Savella

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

• Take Savella exactly as your healthcare provider tells you to take it.
• Take Savella at about the same time each day.
• Your healthcare provider may need to change the dose of Savella until it is the right dose for you.
• Do not start or stop taking Savella without talking to your healthcare provider first. Stopping Savella suddenly can cause side effects. Savella may be taken with or without food.
• Alcohol may intensify some of the side effects of this medication.
• If you miss a dose of Savella, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Savella at the same time.

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:

• a light-headed feeling, like you might pass out;

• pounding heartbeats or fluttering in your chest;

• blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;

• little or no urinating;

• seizure (convulsions);

• easy bruising or bleeding (nosebleeds), or signs of stomach bleeding (bloody or tarry stools, coughing up blood);

• manic episodes--racing thoughts, increased energy, unusual risk-taking behavior, extreme happiness, being irritable or talkative;

• high levels of serotonin in the body--agitation, hallucinations, fever, fast heart rate, overactive reflexes, nausea, vomiting, diarrhea, loss of coordination, fainting;

• low levels of sodium in the body--headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;

• liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

• dangerously high blood pressure--severe headache, blurred vision, pounding in your neck or ears, nosebleed, anxiety, confusion, severe chest pain, shortness of breath, irregular heartbeats.

Some side effects may be more likely in older adults.

Common side effects may include:

• nausea, vomiting, constipation;

• dry mouth;

• increased sweating, flushing (warmth, redness, or tingly feeling);

• headache, dizziness;

• sleep problems (insomnia); or

• high blood pressure, pounding heartbeat.

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.

General

• Allow at least 2 weeks to elapse between discontinuance of an MAO inhibitor intended to treat psychiatric disorders and initiation of milnacipran and allow at least 5 days to elapse between discontinuance of milnacipran and initiation of MAO inhibitor therapy intended to treat psychiatric disorders.1 (See Contraindications and Serotonin Syndrome under Cautions and also see Specific Drugs under Interactions.)

• Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.1 32 33 34 (See Worsening of Depression and Suicidality Risk under Cautions.)

• Avoid abrupt discontinuance after extended use.1 6 Taper dosage gradually and monitor for withdrawal symptoms.1 6 If intolerable symptoms occur following dosage reduction or discontinuance, consider reinstituting previously prescribed dosage until symptoms abate, then resume more gradual dosage reductions.1 (See Withdrawal of Therapy under Cautions.)

Administration

Oral Administration

Administer orally twice daily in divided doses without regard to meals; however, taking the drug with food may improve tolerability.1

Dosage

Available as milnacipran hydrochloride; dosage expressed in terms of the salt.1

Adults

Titrate dosage, based on efficacy and tolerability, according to the following schedule:1 initially, 12.5 mg as a single dose on the first day of therapy.1 Increase to 12.5 mg twice daily (25 mg daily) on days 2 and 3, then increase to 25 mg twice daily (50 mg daily) on days 4–7.1 After day 7, recommended maintenance dosage is 50 mg twice daily (100 mg daily).1

Based on individual patient response, may increase dosage to 100 mg twice daily (200 mg daily).1

Prescribing Limits

Adults

Safety and efficacy of dosages >200 mg daily not evaluated.1

Special Populations

Hepatic Impairment

No dosage adjustment necessary.1 44 Use with caution in patients with severe hepatic impairment.1 Generally should not be prescribed to patients with substantial alcohol use or evidence of chronic hepatic disease.1 (See Hepatic Effects under Cautions and see also Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment necessary in mild renal impairment.1 Use with caution in patients with moderate renal impairment.1 In patients with severe renal impairment (Clcr of 5–29 mL/minute), reduce usual maintenance dosage by 50% to 50 mg daily (given as 25 mg twice daily).1 Based on individual patient response, may increase dosage to 100 mg daily (given as 50 mg twice daily).1 Not recommended in patients with end-stage renal disease.1

Geriatric Patients

No specific dosage recommendations at this time, but consider possibility of age-related decreases in renal function when selecting dosage.1 (See Renal Impairment under Dosage and Administration.)

