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  • CLASSES

    Serotonin Norepinephrine Reuptake Inhibitor Antidepressants, SNRIs

    BOXED WARNING

    Children, suicidal ideation

    Safe and effective use of levomilnacipran in children has not been established. In October 2004, the FDA directed manufacturers of all antidepressants to add a boxed warning to their product labels detailing the risk of suicide in pediatric patients. The risk of suicidally for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidally during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment with antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in pediatrics or young adults for any use must be weighed against the risk of increased suicidally; patients who are started on therapy should be observed closely for clinical worsening, suicidally, or unusual changes in behavior, particularly within the first few months of starting therapy or during dose changes. It is unknown if the suicidally risk in children or young adults extends to longer-term therapy. The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another primary disorder. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment should be closely monitored during treatment with levomilnacipran. In patients who exhibit worsening of depression or suicidally, a decision should be made to change or discontinue treatment. If discontinuing, the medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. All antidepressants should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdose.

    DEA CLASS

    Rx

    DESCRIPTION

    Serotonin norepinephrine reuptake inhibitor (SNRI).
    Used for the treatment of major depressive disorder in adults.
    Requires close monitoring in pediatrics and young adults due to increased risk of suicidality during the initial stages of treatment.

    COMMON BRAND NAMES

    FETZIMA

    HOW SUPPLIED

    FETZIMA Oral Cap ER: 20mg, 40mg, 80mg, 120mg, 20-40mg

    DOSAGE & INDICATIONS

    For the treatment of major depression.
    Oral dosage
    Adults

    Initially, 20 mg per day PO for 2 days, then increase to 40 mg per day. Thereafter, the dose may be increased in increments of 40 mg at intervals of at least 2 days. The recommended dose range is 40 to 120 mg PO once daily, with or without food. Max: 120 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Generally, acute episodes of depression require several months of sustained pharmacologic therapy. Periodically re-evaluate to determine the need for ongoing maintenance treatment.

    MAXIMUM DOSAGE

    Adults

    120 mg/day PO.

    Geriatric

    120 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    Neonates

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Hepatic elimination of levomilnacipran is low. No dosage adjustments are needed in patients with low, moderate, or severe hepatic impairment.

    Renal Impairment

    CrCl 60 mL/minute or greater: No dosage adjustment required.
    CrCl 30 to 59 mL/minute: Do not exceed 80 mg PO once daily.
    CrCl 15 to 29 mL/minute: Do not exceed 40 mg PO once daily.
    CrCl less than 15 mL/minute: Levomilnacipran is not recommended.
     
    Intermittent hemodialysis:
    Levomilnacipran is not recommended. The extent of removal of levomilnacipran by hemodialysis is unknown; therefore use should be avoided.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Extended-release capsules:
    Administer at approximately the same time each day.
    Have patient swallow whole. Do not open, chew or crush the capsule.
    May administer with or without food. Administration with food may help minimize gastrointestinal side effects.

    STORAGE

    FETZIMA:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Milnacipran hypersensitivity

    Levomilnacipran is contraindicated in patients with a hypersensitivity to levomilnacipran or any ingredient in the formulation, and also in patients with a milnacipran hypersensitivity. Levomilnacipran is a single enantiomer of milnacipran, which is a racemic mixture of d-milnacipran and l-milnacipran.

    Closed-angle glaucoma, increased intraocular pressure

    Levomilnacipran is contraindicated in patients with uncontrolled closed-angle glaucoma. Caution is recommended when prescribing levomilnacipran to patients with controlled closed-angle glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.

    Dehydration, hyponatremia, hypovolemia

    Serotonin norepinephrine reuptake inhibitors (SNRIs) may cause hyponatremia, which is frequently the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In some cases, serum sodium levels less than 110 mmol/L have been reported; however, the adverse effect appeared reversible upon discontinuation of the causative SNRI. Elderly patients, those receiving diuretics or prone to dehydration, and those who are otherwise volume depleted (e.g., hypovolemia) appear to be at greatest risk. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of levomilnacipran, as well as implementation of appropriate medical interventions.

    Dialysis, renal failure, renal impairment

    Renal excretion is a major route of elimination of levomilnacipran. Therefore, dosage adjustments are recommended in patients with moderate (CrCl: 30—59 ml/min) or severe (CrCl: 15—29 ml/min) renal impairment. Levomilnacipran is not recommended in patients with end-stage renal disease (e.g., renal failure). The extent of removal of levomilnacipran during hemodialysis is not known; therefore, use of the drug in patients receiving dialysis should be avoided.

