Dosing and uses of Fetzima (levomilnacipran)
Adult dosage forms and strengths
capsule, extended-release
- 20mg
- 40mg
- 80mg
- 120mg
titration packs
- Contains two 20mg capsules and twenty-six 40mg capsules
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
Pediatric dosage forms and strengths
Safety and efficacy not established
Fetzima (levomilnacipran) adverse (side) 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
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
Pregnancy and 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.
Pharmacology of Fetzima (levomilnacipran)
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