Contraindications

• Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor intended to treat psychiatric disorders.1 Use of an MAO inhibitor intended to treat psychiatric disorders within 5 days of milnacipran discontinuance.1 (See Serotonin Syndrome under Cautions and also see Specific Drugs under Interactions.)

• Initiation of milnacipran in patients receiving MAO inhibitors such as linezolid or IV methylene blue.1 (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Possible worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs.1 32 33 34 35 (See Boxed Warning and also see Pediatric Use under Cautions.) However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.1 32 33 34 In clinical trials, no suicides were reported in adult fibromyalgia patients treated with milnacipran.1

Appropriately monitor and closely observe patients receiving milnacipran for any reason for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1 32 33 34

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality.1 33 34 Consider changing or discontinuing therapy in patients whose depression is persistently worse and in those with emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or not part of the patient’s presenting symptoms.1 33 If decision is made to discontinue therapy, taper milnacipran dosage as rapidly as is feasible but consider risks of abrupt discontinuance.1 (See Withdrawal of Therapy under Cautions.)

Prescribe in smallest quantity consistent with good patient management, to reduce risk of overdosage.1

Other Warnings and Precautions

Potentially life-threatening serotonin syndrome reported with SNRIs and SSRIs, including milnacipran, when used alone, but particularly during concurrent therapy with other serotonergic drugs (e.g., 5-HT1 receptor agonists [“triptans”], TCAs, buspirone, fentanyl, lithium, tramadol, tryptophan, St. John's wort [Hypericum perforatum]) and with drugs that impair the metabolism of serotonin (particularly MAO inhibitors, both those used to treat psychiatric disorders and others, such as linezolid and methylene blue).1 36 (See Contraindications under Cautions and also see Interactions.)

Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile BP, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1 36

Concurrent or recent (i.e., within 2 weeks) therapy with MAO inhibitors intended to treat psychiatric disorders is contraindicated.1 Use of an MAO inhibitor intended to treat psychiatric disorders within 5 days of milnacipran discontinuance also contraindicated.1 Do not initiate milnacipran in patients treated with other MAO inhibitors such as linezolid or IV methylene blue.1 (See Specific Drugs under Interactions.)

If concurrent therapy with other serotonergic drugs is clinically warranted, advise patient of potentially increased risk for serotonin syndrome, particularly during initiation of therapy and dosage increases.1

Monitor patients receiving milnacipran for the development of serotonin syndrome.1 If manifestations occur, immediately discontinue milnacipran and any concurrently administered serotonergic agents and initiate supportive and symptomatic treatment.1

Possible increased BP with SNRIs, including milnacipran.1 62 In an ambulatory blood pressure monitoring study, a substantially greater percentage of milnacipran-treated patients experienced clinically important BP elevations compared with placebo recipients.1 62 Sustained hypertension (i.e., treatment-emergent increases in SBP of ≥15 mm Hg and DBP of ≥10 mm Hg for 3 consecutive visits) reported; potential adverse consequences.1 Elevated BP requiring immediate treatment also reported.1 Effects of milnacipran on BP in patients with significant hypertension or cardiovascular disease not evaluated; use with caution.1

Concurrent use of milnacipran with other drugs that increase BP and heart rate not evaluated; use with caution.1 (See Interactions.)

Monitor BP prior to and periodically during therapy.1 Treat preexisting hypertension and other cardiovascular disease before initiating milnacipran therapy.1 If sustained increase in BP occurs during therapy, reduce milnacipran dosage or discontinue the drug, if clinically warranted.1

Increased heart rate reported with SNRIs, including milnacipran.1 62 In an ambulatory blood pressure monitoring study, a substantially greater percentage of milnacipran-treated patients experienced clinically important increases in heart rate compared with placebo recipients.1 62 Use in patients with cardiac rhythm disorders not systematically evaluated.1

Concurrent use of milnacipran with other drugs that increase BP and heart rate not evaluated; use with caution.1 (See Interactions.)

