Savella Side Effects Center

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Medical Editor: John P. Cunha, DO, FACOEP

What Is Savella?

Savella (milnacipran HCl) is a selective norepinephrine and serotonin reuptake inhibitor (SNRI) used to treat a chronic pain disorder called fibromyalgia.

What Are Side Effects of Savella?

Savella may cause serious side effects including:

hives,
difficulty breathing,
swelling of your face, lips, tongue, or throat,
mood or behavior changes,
depression,
anxiety,
panic attacks,
trouble sleeping,
impulsiveness,
irritableness,
agitation,
hostility,
aggression,
restlessness,
hyperactivity (mentally or physically),
thoughts of suicide,
little or no urination,
blurred vision,
tunnel vision,
eye pain or swelling,
seeing halos around lights,
seizure,
lightheadedness,
stomach pain (upper right side),
itching,
dark urine,
yellowing of the skin or eyes (jaundice),
headache,
confusion,
severe weakness,
vomiting,
problems with thinking or memory,
feeling unsteady,
racing thoughts,
increased energy,
unusual risk-taking behavior,
extreme happiness,
being irritable or talkative,
hallucinations,
fever,
sweating,
shivering,
fast heart rate,
muscle stiffness,
twitching,
loss of coordination,
nausea, and
diarrhea

Get medical help right away, if you have any of the symptoms listed above.

Common side effects of Savella include:

nausea,
vomiting,
upset stomach,
bloating,
dry mouth,
constipation,
loss of appetite,
dizziness,
drowsiness,
tired feeling,
increased sweating,
headache,
hot flashes (flushing),
swelling in your hands or feet,
sleep problems (insomnia),
weight changes,
decreased sex drive,
impotence, or
difficulty having an orgasm.

Savella is similar to some drugs used for the treatment of depression and other psychiatric disorders. Antidepressants such as Savella may increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults. Tell your doctor if this occurs while taking Savella. Tell your doctor if you have serious side effects of Savella including:

fast or pounding heartbeat,
painful or difficult urination,
seizures,
yellowing eyes or skin,
dark urine,
severe stomach or abdominal pain,
black or bloody stools,
vomit that looks like coffee grounds, or
easy bruising or bleeding.

Seek medical care or call 911 at once if you have the following serious side effects:

Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
Serious heart symptoms such as fast, irregular, or pounding heartbeats; fluttering in your chest; shortness of breath; and sudden dizziness, lightheadedness, or passing out;
Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors.

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

Dosage for Savella

The recommended dose of Savella is 100 mg/day (50 mg twice daily).

What Drugs, Substances, or Supplements Interact with Savella?

Savella may interact with blood thinners, clonidine, diuretics (water pills), digoxin, epinephrine, lithium, tramadol, tryptophan, migraine headache medicine, or antidepressants. Tell your doctor all medications you are taking.

Savella During Pregnancy and Breastfeeding

During pregnancy, Savella should be used only when prescribed. Babies born to mothers who have used this drug during the last 3 months of pregnancy may infrequently develop withdrawal symptoms such as feeding/breathing difficulties, seizures, muscle stiffness, or constant crying. If you notice any of these symptoms in your newborn, tell the doctor. It is unknown if this medication passes into breast milk. Discuss the risks and benefits with your doctor before breastfeeding. Do not stop using Savella suddenly, or you could have withdrawal symptoms such as dizziness, anxiety, feeling irritable, confusion, headache, ringing in your ears, and sleep problems.

Additional Information

Our Savella (milnacipran HCl) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

SLIDESHOW

Fibromyalgia Symptoms, Diagnosis & Treatment See Slideshow

Savella Consumer Information

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, depression, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), or have thoughts about suicide or hurting yourself.

Call your doctor at once if you have:

little or no urination;
blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
a seizure;
a light-headed feeling, like you might pass out;
liver problems--stomach pain (upper right side), itching, dark urine, jaundice (yellowing of the skin or eyes);
low sodium level--headache, confusion, severe weakness, vomiting, problems with thinking or memory, feeling unsteady; or
manic episodes--racing thoughts, increased energy, unusual risk-taking behavior, extreme happiness, being irritable or talkative.

Seek medical attention right away if you have symptoms of serotonin syndrome, such as: agitation, hallucinations, fever, sweating, shivering, fast heart rate, muscle stiffness, twitching, loss of coordination, nausea, vomiting, or diarrhea.

Some side effects may be more likely in older adults.

Common side effects may include:

nausea, vomiting, constipation;
dry mouth;
increased blood pressure;
fast or pounding heartbeats;
increased sweating, flushing (warmth, redness, or tingly feeling);
headache, dizziness; or
trouble sleeping.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

QUESTION

What characterizes fibromyalgia? See Answer

Savella Professional Information

SIDE EFFECTS

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

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, Takotsubo cardiomyopathy

Eye Disorders - accommodation disorder

Endocrine Disorders - hyperprolactinemia

Gastrointestinal Disorders - acute pancreatitis

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, decreased libido, delayed or absent orgasm

Skin Disorders - erythema multiforme, Stevens Johnson syndrome

Vascular Disorders - hypertensive crisis

DRUG INTERACTIONS

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 [see Pharmacokinetics in Special Populations].

Monoamine Oxidase Inhibitors (MAOIs)

[See DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].

Serotonergic Drugs

[See DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].

Triptans

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 [see WARNINGS AND PRECAUTIONS].

Catecholamines

SAVELLA inhibits the reuptake of norepinephrine. Therefore, concomitant use of SAVELLA with epinephrine and norepinephrine may be associated with paroxysmal hypertension and possible arrhythmia [see WARNINGS AND PRECAUTIONS].

CNS-active drugs

Given the primary CNS effects of SAVELLA, use caution 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). Avoid co-administration of SAVELLA and intravenous digoxin [see WARNINGS AND PRECAUTIONS].

Clonidine

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

Drug Abuse And Dependence

Controlled Substance

Milnacipran is not a controlled substance.

Abuse

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

Dependence

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, taper SAVELLA and do not abruptly discontinue after extended use [see WARNINGS AND PRECAUTIONS].

Read the entire FDA prescribing information for Savella (Milnacipran HCl Tablets)