levomilnacipran (Rx)

Brand and Other Names:Fetzima
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule, extended-release

  • 20mg
  • 40mg
  • 80mg
  • 120mg

titration packs

  • Contains two 20mg capsules and twenty-six 40mg capsules
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Major Depressive Disorders

SNRI indicated for major depressive disorders in adults

20 mg PO qDay x2 days initially; THEN

Increase to 40 mg PO qDay

Based on efficacy and tolerability, increase dose in increments of 40 mg/day at intervals of 2 or more days; not to exceed 120 mg/day

Dosage range: 40-120 mg/day

Dosage Modifications

Strong CYP3A4 inhibitors: Do not exceed 80 mg/day

Hepatic impairment: Hepatic elimination is low, no dosage adjustment required with mild, moderate, or severe hepatic impairment

Renal impairment

  • Mild (CrCl 60-89 mL/min): No dosage adjustment required
  • Moderate (CrCl 30-59 mL/min): Do not exceed 80 mg/day
  • Severe (CrCl 15-29 mL/min): Do not exceed 40 mg/day
  • End-stage renal disease: Not recommended

Dosing Considerations

Not approved for the management of fibromyalgia

Administration

May take with or without food

Take at approximately the same time each day

Swallow capsules whole; do not open, chew, or crush

Safety and efficacy not established

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Interactions

Interaction Checker

and levomilnacipran

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10%

            Nausea (17%)

            1-10%

            Erectile dysfunction, dose-related (6-10%)

            Constipation (9%)

            Tachycardia (6%)

            Urinary hesitation, dose-related (4-6%)

            Palpitations (5%)

            Vomiting (5%)

            Hyperhidrosis (2%)

            Increased heart rate (1%)

            Increased blood pressure (1%)

            Hot flush (1%)

            Hypotension (1%)

            Decreased appetite (1%)

            <1%

            Testicular pain

            Ejaculation disorder

            Postmarketing Results

            Takotsubo cardiomyopathy

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            Warnings

            Black Box Warnings

            In short-term studies, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults (<24 yr of age) taking antidepressants for major depressive disorders and other psychiatric illnesses

            This increase was not seen in patients aged >24 years; a slight decrease in suicidal thinking was seen in adults >65 years

            In children and young adults, risks must be weighed against the benefits of taking antidepressants

            Patients should be monitored closely for changes in behavior, clinical worsening, and suicidal tendencies; this should be done during initial 1-2 months of therapy and dosage adjustments

            The patient’s family should communicate any abrupt changes in behavior to the healthcare provider

            Worsening behavior and suicidal tendencies that are not part of the presenting symptoms may require discontinuation of therapy

            This drug is not approved for use in pediatric patients

            Contraindications

            Hypersensitivity

            Uncontrolled narrow-angle glaucoma

            MAOIs

            • Do not use MAOIs intended to treat psychiatric disorders with levomilnacipran or within 7 days of stopping levomilnacipran due to an increased risk of serotonin syndrome
            • Do not initiate levomilnacipran within 14 days of stopping an MAOI
            • Starting in a patient who is being treated with MAOIs such as linezolid or IV methylene blue is also contraindicated due to an increased risk of serotonin syndrome
            • If methylene blue or linezolid must be administered for an urgent condition to a patient currently taking a serotonergic drug, stop serotonergic drug immediately and monitor for CNS toxicity; serotonergic therapy may be resumed 24 hr after the last dose of methylene blue, or after 2 weeks of monitoring (5 weeks if fluoxetine was taken), whichever comes first

            Cautions

            All patients being treated with antidepressants should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the first few months of treatment and when increasing or decreasing the dose (see Black Box Warnings)

            Potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs both when taken alone, but especially when coadministered with other serotonergic agents; thoroughly review patient medications for other serotonergic drugs (eg, tryptophan supplements, tramadol, 5-HT agonists [triptans], MAOIs, TCAs, SSRIs)

            May increase blood pressure BP or heart rate (HR); BP should be controlled before initiating; monitor BP and HR while patient taking drug

            SSRIs and SNRIs may impair platelet aggregation and increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and GI hemorrhage to life-threatening hemorrhage; concomitant use of aspirin, NSAIDs, warfarin, other anticoagulants, or other drugs known to affect platelet function may add to this risk

            Risk of mydriasis; may trigger angle closure attack in patients with angle closure glaucoma with anatomically narrow angles without a patent iridectomy

            Can affect urinary hesitation or retention; caution with obstructive urinary disorders and discontinue is symptoms present

            May activate mania/hypomania in patients with bipolar disorder; screen patients for bipolar disorder prior to initiating

            Caution with seizure disorders

            Discontinuation symptoms (some serious) reported with abrupt withdrawal of serotonergic antidepressants; gradual dose reduction recommended

            Risk of hyponatremia in association with SIADH, particularly in patients taking diuretics or are otherwise volume depleted, or are elderly; discontinue if symptomatic hyponatremia occurs

            Bone fractures reported with antidepressant use; if antidepressant-treated patient presents with unexplained bone pain, swelling, point tenderness or bruising, consider the possibility of fragility fracture

            May cause urinary hesitation or resistance; patient should report symptoms of urinary hesitation/difficulty; use caution in patients prone to obstructive urinary disorders

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            Pregnancy & Lactation

            Pregnancy Category: C; Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding; such complications can arise immediately upon delivery

            Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying

            Lactation: Unknown if distributed in human breast milk; because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Active enantiomer milnacipran; potent inhibitor of neuronal serotonin and norepinephrine reuptake (SNRI); inhibits norepinephrine uptake with ~3-fold higher potency in vitro than serotonin without directly affecting the uptake of dopamine or other neurotransmitters

            Absorption

            Bioavailability: 92%

            Peak plasma time: 6-8 hr

            Peak plasma concentration: 341 ng/mL

            AUC: 5196 ng•h/mL

            Distribution

            Protein bound: 22%

            Vd: 387-473 L

            Metabolism

            Undergoes desethylation to form desethyl levomilnacipran and hydroxylation to form p-hydroxy-levomilnacipran; both oxidative metabolites undergo further conjugation with glucuronide to form conjugates and are inactive

            Desethylation is catalyzed primarily by CYP3A4 with minor contribution by CYP2C8, 2C19, 2D6, and 2J2

            Elimination

            Half-life, terminal: 12 hr

            Total clearance: 21-29 L/hr

            Excretion: 58% unchanged in urine; 18% N-desethyl metabolite in urine

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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