    Urinary retention, urinary tract obstruction

    Caution is advisable when administering levomilnacipran to patients with pre-existing urinary retention, urinary hesitancy, urinary tract obstruction, or those prone to obstructive urinary disorders. Levomilnacipran is in a class of drugs known to affect urethral resistance. Urinary hesitancy (or urinary retention) was an infrequently reported adverse effect in levomilnacipran clinical trials.

    Cardiac arrhythmias, cardiac disease, cerebrovascular disease, coronary artery disease, hypertension, hypotension, myocardial infarction, tachycardia

    Levomilnacipran should be used cautiously in patients with cardiac disease, including those with a recent history of myocardial infarction, unstable coronary artery disease, hypertension, or cerebrovascular disease since levomilnacipran has been associated with elevations in heart rate and blood pressure. Pre-existing hypertension should be controlled and pre-existing cardiac arrhythmias (e.g., tachycardia or other tachyarrhythmias) and other cardiac disease should be treated prior to initiating treatment. Levomilnacipran has not been systematically evaluated in patients with a cardiac rhythm disorder. Further, patients with pre-existing hypotension should be cautioned appropriately and monitored closely since orthostatic hypotension and syncope are possible. Evaluation of blood pressure and heart rate prior to initiating treatment and periodically thereafter during maintenance therapy is recommended. For patients experiencing sustained hypertension or increased heart rate, discontinuation of levomilnacipran or other medical intervention should be considered. Levomilnacipran does not produce a clinically relevant prolongation of the QTc at 2.5 times the maximum recommended dose.

    Children, suicidal ideation

    Safe and effective use of levomilnacipran in children has not been established. In October 2004, the FDA directed manufacturers of all antidepressants to add a boxed warning to their product labels detailing the risk of suicide in pediatric patients. The risk of suicidally for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidally during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment with antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in pediatrics or young adults for any use must be weighed against the risk of increased suicidally; patients who are started on therapy should be observed closely for clinical worsening, suicidally, or unusual changes in behavior, particularly within the first few months of starting therapy or during dose changes. It is unknown if the suicidally risk in children or young adults extends to longer-term therapy. The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another primary disorder. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment should be closely monitored during treatment with levomilnacipran. In patients who exhibit worsening of depression or suicidally, a decision should be made to change or discontinue treatment. If discontinuing, the medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. All antidepressants should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdose.

    Bipolar disorder, mania

    Levomilnacipran should be used cautiously in patients with a personal or family history of bipolar disorder, mania, or hypomania. Use of an antidepressant alone can precipitate mania in patients with bipolar disorder. If a patient develops manic symptoms, levomilnacipran should be withheld, and appropriate therapy initiated to treat the manic symptoms. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant, to include obtaining a detailed personal and family psychiatric history. Patients with depression or co-morbid depression associated with other psychiatric illness being treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of drug therapy or during dose changes. Caregivers should be advised to closely observe the patient and to communicate immediately with the prescriber the emergence of agitation, irritability, unusual changes in behavior, or suicidality.

    Anticoagulant therapy, bleeding, thrombolytic therapy

    Monitor patients taking a serotonin norepinephrine reuptake inhibitor (SNRI) for signs and symptoms of bleeding. Platelet aggregation may be impaired by SNRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage). Concurrent use of anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase this risk. Patients taking levomilnacipran should be cautioned about the risks of combining levomilnacipran with NSAIDs, aspirin, or anticoagulants and instructed to promptly report any bleeding events to the practitioner.

    Seizure disorder, seizures

    Levomilnacipran should be used cautiously in patients with seizures or a seizure disorder. In rare instances, seizures have been reported during treatment with antidepressants. Seizures were reported in one patient during pre-marketing evaluation of levomilnacipran.

    MAOI therapy

    Due to the effects of levomilnacipran on serotonin and norepinephrine, the drug is contraindicated during MAOI therapy or within 14 days of taking an MAOI. A washout period of at least 7 days is required after stopping levomilnacipran before initiation of an MAOI.

