Fetzima

• Fetzima^®

• Forest Pharmaceuticals, Inc.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• Triptans such as sumatriptan (Imitrex, Treximet), eletriptan (Relpax), almotriptan (Axert), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), and zolmitriptan (Zomig)
• Medications that could lead to serotonin syndrome such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), desvenlafaxine (Pristiq), nefazodone (Serzone), paroxetine (Paxil, Pexeva), sertraline (Zoloft), venlafaxine (Effexor), trimipramine (Surmontil), amitriptyline (Elavil), nortriptyline (Pamelor, Aventyl), protriptyline (Vivactil), and clomipramine (Anafranil), and linezolid (Zyvox)
• Monoamine oxidase inhibitors such as isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate), selegiline (Emsam, Eldepryl, Zelapar), rasagiline (Azilect)

• tramadol (Ultram)
• fentanyl (Duragesic)
• Tryptophan 
• St. John's Wort
• Aspirin and other NSAIDs (nonsteroidal anti-inflammatory drugs) such as celecoxib (Celebrex), diclofenac (Cambia, Cataflam, Flector, Voltaren, Zipsor and others), etodolac (Lodine), ibuprofen (Advil, Motrin, Nuprin), indomethacin (Indocin, Indocin SR), ketoprofen (Orudis, Actron, Oruvail), ketorolac (Toradol), meloxicam (Mobic), nabumetone (Relafen), naproxen (Naprosyn), naproxen sodium (Aleve, Anaprox, Naprelan), oxaprozin (Daypro), piroxicam (Feldene)

• Blood thinners such as warfarin (Coumadin, Jantoven)
• Diuretics (water pills) such as acetazolamide (Diamox), amiloride (Midamor), bumetanide (Bumex), chlorothiazide (Diuril), chlorthalidone (Thalitone), ethacrynic acid (Edecrin), furosemide (Lasix), hydrochlorothiazide (Microzide, HCTZ), metolazone (Zaroxolyn), torsemide (Demadex), triamterene (Dyrenium, Dyazide, Maxzide)

This is not a complete list of Fetzima drug interactions. Ask your doctor or pharmacist for more information.

Before taking Fetzima, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Fetzima or to any of its ingredients
• Have high blood pressure or tend to have a fast heart rate
• Have heart or kidney problems
• Have or had bleeding problems. Fetzima may increase your risk of bleeding or bruising
• Have an eye condition called glaucoma
• Have or had trouble urinating
• Have or had mania, bipolar disorder (manic depression), seizures or convulsions
• Have low salt (sodium) levels in your blood
• Drink alcohol
• Are pregnant, nursing, or are planning to become pregnant or to breastfeed

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

It is not known if Fetzima crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Fetzima.

Suicidality and Antidepressant Drugs

Antidepressants increased the risk of suicidal thoughts and behavior in children, teenagers, and young adults.
In patients of all ages who are started on antidepressant therapy, watch closely for worsening depression and for suicidal thoughts and behaviors. Families and caregivers of patients on antidepressants should talk with the patient's doctor if depression becomes worse.
Fetzima is not approved for use in patients under 18.

You should not use levomilnacipran if you have untreated or uncontrolled narrow-angle glaucoma.

Do not use levomilnacipran within 7 days before or 14 days after you have taken an MAO inhibitor, such as isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, and tranylcypromine.

Some young people have thoughts about suicide when first taking an antidepressant. Stay alert to changes in your mood or symptoms. Report any new or worsening symptoms to your doctor.

Levomilnacipran is not approved for use by anyone younger than 18 years old.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

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

Tell your doctor about all your current medicines and any you start or stop using, especially:

• any other antidepressant;

• sibutramine;

• tramadol;

• St. John's wort;

• tryptophan (sometimes called L-tryptophan);

• a diuretic or "water pill";

• a blood thinner (warfarin, Coumadin, Jantoven);

• medicine to treat anxiety, mood disorders, thought disorders, or mental illness--buspirone, lithium, and many others; or

• migraine headache medicine--sumatriptan, rizatriptan, zolmitriptan, and others.