Treat preexisting tachyarrhythmias and other cardiovascular disease before initiating milnacipran therapy.1

Monitor heart rate prior to and periodically during therapy.1 If sustained increase in heart rate occurs during therapy, reduce milnacipran dosage or discontinue the drug, if clinically warranted.1

Milnacipran not systematically evaluated in patients with seizure disorders.1 Seizures not reported during clinical trials of milnacipran for fibromyalgia; seizures reported infrequently in patients receiving the drug for other conditions.1 Use with caution in patients with a history of seizure disorder.1

Increased serum transaminase (ALT, AST) concentrations and severe hepatic injury, including fulminant hepatitis, reported.1 Clinically important increases in serum bilirubin concentrations not reported.1

Discontinue milnacipran in any patient who develops jaundice or other evidence of hepatic dysfunction; do not resume therapy unless another cause for the hepatic dysfunction established.1

Use not generally recommended in patients with a history of substantial alcohol consumption or evidence of chronic hepatic disease.1

Withdrawal effects (e.g., dysphoric mood, irritability, agitation, dizziness, sensory disturbances [e.g., paresthesias, such as electric shock sensation], anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, seizures) reported following discontinuance of milnacipran, other SNRIs, and SSRIs, particularly when discontinuance was abrupt.1 Events generally self-limiting, but severe cases reported.1

Taper dosage gradually; monitor patients for withdrawal symptoms when discontinuing therapy.1 6 If intolerable symptoms occur following dosage reduction or discontinuance, consider reinstituting previously prescribed dosage until symptoms abate, then resume more gradual dosage reductions.1

Treatment with SSRIs and SNRIs, including milnacipran, may cause hyponatremia; in many cases, SIADH is apparent cause.1 48 49 51 54 Increased risk in patients who are volume-depleted, elderly, or taking diuretics.1 49 50 54 Consider drug discontinuance in patients with symptomatic hyponatremia.1 51 54

Possible increased risk of bleeding with SSRIs and SNRIs, including milnacipran; events ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.1 Concomitant use of aspirin, NSAIAs, warfarin, or other anticoagulants may increase risk.1 (See Drugs Affecting Hemostasis and Specific Drugs under Interactions and also see Advice to Patients.)

Activation of mania or hypomania not reported in fibromyalgia clinical trials, but has been reported with similar drugs in patients with major depressive disorder.1 5 Use with caution in patients with a history of mania.1

May affect urethral resistance and micturition.1 Increased risk of adverse GU effects (e.g., dysuria, urinary retention, testicular pain, ejaculation disorders) in male patients.1 Use with caution in patients with a history of dysuria, particularly in males with prostatic hypertrophy, prostatitis, and other lower urinary tract obstructive disorders.1

Pupillary dilation (mydriasis) occurs with SNRIs, including milnacipran, and may trigger an acute attack of angle-closure glaucoma (narrow-angle glaucoma) in patients with anatomically narrow angles who do not have a patent iridectomy.1 (See Advice to Patients.)

Possible hepatotoxicity when milnacipran and alcohol are used together.1 Avoid concomitant milnacipran use in patients with substantial alcohol consumption or evidence of chronic hepatic disease.1 (See Hepatic Effects under Cautions.)

Specific Populations

Category C.1

Pregnancy registry at 1-877-643-3010; registry information also available at or by email at pregnancyregistries2@INCResearch.com.1 66

Possible complications, sometimes severe and requiring prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care, in neonates exposed to SSRIs or SNRIs late in the third trimester; may arise immediately upon delivery.1 11 12 13 14 15 16

Distributed into milk; use with caution in nursing women.1 (See Distribution under Pharmacokinetics.)

Safety and efficacy not established in pediatric patients <18 years of age; not recommended for use in such patients.1

Milnacipran is an SNRI and is similar to some drugs used for the treatment of depression and other psychiatric disorders.1 FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during the first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and others).1 33 However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.35 No suicides occurred in these pediatric trials.1 33 35

Carefully consider these findings when assessing potential benefits and risks of milnacipran in a child or adolescent for any clinical use.1 33 34 35 (See Boxed Warning and Worsening of Depression and Suicidality Risk under Cautions.)

No overall differences in safety or efficacy relative to younger adults.1 Consider possible reduced renal clearance of the drug in geriatric patients.1 (See Geriatric Patients under Dosage and Administration and see Pharmacokinetics.)

