Drug.pentazocineMonitor Closely (1)milnacipran and pentazocine both increase serotonin levels. Modify Therapy/Monitor Closely.perphenazineMonitor Closely (1)milnacipran, perphenazine. unspecified interaction mechanism. 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).phenelzineContraindicated (1)phenelzine and milnacipran both increase serotonin levels. Contraindicated.phentermineSerious - Use Alternative (1)milnacipran, phentermine. Either increases toxicity of the other by Mechanism: unknown. Avoid or Use Alternate Drug. Risk of serotonin syndrome.pimavanserinMonitor Closely (1)milnacipran, pimavanserin. unspecified interaction mechanism. 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).pimozideMonitor Closely (1)milnacipran, pimozide. unspecified interaction mechanism. 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).piroxicamMonitor Closely (1)milnacipran, piroxicam. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Increased risk of upper GI bleeding. SSRIs inhib. serotonin uptake by platelets.pleurisy rootMinor (1)pleurisy root decreases effects of milnacipran by unspecified interaction mechanism. Minor/Significance Unknown. Theoretical interaction.pregabalinMonitor Closely (1)pregabalin, milnacipran. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Coadministration of CNS depressants can result in serious, life-threatening, and fatal respiratory depression. Use lowest dose possible and monitor for respiratory depression and sedation.procarbazineContraindicated (1)procarbazine and milnacipran both increase serotonin levels. Contraindicated. Combination is contraindicated within 2 weeks of MAOI use.protriptylineSerious - Use Alternative (1)milnacipran and protriptyline both increase serotonin levels. Avoid or Use Alternate Drug.pseudoephedrineSerious - Use Alternative (1)milnacipran increases effects of pseudoephedrine by sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Avoid or Use Alternate Drug.quetiapineMonitor Closely (1)milnacipran, quetiapine. unspecified interaction mechanism. 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).rasagilineContraindicated (1)rasagiline and milnacipran both increase serotonin levels. Contraindicated. Concomitant use with MAOIs or within 14 days of discontinuing treatment with an MAOI is contraindicated.remifentanilMonitor Closely (1)remifentanil increases toxicity of milnacipran by serotonin levels. Modify Therapy/Monitor Closely. Increases risk of serotonin syndrome.remimazolamMonitor Closely (1)remimazolam, milnacipran. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely. Coadministration may result in profound sedation, respiratory depression, coma, and/or death. Continuously monitor vital signs during sedation and recovery period if coadministered. Carefully titrate remimazolam dose if administered with opioid analgesics and/or sedative/hypnotics.risperidoneMonitor Closely (1)milnacipran, risperidone. unspecified interaction mechanism. 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).rizatriptanMonitor Closely (1)rizatriptan and milnacipran both increase serotonin levels. Modify Therapy/Monitor Closely.Minor (1)milnacipran, rizatriptan. Mechanism: unknown. Minor/Significance Unknown. Risk of weakness, dyspnea, chest pain.safinamideContraindicated (1)milnacipran, safinamide. Either increases toxicity of the other by serotonin levels. Contraindicated. Concomitant use could result in life-threatening serotonin syndrome.salicylates (non-asa)Monitor Closely (1)milnacipran, salicylates (non-asa). Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Increased risk of upper GI bleeding. SSRIs inhib. serotonin uptake by platelets.salsalateMonitor Closely (1)milnacipran, salsalate. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Increased risk of upper GI bleeding. SSRIs inhib. serotonin uptake by platelets.SAMeMonitor Closely (1)milnacipran and SAMe both increase serotonin levels. Modify Therapy/Monitor Closely.selegilineSerious - Use Alternative (1)selegiline and milnacipran both increase serotonin levels. Avoid or Use Alternate Drug.selegiline transdermalSerious - Use Alternative (1)selegiline transdermal and milnacipran both increase serotonin levels. Avoid or Use Alternate Drug.serdexmethylphenidate/dexmethylphenidateMinor (1)serdexmethylphenidate/dexmethylphenidate increases effects of milnacipran by decreasing metabolism. Minor/Significance Unknown.sertralineSerious - Use Alternative (1)milnacipran and sertraline both increase serotonin levels. Avoid