This list is not complete. Other drugs may interact with levomilnacipran, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Contraindications

• Known hypersensitivity to levomilnacipran, milnacipran, or any ingredient in the formulation.1

• 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 7 days of levomilnacipran discontinuance.1 (See Serotonin Syndrome under Cautions and also see Specific Drugs under Interactions.)

• Initiation of levomilnacipran 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 12 14 15 28 (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 12 14 15

Appropriately monitor and closely observe patients receiving levomilnacipran for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1 12 14 15

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality.1 14 15 Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or were not part of the patient’s presenting symptoms.1 14 If a decision is made to discontinue therapy, taper levomilnacipran dosage as rapidly as is feasible but consider risks of abrupt discontinuance.1 14 (See Withdrawal of Therapy under Cautions.)

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.1 14

Other Warnings and Precautions

Potentially life-threatening serotonin syndrome reported with SSRIs and SNRIs 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 18 31 (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 18 31

Concurrent or recent (i.e., within 2 weeks) therapy with MAO inhibitors intended to treat psychiatric disorders is contraindicated.1 Do not initiate levomilnacipran 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 levomilnacipran for the development of serotonin syndrome.1 If manifestations occur, immediately discontinue levomilnacipran and any concurrently administered serotonergic agents and initiate supportive and symptomatic treatment.1

Possible increased BP with SNRIs, including levomilnacipran.1 Orthostatic hypotension also reported.1 Effects of levomilnacipran on BP in patients with clinically important hypertension or cardiovascular disease not evaluated; use with caution.1

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

Control preexisting hypertension before initiating levomilnacipran therapy.1 Monitor BP prior to and periodically during treatment.1 Use caution in treating patients with preexisting hypertension, cardiovascular conditions, or cerebrovascular conditions that might be compromised by BP increases.1

If sustained increase in BP occurs during therapy, consider levomilnacipran discontinuance or other appropriate medical intervention.1

Increased heart rate reported with SNRIs, including levomilnacipran.1 Use in patients with cardiac rhythm disorders not systematically evaluated.1

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

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

Monitor heart rate prior to and periodically during therapy.1 If sustained increase in heart rate occurs during therapy, consider levomilnacipran discontinuance or other appropriate medical intervention.1

Possible increased risk of bleeding with SSRIs and SNRIs, including levomilnacipran; events ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.1 Concurrent 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.)

Pupillary dilation (mydriasis) occurs with many antidepressants, including levomilnacipran, 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.)

SNRIs, including levomilnacipran, may affect urethral resistance.1 Use with caution in patients prone to obstructive urinary disorders.1

If symptoms of urinary hesitation, urinary retention, or dysuria develop, consider possibility of drug-related effects.1 Also consider drug discontinuance or other appropriate medical intervention.1

Possible activation of mania and hypomania; use with caution in patients with personal or family history of bipolar disorder, mania, or hypomania.1

Levomilnacipran has not been systematically evaluated in patients with seizure disorders; use with caution in patients with a history of seizure disorder.1

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

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

Although not reported with levomilnacipran therapy, treatment with SSRIs and SNRIs may cause hyponatremia; in many cases, SIADH is apparent cause.1 Increased risk in patients who are volume-depleted, elderly, or taking diuretics.1 Discontinue levomilnacipran and institute appropriate medical intervention in patients with symptomatic hyponatremia.1

Specific Populations

Category C.1

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 22 23 24 25 26 27

Consult joint APA and ACOG guidelines (at ) for additional information on management of depression in women prior to conception and during pregnancy, including treatment algorithms.32

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Safety and efficacy not established in pediatric patients; not recommended for use in such patients.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 14 However, a later 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.28 No suicides occurred in these pediatric trials.1 14 28

Carefully consider these findings when assessing potential benefits and risks of levomilnacipran in a child or adolescent for any clinical use.1 14 15 28 (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

In clinical trials with levomilnacipran, 2.8% of patients were ≥65 years of age.1

Slightly higher exposure possible in geriatric patients.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Because levomilnacipran is eliminated principally by renal excretion, consider renal function when determining dosage in geriatric patients.1 (See Geriatric Patients under Dosage and Administration.)

