General

Pronunciation:
lee-voe-mil-na-si-pran

Trade Name(s)

• Fetzima

Ther. Class.
antidepressants

Pharm. Class.
selective serotonin and norepinephrine reuptake inhibitors-SSNRIs

Indications

Treatment of major depressive disorder.

Action

Inhibits neuronal reuptake of norepinephrine and serotonin in the CNS (SNRI).

Therapeutic Effect(s):

Decrease in depressive symptomatology, with fewer relapses/recurrences.

Pharmacokinetics

Absorption: Well absorbed (92%) following oral administration.

Distribution: Widely distributed.

Metabolism and Excretion: 58% eliminated unchanged in urine; 42% metabolized, primarily by the CYP3A4 enzyme system; metabolites are renally eliminated.

Half-life: 12 hr.

TIME/ACTION PROFILE

Contraindication/Precautions

Contraindicated in:

• Hypersensitivity to levomilnacipran or milnacipran;
• Uncontrolled narrow-angle glaucoma;
• Concurrent use of or in close temporal proximity to MAO inhibitors, linezolid or methylene blue (risk of serotonin syndrome);
• Concurrent use of alcohol.
• Lactation;

Use Cautiously in:

• History of hypertension, cardiovascular or cerebrovascular disease (BP should be controlled prior to treatment);
• History of bipolar disorder (may activate mania/hypomania);
• Renal impairment (dose ↓ required for CCr <60 mL/min);
• OB:  Use only if potential maternal benefit justifies potential fetal risk;
• Pedi:  ↑ risk of suicidal thinking and behavior (suicidality) in adolescents and young adults up to 24 yrs with major depressive disorder.
• Geri:  Consider age-related ↓ in renal function, chronic disease state and concurrent drug therapy; may have ↑ risk of hyponatremia;

Exercise Extreme Caution in:

Concurrent use with other serotonergic drugs (↑ risk of serotonin syndrome especially during initiation and dose adjustment).

Adverse Reactions/Side Effects

CNS: activation of mania/hypomania

CV: hypertension, hypotension, palpitations, tachycardia

Derm: hot flush, hyperhydrosis, rash

EENT: mydrasis

F and E: hyponatremia (in association with syndrome of inappropriate antidiuretic hormone [SIADH])

GI: nausea, ↓ appetite, constipation, vomiting

GU: ejaculation disorder, erectile dysfunction, testicular pain, urinary hesitation/retention

Hemat: bleeding

Misc: SEROTONIN SYNDROME

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

• Concurrent use with  MAO inhibitors used for psychiatric disorders  may result in serious, potentially fatal reactions; wait at least 14 days following discontinuation of MAO inhibitor before initiation of levomilnacipran. Wait at least 7 days after discontinuing levomilnacipran before initiation of MAO inhibitor.
• Concurrent use with MAO-inhibitor like drugs, such as  linezolid  or methylene blue, may ↑ risk of serotonin syndrome; concurrent use contraindicated; do not start therapy in patients receiving  linezolid  or  methylene blue ; if  linezolid  or  methylene blue  need to be started in a patient receiving levomilnacipran, immediately discontinue levomilnacipran and monitor for signs/symptoms of serotonin syndrome for 2 wk or until 24 hr after last dose of linezolid or methylene blue, whichever comes first (may resume levomilnacipran therapy 24 hr after last dose of linezolid or methylene blue).
• Drugs that affect serotonergic neurotransmitter systems, including tricyclic antidepressants, SNRIs, fentanyl, buspirone, tramadol, amphetamines, and  triptans  ↑ risk of serotonin syndrome.
• Concurrent use of NSAIDs, aspirin,  warfarin  or other drugs that affect coagulation  may ↑ the risk of bleeding.
• Blood levels and risk of toxicity ↑ by concurrent use of  CYP3A4 inhitors  including ketoconazole, clarithromycin,  ritonavir ; daily dose should not exceed 80 mg.
• Concurrent use of other  medications that may ↑ BP  may ↑ risk of hypertension.
• Concurrent use with  alcohol  may cause a rapid release of drug and should be avoided.
• Concurrent use with other CNS-active medications, especially other  NSRIs .