or Use Alternate Drug.sodium sulfate/potassium chloride/magnesium sulfate/polyethylene glycolMonitor Closely (1)milnacipran, sodium sulfate/potassium chloride/magnesium sulfate/polyethylene glycol. Other (see comment). Use Caution/Monitor. Comment: Caution when bowel preps are used with drugs that cause SIADH or NSAIDs; increased risk for water retention or electrolyte imbalance.St John's WortSerious - Use Alternative (1)milnacipran and St John's Wort both increase serotonin levels. Avoid or Use Alternate Drug.sufentanil SLMonitor Closely (1)sufentanil SL, milnacipran. Either increases effects of the other by serotonin levels. Use Caution/Monitor. Coadministration of drugs that affect the serotonergic neurotransmitter system may result in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.sulfasalazineMonitor Closely (1)milnacipran, sulfasalazine. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Increased risk of upper GI bleeding. SSRIs inhib. serotonin uptake by platelets.sulindacMonitor Closely (1)milnacipran, sulindac. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Increased risk of upper GI bleeding. SSRIs inhib. serotonin uptake by platelets.sumatriptanMonitor Closely (1)sumatriptan and milnacipran both increase serotonin levels. Modify Therapy/Monitor Closely.Minor (1)milnacipran, sumatriptan. Mechanism: unknown. Minor/Significance Unknown. Risk of weakness, dyspnea, chest pain.sumatriptan intranasalMonitor Closely (1)sumatriptan intranasal and milnacipran both increase serotonin levels. Modify Therapy/Monitor Closely.Minor (1)milnacipran, sumatriptan intranasal. Mechanism: unknown. Minor/Significance Unknown. Risk of weakness, dyspnea, chest pain.tapentadolMonitor Closely (1)milnacipran and tapentadol both increase serotonin levels. Modify Therapy/Monitor Closely.thiothixeneMonitor Closely (1)milnacipran, thiothixene. unspecified interaction mechanism. 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).tolfenamic acidMonitor Closely (1)milnacipran, tolfenamic acid. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Increased risk of upper GI bleeding. SSRIs inhib. serotonin uptake by platelets.tolmetinMonitor Closely (1)milnacipran, tolmetin. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Increased risk of upper GI bleeding. SSRIs inhib. serotonin uptake by platelets.torsemideMinor (1)torsemide, milnacipran. Mechanism: pharmacodynamic synergism. Minor/Significance Unknown. Possible additive hyponatremia.tramadolMonitor Closely (1)milnacipran and tramadol both increase serotonin levels. Modify Therapy/Monitor Closely.tranylcypromineContraindicated (1)tranylcypromine and milnacipran both increase serotonin levels. Contraindicated.trazodoneSerious - Use Alternative (1)milnacipran and trazodone both increase serotonin levels. Avoid or Use Alternate Drug.trifluoperazineMonitor Closely (1)milnacipran, trifluoperazine. unspecified interaction mechanism. 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).trimipramineSerious - Use Alternative (1)milnacipran and trimipramine both increase serotonin levels. Avoid or Use Alternate Drug.valerianMonitor Closely (1)valerian and milnacipran both increase sedation. Use Caution/Monitor.venlafaxineSerious - Use Alternative (1)milnacipran and venlafaxine both increase serotonin levels. Avoid or Use Alternate Drug.vilazodoneSerious - Use Alternative (1)milnacipran, vilazodone. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug. Concomitant therapy should be discontinued immediately if signs or symptoms of serotonin syndrome emerge and supportive symptomatic treatment should be initiated. .vorapaxarMonitor Closely (1)milnacipran, vorapaxar. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Additive antiplatelet effect may occur; SSRIs and SNRIs may cause platelet serotonin depletion .vortioxetineSerious - Use Alternative (1)milnacipran, vortioxetine. Either increases effects of the other by serotonin levels. Avoid or Use Alternate Drug.warfarinMonitor Closely (1)milnacipran, warfarin. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Serotonin release by platelets plays an important role in hemostasis. SSRIs and SNRIs may increase anticoagulation effect of warfarin. .ziprasidoneMonitor Closely (1)milnacipran, ziprasidone. unspecified interaction mechanism. 