry mouth, and high blood pressure. Taking Savella during pregnancy may cause serious lung problems or other complications in the baby. Savella is excreted in human breast milk.

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