Clinically important hyponatremia reported in geriatric patients.1 48 49 50 51 54 (See Hyponatremia/SIADH under Cautions.)

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.1 32 33 (See Boxed Warning and see Worsening of Depression and Suicidality Risk under Cautions.)

Pharmacokinetics not substantially affected by mild to moderate hepatic impairment.1 44 45 Use with caution in patients with severe hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration and see Pharmacokinetics.)

Use with caution in patients with moderate renal impairment.1 Dosage adjustment necessary in severe renal impairment (Clcr of 5–29 mL/minute).1 Use not recommended in patients with end-stage renal disease.1 (See Renal Impairment under Dosage and Administration and see Pharmacokinetics.)

Common Adverse Effects

Nausea,1 21 28 41 vomiting,1 28 41 constipation,1 21 28 41 headache,1 28 41 insomnia,1 28 dizziness,1 28 41 hot flushes,1 21 28 41 hyperhidrosis,1 28 41 palpitations,1 21 28 41 increased heart rate,1 41 hypertension,1 41 dry mouth,1 28 41 migraine.1

• Milnacipran is a racemic mixture of the 1S,2R and 1R,2S enantiomers;1 the more active 1S,2R enantiomer of milnacipran, levomilnacipran, is used in the treatment of major depressive disorder.61 Also pharmacologically related to duloxetine, desvenlafaxine, and venlafaxine.1 6 8 9 10

• Exact mechanisms of central pain inhibitory action and ability to improve symptoms of fibromyalgia not fully elucidated; apparently related to inhibitory effect on reuptake of both serotonin and norepinephrine.1 4 6

• Antidepressant activity demonstrated in clinical studies, presumably due to potentiation of serotonergic and noradrenergic activity in CNS.4 6 7 8 9 10

• Inhibits reuptake of norepinephrine with approximately threefold greater potency than serotonin in vitro without directly affecting uptake of dopamine or other neurotransmitters.1 3 4 6

• Substantial affinity not demonstrated for serotonergic (5-HT1–7), α- and β-adrenergic, muscarinic (M1–5), histaminergic (H1–4), dopaminergic (D1–5), opiate, benzodiazepine, and GABA receptors in vitro.1 4 6 18

• No appreciable affinity for calcium, potassium, sodium, or chloride ion channels.1

• Does not inhibit human monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase.1

In the U.S.

• Savella

Available Dosage Forms:

• Tablet

Therapeutic Class: Central Nervous System Agent

Pharmacologic Class: Serotonin/Norepinephrine Reuptake Inhibitor

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of milnacipran in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of milnacipran in the elderly. However, elderly patients are more likely to have hyponatremia (low sodium in the blood) and age-related kidney problems, which may require an adjustment in the dose for patients receiving milnacipran.

Pregnancy

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Furazolidone
• Iproniazid
• Isocarboxazid
• Linezolid
• Methylene Blue
• Moclobemide
• Phenelzine
• Procarbazine
• Rasagiline
• Safinamide
• Selegiline
• Tranylcypromine