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 milnacipran both increase serotonin levels. Modify Therapy/Monitor Closely.Minor (1)milnacipran, zolmitriptan. Mechanism: unknown. Minor/Significance Unknown. Risk of weakness, dyspnea, chest pain. >10% Nausea (37%) Headache (18%) Constipation (16%) Hot flush (12%) Insomnia (12%) 1-10% (selected) Dizziness Hyperhidrosis Hypertension Migraine Palpitations Tachycardia Vomiting Xerostomia Frequency Not Defined Abnormal bleeding Depression (worsening) Serotonin syndrome Suicidal thoughts Withdrawal signs or symptoms Postmarketing Reports Hematologic disorders: Leukopenia, neutropenia, thrombocytopenia Cardiac disorders: Supraventricular tachycardia, takotsubo cardiomyopathy Eye disorders: Accommodation disorder Endocrine disorders: Hyperprolactinemia Gastrointestinal disorders: Acute pancreatitis Hepatobiliary disorders: Hepatitis Metabolic and nutritional disorders: Anorexia, hyponatremia Musculoskeletal and connective tissue disorders: Rhabdomyolysis Neurologic disorders: Convulsions (including grand mal), loss of consciousness, parkinsonism Psychiatric disorders: Aggression, anger, delirium, hallucination, homicidal ideation Renal and urinary disorders: Acute renal failure Reproductive system and breast disorders: Galactorrhea, decreased libido, delayed or absent orgasm Skin disorders: Erythema multiforme, Stevens-Johnson syndrome Vascular disorders: Hypertensive crisis Black Box Warnings In short-term studies, antidepressants increased risk of suicidal thinking and behavior in children, adolescents, and young (<24 years) adults taking antidepressants for major depressive disorders and other psychiatric illnesses This increase was not seen in patients aged >24 years; slight decrease in suicidal thinking was seen in adults aged >65 years In children and young adults, risks must be weighed against 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 Patient’s family should communicate any abrupt behavioral changes to healthcare provider Worsening behavior and suicidal tendencies that are not part of presenting symptoms may necessitate discontinuance of therapy Drug is not approved for use in pediatric patientsContraindications Concomitant use of monoamine oxidase inhibitors (MAOIs), use of MAOIs within 5 days after discontinuance of milnacipran, or initiation of milnacipran within 14 days after discontinuance of MAOIs Patients being treated with linezolid or intravenous methylene blue Cautions Milnacipran is serotonin-norepinephrine reuptake inhibitor (SNRI) similar to those used for depression and other psychiatric disorders; monitoring and close observation for clinical worsening, suicidality, and unusual changes in behavior are necessary, especially during first few months of treatment and when dosage is increased or decreased (see Black Box Warnings) Potentially life-threatening serotonin syndrome has been reported with both SNRIs and selective serotonin reuptake inhibitors (SSRIs) when these agents are taken alone, but especially when they are coadministered with other serotonergic agents; thus, patient medications should be thoroughly reviewed for other serotonergic drugs (eg, tryptophan supplements, tramadol, serotonin agonists [triptans], MAOIs, tricyclic antidepressants [TCAs], SSRIs, methylene blue, buspirone, amphetamines, linezolid) May increase blood pressure (BP) or heart rate (HR); BP should be controlled before initiation of milnacipran; BP and HR should be monitored while patient is taking drug; consider dose reduction or discontinuation of therapy in patients with sustained hypertension or tachycardia during therapy 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 Neonates exposed to SNRIs or SSRIs late in third trimester are at risk for complications such as feeding difficulties, irritability, and respiratory problems Prescription should be written for smallest amount consistent with good patient care; alert family members to monitor for emergence of suicidality, including panic attacks, hostility, irritability, insomnia, anxiety, agitation, mania and hypomania Bone fracture reported with antidepressant treatment; consider possibility of fracture in patients that present with unexplained bone pain, swelling, or bruising Use caution in patients with history of seizures Moderate renal impairment Avoid use in severe hepatic impairment; discontinue therapy with signs of hepatic dysfunction or jaundice; do not reinitiate therapy unless another source or cause identified Avoid concomitant use in patients with substantial alcohol use or chronic liver disease Withdrawal symptoms reported in patients when discontinuing treatment; gradual dose reduction recommended Pupillary