SSRIs and SNRIs, including levomilnacipran, associated with clinically important hyponatremia in geriatric patients, who may be at greater risk for this adverse effect.1 (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 12 14 (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Hepatic elimination of levomilnacipran is low; pharmacokinetics not substantially affected by hepatic impairment.1 Dosage adjustment not necessary in patients with mild (Child-Pugh score of 1–6), moderate (Child-Pugh score of 7–9), or severe (Child-Pugh score of 10–13) hepatic impairment.1

Levomilnacipran is primarily eliminated by renal excretion.1

Dosage adjustment not necessary in mild renal impairment.1 However, dosage adjustment is recommended in moderate or severe renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Use not recommended in patients with end-stage renal disease.1

Because of levomilnacipran's large volume of distribution, hemodialysis not expected to reduce plasma concentrations of the drug.1

Common Adverse Effects

Nausea,1 2 3 4 constipation,1 2 3 4 hyperhidrosis,1 2 3 4 increased heart rate,1 2 3 erectile dysfunction,1 2 3 tachycardia (including sinus tachycardia and postural orthostatic tachycardia syndrome),1 2 4 vomiting,1 2 4 palpitations.1 2 Incidence of erectile dysfunction was dose related in a pooled analysis of studies.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Levomilnacipran administered by oral gavage to rats for 2 years and Tg.rasH2 mice for 6 months did not increase the incidence of tumors in either study.

Rats received levomilnacipran at doses up to 90/70 mg/kg/day (the dose was lowered in males after 45 weeks of dosing). The 90 mg/kg/day dose is 7 times the maximum recommended human dose (MRHD) of 120 mg on a mg/m2 basis.

Tg.rasH2 mice received levomilnacipran at doses up to 150 mg/kg/day. This dose is 6 times the MRHD.

Mutagenesis

Levomilnacipran was not mutagenic in the in vitro bacterial mutation assay (Ames test) and was not clastogenic in an in vivo micronucleus assay in rats. Additionally, levomilnacipran was not genotoxic in the in vitro mouse lymphoma (L5178Y TK+/-) cell forward mutation assay.

Impairment of Fertility

When levomilnacipran was administered orally to male and female rats before mating, through mating and up to Day 7 of gestation at doses up to 100 mg/kg/day, no effects were observed on fertility. This dose is 8 times the MRHD.

Fetzima extended-release capsules are supplied in the following configurations:

Fetzima Titration Pack is supplied in the following configuration:

Storage and Handling

All package configurations: Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature].

Get emergency medical help if you have any signs of an allergic reaction to Fetzima: skin rash or 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, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Call your doctor at once if you have:

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

• painful or difficult urination;

• seizure (convulsions);

• easy bruising, unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin;

• pounding heartbeats or fluttering in your chest; or

• low levels of sodium in the body - headache, confusion, slurred speech, severe weakness, muscle cramps, loss of coordination, feeling unsteady, fainting, shallow breathing.

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.

Older adults may be more sensitive to the side effects of this medication.

Common Fetzima side effects may include:

• nausea, vomiting, constipation;

• vision changes;

• increased sweating;

• fast heart rate; or

• decreased sex drive, impotence, or difficulty having an orgasm.

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.

Common side effects of Fetzima include: erectile dysfunction, nausea, and orthostatic hypotension. Other side effects include: constipation, ejaculatory disorder, epididymitis, increased heart rate, palpitations, premature ejaculation, sinus tachycardia, tachycardia, testicular pain, urinary hesitancy, vomiting, delayed ejaculation, ejaculation failure, and hyperhidrosis. See below for a comprehensive list of adverse effects.