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abciximab
• Aceclofenac
• Acemetacin
• Acenocoumarol
• Alfentanil
• Almotriptan
• Amisulpride
• Amitriptyline
• Amoxapine
• Amphetamine
• Amtolmetin Guacil
• Anagrelide
• Ancrod
• Anisindione
• Antithrombin III Human
• Apixaban
• Aripiprazole
• Aspirin
• Avitriptan
• Bemiparin
• Benperidol
• Benzphetamine
• Bivalirudin
• Bromfenac
• Bufexamac
• Buprenorphine
• Bupropion
• Butorphanol
• Celecoxib
• Chlorpromazine
• Choline Salicylate
• Cilostazol
• Citalopram
• Clonixin
• Clopidogrel
• Clovoxamine
• Clozapine
• Codeine
• Cyclobenzaprine
• Danaparoid
• Defibrotide
• Dermatan Sulfate
• Desirudin
• Desvenlafaxine
• Dexibuprofen
• Dexketoprofen
• Dextroamphetamine
• Dextromethorphan
• Diclofenac
• Dicumarol
• Diflunisal
• Dihydrocodeine
• Dipyridamole
• Dipyrone
• Dolasetron
• Donepezil
• Droxicam
• Duloxetine
• Edoxaban
• Eletriptan
• Epoprostenol
• Eptifibatide
• Escitalopram
• Etodolac
• Etofenamate
• Etoricoxib
• Felbinac
• Femoxetine
• Fenoprofen
• Fentanyl
• Fepradinol
• Feprazone
• Floctafenine
• Fluconazole
• Flufenamic Acid
• Fluoxetine
• Fluphenazine
• Flurbiprofen
• Fluvoxamine
• Fondaparinux
• Frovatriptan
• Granisetron
• Haloperidol
• Heparin
• Hydrocodone
• Hydromorphone
• Ibuprofen
• Iloprost
• Indomethacin
• Iobenguane I 123
• Ketoprofen
• Ketorolac
• Lamifiban
• Levomilnacipran
• Levorphanol
• Lexipafant
• Lisdexamfetamine
• Lithium
• Lorcaserin
• Lornoxicam
• Loxapine
• Loxoprofen
• Lumiracoxib
• Meclofenamate
• Mefenamic Acid
• Meloxicam
• Meperidine
• Mesoridazine
• Methadone
• Methamphetamine
• Metoclopramide
• Mirtazapine
• Molindone
• Morniflumate
• Morphine
• Morphine Sulfate Liposome
• Nabumetone
• Nadroparin
• Nalbuphine
• Naproxen
• Naratriptan
• Nefazodone
• Nepafenac
• Niflumic Acid
• Nimesulide
• Nimesulide Beta Cyclodextrin
• Olanzapine
• Oxaprozin
• Oxycodone
• Oxymorphone
• Oxyphenbutazone
• Palonosetron
• Parecoxib
• Paroxetine
• Pentazocine
• Pentosan Polysulfate Sodium
• Perphenazine
• Phenindione
• Phenprocoumon
• Phenylbutazone
• Piketoprofen
• Pimozide
• Piroxicam
• Pranoprofen
• Proglumetacin
• Promazine
• Propyphenazone
• Proquazone
• Quetiapine
• Remifentanil
• Risperidone
• Rivaroxaban
• Rizatriptan
• Rofecoxib
• Salicylic Acid
• Salsalate
• Sertraline
• Sibrafiban
• Sibutramine
• Sodium Salicylate
• Sufentanil
• Sulfinpyrazone
• Sulindac
• Sulodexide
• Sumatriptan
• Tapentadol
• Tenoxicam
• Thioridazine
• Thiothixene
• Tiaprofenic Acid
• Ticlopidine
• Tirofiban
• Tolfenamic Acid
• Tolmetin
• Tramadol
• Trazodone
• Trifluoperazine
• Tryptophan
• Valdecoxib
• Venlafaxine
• Vilazodone
• Vortioxetine
• Warfarin
• Xemilofiban
• Zimeldine
• Ziprasidone
• Zolmitriptan

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse, or history of or
• Bleeding problems or
• Depression, history of or
• Enlarged prostate or
• Glaucoma, angle-closure or
• Heart disease or
• Heart rhythm problems (eg, tachyarrhythmia) or
• Hypertension (high blood pressure) or
• Hyponatremia (low sodium in the blood) or
• Liver disease or
• Mania, history of or
• Painful or difficult urination, history of or
• Seizures, history of or
• Urinary tract blockage—Use with caution. May make these conditions worse.

• Kidney disease, end-stage—Use is not recommended in patients with this condition.

• Kidney disease, moderate or severe—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

Take this medicine only as directed by your doctor to benefit your condition as much as possible. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

You may take this medicine with or without food.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For treatment of fibromyalgia:
    • Adults—
      • Day 1: 12.5 milligrams (mg) once.
      • Days 2 to 3: 25 mg per day (12.5 mg two times a day).
      • Days 4 to 7: 50 mg per day (25 mg two times a day).
      • After day 7: 100 mg per day (50 mg two times a day).
      • Your doctor may increase your dose up to 200 mg per day (100 mg two times a day).
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Suicide Risk

Savella is a selective serotonin and norepinephrine re-uptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders.