Drug-Natural Products:

Concurrent use with  St. John's wort or  tryptophan  may ↑ the risk of serotinin syndrome; also ↑ risk of coronary vasoconstriction and hypertension.

Route/Dosage

PO  (Adults)   20 mg once daily for 2 days, then ↑ to 40 mg once daily, may then ↑ by 40 mg every two or more days; may ↑ up to 120 mg/day;  Concurrent use of CYP3A4 inhibitors (including ketoconazole, clarithromycin, ritonavir)– not to exceed 80 mg/day.

Renal Impairment 
PO  (Adults)   CCr 30–59 mL/min– not to exceed 80 mg/day;  CCr 15–29 mL/min– not to exceed 40 mg/day.

Availability

Extended-release capsules: 20 mg, 40 mg, 80 mg, 120 mg

Assessment

• Monitor BP and heart rate before and periodically during therapy. Treat per-existing hypertension and cardiac disease prior to therapy. Sustained hypertension may require discontinuation of therapy.
• Monitor closely for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.
• Assess for serotonin syndrome (mental changes [agitation, hallucinations, coma], autonomic instability [tachycardia, labile BP, hyperthermia], neuromuscular aberrations [hyperreflexia, incoordination], and/or GI symptoms [nausea, vomiting, diarrhea]), especially in patients taking other serotonergic drugs (SSRIs, SNRIs, triptans).

Lab Test Considerations:

May cause hyponatremia.

Potential Diagnoses

• Ineffective coping (Indications) 
• Risk for suicide (Adverse Reaction) 

Implementation

• High Alert: Do not confuse Fetzima (levomilnacipran) with Farxiga (dapagliflozin).
• PO  Administer daily without regard to food. Swallow capsule whole; do not open, crush, or chew.

Patient/Family Teaching

• Instruct patient to take levomilnacipran as directed at the same time each day. Take missed doses as soon as possible unless time for next dose; do not double dose. Do not stop abruptly; must be decreased gradually. Abrupt discontinuation may cause dysphoric mood, irritability, agitation, dizziness, paresthesia, electric shock sensation, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus and seizures. Advise patient to read  Medication Guide  prior to therapy and with each Rx refill in case of changes.
• May cause drowsiness and may affect ability to make decisions or react quickly. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
• Advise patient, family, and caregivers to look for activation of mania/hypomania and suicidality, especially during early therapy or dose changes. Notify health care professional immediately if thoughts about suicide or dying, attempts to commit suicide; new or worse depression or anxiety; agitation or restlessness; panic attacks; insomnia; new or worse irritability; aggressiveness; acting on dangerous impulses, mania, or other changes in mood or behavior or if symptoms of serotonin syndrome occur.
• Caution patient of the risk or serotonin syndrome (agitation, hallucinations, changes in mental status, muscle twitching, fast heartbeat, high or low BP, sweating or fever, nausea or vomiting, diarrhea, muscle stiffness or tightness), especially when taking triptans, tramadol, tryptophan supplements and other serotonergic or antipsychotic agents.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to avoid concurrent use of Rx, OTC, and herbal products, especially NSAIDs, aspirin, and warfarin, without consulting health care professional; may increase bleeding.
• Instruct patient to notify health care professional if signs of hyponatremia (headache, difficulty concentrating, memory impairment, confusion, weakness, unsteadiness) occur.
• Advise patient to avoid taking alcohol during levomilnacipran therapy.
• Instruct patient to notify health care professional if pregnancy is planned or suspected, and to avoid breast feeding during therapy.
• Encourage patient to maintain routine follow-up visits with health care provider to determine effectiveness.

Evaluation/Desired Outcomes

• Renewed interest in surroundings. Need for therapy should be periodically reassessed.