Use Caution/Monitor. Serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotics may enhance serotonergic effect of serotonin modulators, which may result in serotonin syndrome. Monitor for evidence of serotonin toxicity (eg, mental status changes, autonomic instability, and neuromuscular hyperactivity) or neuroleptic malignant syndrome (eg, hyperthermia, muscle rigidity, autonomic dysfunction).zolmitriptanMonitor Closely (1)zolmitriptan and levomilnacipran both increase serotonin levels. Modify Therapy/Monitor Closely. >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 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 patientsContraindications Hypersensitivity 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, 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; consider changing therapeutic regimen, including possibly discontinuing therapy, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors 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 other drugs that inhibit platelets or anticoagulants may increase this risk; inform patients about risk of bleeding associated with concomitant use of drug and NSAIDs, aspirin, or other drugs that affect coagulation Risk of mydriasis; may trigger angle closure attack in patients with angle-closure glaucoma with anatomically narrow angles without a patent iridectomy; avoid use of this medication in patients with anatomically narrow angles; pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy; open-angle glaucoma is not a risk factor for angle-closure glaucoma Can affect urinary hesitation or retention; caution with obstructive urinary disorders and discontinue is symptoms present; the noradrenergic effect of the drug, can affect urethral resistance; if symptoms of urinary hesitation, urinary retention, or dysuria develop during treatment, consideration should be given to possibility that they might be drug-related, and discontinuation or other appropriate medical intervention should be considered May activate mania/hypomania in patients with bipolar disorder; screen patients for bipolar disorder and for any personal or family history of bipolar disorder, mania, or hypomania prior to initiating; use cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania Caution with seizure disorders; not systematically evaluated in patients with seizure disorder Sexual dysfunction Use may cause symptoms of sexual dysfunction in both male and female patients; inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider Use of SSRIs, may cause symptoms of sexual dysfunction; in male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction In female patients, SSRI/SNRI use may result in decreased libido and delayed or absent orgasm Important for prescribers to inquire about sexual function prior to initiation of therapy and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including underlying psychiatric disorder Discuss potential management strategies to support patients in making informed decisions about treatment Serotonin syndrome 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) Serotonin syndrome symptoms may include mental status changes (eg, agitation, hallucinations, delirium, and coma), autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea) Monitor all patients receiving therapy for emergence of serotonin syndrome; discontinue treatment with drug and any concomitant serotonergic agents immediately if above events occur and initiate supportive symptomatic treatment; if concomitant use of drug with other serotonergic drugs is clinically warranted, inform patients of increased risk for serotonin syndrome and monitor for symptoms Blood pressure May increase blood pressure; blood pressure should be measured prior to initiating treatment and periodically throughout treatment Pre-existing hypertension should be controlled before initiating therapy Use caution when treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure For patients who experience a sustained increase in blood pressure while receiving drug, discontinuation or other appropriate medical intervention should be considered Heart rate Therapy may increase heart rate; heart rate should be measured prior to initiating treatment and periodically throughout treatment Pre­existing tachyarrhythmias and other cardiac disease should be treated before starting therapy; for patients who experience a sustained increase in heart rate while receiving therapy, discontinuation or other appropriate medical intervention should be considered Drug has not been systematically evaluated in patients with a cardiac rhythm disorder Discontinuation syndrome Discontinuation symptoms (some serious) reported with abrupt withdrawal of serotonergic antidepressants Some symptoms include dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures Monitor patients for these symptoms when discontinuing therapy; reduce dose gradually whenever possible; if intolerable symptoms occur following a decrease in dose or upon discontinuation of treatment, consider resuming previously prescribed dose; subsequently, the dose may be decreased, but at a more gradual rate Hyponatremia Hyponatremia may occur; in many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH); cases with serum sodium lower than 110 mmol/L reported Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs; patients taking diuretics or who are otherwise volume depleted can be at greater risk Therapy should be discontinued in patients with symptomatic hyponatremia and appropriate medical intervention instituted Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death Drug interaction overview Contraindicated with an MAOI (or within 14 days of stopping an MAOI) intended to treat psychiatric disorders or within 7 days of stopping treatment with levomilnacipran; it is also contraindicated in patients treated with linezolid or IV methylene blue Coadministration with strong CYP3A4 inhibitors may increase levomilnacipran levels; see Dosage Modifications Avoid alcohol with levomilnacipran; concomitant use may result in accelerated release of levomilnacipran from the extended-release capsules SSRIs and SNRIs may impair platelet aggregation and increase the risk of bleeding events; coadministration with other antiplatelet drug or anticoagulants may cause additive risk Coadministration with other serotonergic drugs may increase risk of serotonin syndrome Pregnancy There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy; healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants Available data on pregnant women are insufficient to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes; there are risks associated with untreated depression in pregnancy and with exposure to SNRIs and SSRIs during pregnancy Clinical considerations Women who discontinued antidepressants during pregnancy were more likely to experience relapse of major depression than women who continued antidepressants; consider risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum Use of SNRIs in late pregnancy may be associated with an increased risk of postpartum hemorrhage Fetal/neonatal effects Neonates exposed to SNRIs or SSRIs, 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 Animal data In animal reproduction studies, drug was not associated with malformations in rats or rabbits when given during the period of organogenesis at doses up to 8 or 16 times maximum recommended human dose (MRHD) of 120 mg on a mg/m2 basis, respectively However, an increase in early post-natal rat pup mortality was seen at a dose equivalent to 5 times the MRHD given during pregnancy and lactation Lactation There are no available data on presence of drug in human milk; however, racemic milnacipran is present in human milk; there are no reports on effects of drug or milnacipran on breastfed infant or effects on milk production; however, there are reports of agitation, irritability, poor feeding and poor weight gain in infants exposed to SSRIs or SNRIs through breast milk The developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from drug or from underlying maternal conditions Clinical considerations Infants exposed to drug should be monitored for agitation, irritability, poor feeding and poor weight gain 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. 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 Oral Administration May take with or without food Take at approximately the same time each day Swallow capsules whole; do not open, chew, or crush Discontinuing drug Avoid abrupt discontinuation if possible; gradual dose reduction recommended to avoid discontinuation symptoms associated with serotonergic drugs BRAND FORM. UNIT PRICE PILL IMAGE Fetzima oral- 120 mg capsuleFetzima