Patients, both adult and pediatric, with depression or other psychiatric disorders may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking these medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants, including drugs that inhibit the reuptake of norepinephrine and/or serotonin, may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

In the placebo-controlled clinical trials of adults with fibromyalgia, among the patients who had a history of depression at treatment initiation, the incidence of suicidal ideation was 0.5% in patients treated with placebo, 0% in patients treated with Savella 100 mg/day, and 1.3% in patients treated with Savella 200 mg/day. No suicides occurred in the short-term or longer-term (up to 1 year) fibromyalgia trials.

Pooled analyses of short-term placebo-controlled trials of drugs used to treat depression (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with these drugs compared to placebo in adults beyond age 24; there was a reduction in suicidality risk with antidepressants compared to placebo in adults age 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 drugs used to treat depression in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.

There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.

However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, have been reported in adult and pediatric patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who may experience worsening depressive symptoms, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe or abrupt in onset, or were not part of the patient's presenting symptoms.

If the decision has been made to discontinue treatment due to worsening depressive symptoms or emergent suicidality, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can produce withdrawal symptoms [see Dosage and Administration (2.1, 2.4), and Warnings and Precautions (5.7)].

Families and caregivers of patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Savella should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

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.

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.

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).

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.

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.

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.

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.

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)].

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.

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.

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.

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.

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.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Dietary administration of milnacipran to rats at doses of 50 mg/kg/day (2 times the MRHD on a mg/m2 basis) for 2 years caused a statistically significant increase in the incidence of thyroid C-cell adenomas and combined adenomas and carcinomas in males. A carcinogenicity study was conducted in Tg.rasH2 mice for 6 months at oral gavage doses of up to 125 mg/kg/day.

Milnacipran did not induce tumors in Tg.rasH2 mice at any dose tested.

Mutagenesis

Milnacipran was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) or in the L5178Y TK +/- mouse lymphoma forward mutation assay. Milnacipran was also not clastogenic in an in vitro chromosomal aberration test in human lymphocytes or in the in vivo mouse micronucleus assay.

Impairment of Fertility

Although administration of milnacipran to male and female rats had no statistically significant effect on mating or fertility at doses up to 80 mg/kg/day (4 times the MRHD on an mg/m2 basis), there was an apparent dose-related decrease in the fertility index at clinically relevant doses based on body surface area.

Animal Toxicology and/or Pharmacology

Hepatic Effects

Chronic administration (2 years) of milnacipran to rats at 15 mg/kg (0.6 times the MRHD on an mg/m2 basis) and higher doses showed increased incidences of centrilobular vacuolation of the liver in male rats and eosinophilic foci in male and female rats in the absence of any change in hepatic enzymes. The clinical significance of the finding is not known. Chronic (1 year) administration in the primate at doses up to 25 mg/kg (2 times the MRHD on a mg/m2 basis) did not demonstrate similar evidence of hepatic changes.

Ocular Effects

Chronic (2 years) administration of milnacipran to rats at 15 mg/kg (0.6 times the MRHD on a mg/m2 basis) and higher doses showed increased incidence of keratitis of the eye. One-year studies in the rat and primate did not show this response.

Take Savella exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

You may take Savella with or without food, but food may help you tolerate the medicine better.

Your blood pressure and heart rate will need to be checked often.

Do not stop using Savella suddenly, or you could have unpleasant withdrawal symptoms. Ask your doctor how to safely stop using this medicine.

Tell your doctor if the medicine seems to stop working as well in relieving your fibromyalgia pain.

Store at room temperature away from moisture and heat.

Usual Adult Dose for Fibromyalgia:

Maintenance dose: 50 mg orally twice a day
Maximum dose: 100 mg orally twice a day (200 mg orally per day)

Comments:
-Dosing may be titrated according to the following schedule:
-Initial dose on day 1: 12.5 mg orally once
-Days 2 and 3: 12.5 mg orally twice a day
-Days 4 through 7: 25 mg orally twice a day
-After day 7: 50 mg orally twice a day

Use: Management of fibromyalgia

Taking this medicine with other drugs that make you sleepy can worsen this effect. Ask your doctor before taking Savella with a sleeping pill, narcotic pain medicine, prescription cough medicine, muscle relaxer, or medicine for anxiety, depression, or seizures.

Some medicines can interact with milnacipran and cause a serious condition called serotonin syndrome. Be sure your doctor knows if you also take medicine for depression, mental illness, Parkinson's disease, migraine headaches, ADHD, narcolepsy, serious infections, or prevention of nausea and vomiting. Ask your doctor before making any changes in how or when you take your medications.

Other drugs may interact with milnacipran, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Applies to milnacipran: oral tablet

Along with its needed effects, milnacipran (the active ingredient contained in Savella) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking milnacipran:

• Blurred vision
• body aches or pain
• chills
• cough
• difficulty with breathing
• dizziness
• ear congestion
• fast, irregular, pounding, or racing heartbeat or pulse
• fear or nervousness
• fever
• headache
• increased sweating
• loss of voice
• nasal congestion
• pounding in the ears
• runny nose
• slow or fast heartbeat
• sneezing
• sore throat
• unusual tiredness or weakness

• Back pain
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest pain or discomfort
• chills
• decrease in frequency of urination
• decrease in urine volume
• difficult or painful urination
• difficulty in passing urine (dribbling)
• frequent urination
• groin pain
• muscle aches
• pain or burning with urination
• shakiness in the legs, arms, hands, or feet
• swollen, tender prostate
• tightness in the chest

• Bladder pain
• bloating or swelling of the face, arms, hands, lower legs, or feet
• bloody or cloudy urine
• bruise
• discouragement
• fall
• feeling sad or empty
• frequent urge to urinate
• full or bloated feeling
• heartburn
• increased or decreased weight
• irritability
• lack of appetite
• loss of interest or pleasure
• lower back or side pain
• pressure in the stomach
• rapid weight gain
• swelling of the abdominal or stomach area
• tingling of the hands or feet
• tiredness
• trouble concentrating
• trouble sleeping
• unusual weight gain or loss
• vomiting

• Agitation
• black, tarry stools
• bleeding gums
• blistering, peeling, or loosening of the skin
• blood in the urine or stools
• coma
• confusion as to time, place, or person
• convulsions
• dark-colored urine
• decreased urine output
• diarrhea
• difficulty with swallowing
• general tiredness and weakness
• high fever
• holding false beliefs that cannot be changed by fact
• increased sweating
• increased thirst
• itching
• joint or muscle pain
• light-colored stools
• loss of balance control
• loss of consciousness
• mask-like face
• muscle cramps or spasms
• muscle pain or stiffness
• overactive reflexes
• pinpoint red spots on the skin
• poor coordination
• red skin lesions, often with a purple center
• red, irritated eyes
• restlessness
• seeing, hearing, or feeling things that are not there
• seizures
• severe muscle stiffness
• shuffling walk
• slowed movements
• slurred speech
• sores, ulcers, or white spots on the lips or in the mouth
• stiffness of the arms and legs
• sweating
• swelling of the face, ankles, fingers, or lower legs
• swollen glands
• talking or acting with excitement you cannot control
• tic-like (jerky) movements of the head, face, mouth, and neck
• tiredness
• trembling and shaking of the fingers and hands
• twitching
• unusual bleeding or bruising
• unusual excitement, nervousness, or restlessness
• unusually pale skin
• upper right abdominal or stomach pain
• weight gain
• yellow eyes and skin

Some side effects of milnacipran may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Feeling of warmth
• headache, severe and throbbing
• redness of the face, neck, arms, and occasionally, upper chest
• sudden sweating

• Abdominal or stomach pain
• change or problem with discharge of semen
• decreased appetite
• decreased interest in sexual intercourse
• inability to have or keep an erection
• loss in sexual ability, desire, drive, or performance
• not able to ejaculate semen
• rash
• swelling of the testes

• Acid or sour stomach
• belching
• bloated
• change in taste
• excess air or gas in the stomach or intestines
• full feeling
• heartburn
• indigestion
• irritability
• loss of taste
• night sweats
• passing gas
• sleepiness or unusual drowsiness
• stomach discomfort or upset

• Swelling of the breasts or unusual milk production
• unexpected or excess milk flow from the breasts