    Geriatric

    Of the total number of subjects in clinical studies of levomilnacipran, 2.8% of patients were age 65 or older. Some geriatric patients may experience an increased sensitivity to the adverse effects of antidepressants. An age-related decline in renal function may reduce levomilnacipran clearance, and renal function should be assessed prior to determining dosage. Geriatric adults have an increased risk of developing clinically significant hyponatremia, a known side effect of serotonin norepinephrine reuptake inhibitors (SNRIs). According to the Beers Criteria, SNRIs are considered potentially inappropriate medications (PIMs) in older adults and should be used cautiously because SNRIs can cause or exacerbate hyponatremia and SIADH and the elderly are at increased risk of developing these conditions. Sodium levels should be closely monitored when starting or changing dosages in older adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities. According to OBRA, the duration of therapy should be in accordance with pertinent literature for the condition being treated, including clinical practice guidelines. All residents being treated for depression with any antidepressant should be monitored closely for worsening of depression and/or suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Antidepressants may cause dizziness, nausea, diarrhea, anxiety, nervousness, insomnia, somnolence, weight gain, anorexia, or increased appetite. Many of these effects can increase the risk for falls. Prior to discontinuation, many antidepressants may need a taper to avoid a withdrawal syndrome. Concurrent use of 2 or more antidepressants may increase the risk of side effects; in such cases there should be documentation of expected benefits that outweigh the associated risks and monitoring for any increase in side effects. Monitoring should consist of a review for continued need at least quarterly, and documentation of the rationale for continuation. When the drug is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the medication as outlined in the OBRA guidelines, unless a taper is clinically contraindicated.

    Neonates, pregnancy

    Levomilnacipran is classified as FDA pregnancy risk category C. There are no adequate or well-controlled studies on the use of levomilnacipran during human pregnancy; therefore, alternative agents should be considered. In patients stable on levomilnacipran, the risks of discontinuing treatment should be weighed against the potential risk of levomilnacipran exposure to the fetus. Neonates exposed to serotonergic antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Features are consistent with either a direct toxic effect of serotonergic agents or, possibly, a neonatal abstinence syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. Levomilnacipran did not impair fertility and was not teratogenic, carcinogenic, or mutagenic in animal studies, although an increase in early postnatal mortality was seen in rat studies during use of doses exceeding the maximum recommended human dose.

    Breast-feeding

    According to the manufacturer, a decision should be made to discontinue levomilnacipran or discontinue breast-feeding, taking into account the importance of the drug to the mother. It is not known if levomilnacipran is excreted into breast milk. Other serotonergic antidepressants (e.g., fluoxetine) that are excreted in breast milk have caused increased irritability, colic, vomiting, and decreased sleep in infants. The American Academy of Pediatrics has suggested that the use of serotonin reuptake inhibitors during breast-feeding may be of concern. A pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum and, therefore, may be the preferred antidepressants in breast-feeding mothers. Consider the benefits of breast-feeding, the risk of potential drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding baby experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Infants

    Levomilnacipran is not approved for use in neonates, infants or children under 18 years of age.

    Substance abuse

    Levomilnacipran is not classified as a controlled substance; however, the manufacturer advises caution in patients with a history of substance abuse since the drug has CNS active properties and has not been formally evaluated for its abuse, tolerance, or physical dependence potential.

    Abrupt discontinuation

    Whenever possible, the dosage of levomilnacipran should be tapered gradually and the patient monitored when treatment is discontinued. Adverse effects have been reported following discontinuation of antidepressants, and may be particularly evident during abrupt discontinuation of agents with a short half-life and no active metabolites. Adverse effects may include agitation, anorexia, anxiety, confusion, coordination impaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, vomiting, or other adverse effects. If intolerable symptoms occur during a dose decrease or upon discontinuation of levomilnacipran, consider resuming the previous dose and proceeding with a more gradual taper.

    Driving or operating machinery, ethanol ingestion

    Caution patients about driving or operating machinery, including hazardous tasks, until they are reasonably certain that levomilnacipran therapy does not adversely affect their ability to engage in such activities. Patients should be advised to avoid ethanol ingestion (alcohol ingestion) during levomilnacipran therapy.

    ADVERSE REACTIONS

    Severe

    ocular hemorrhage / Delayed / 0-2.0
    seizures / Delayed / 0-1.0
    serotonin syndrome / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    neonatal abstinence syndrome / Early / Incidence not known

    Moderate

    orthostatic hypotension / Delayed / 11.6-11.6
    urinary retention / Early / 1.0-10.0
    constipation / Delayed / 9.0-9.0
    sinus tachycardia / Rapid / 6.0-6.0
    impotence (erectile dysfunction) / Delayed / 6.0-6.0
    palpitations / Early / 5.0-5.0
    ejaculation dysfunction / Delayed / 5.0-5.0
    hypotension / Rapid / 3.0-3.0
    hypertension / Early / 3.0-3.0
    hot flashes / Early / 3.0-3.0
    elevated hepatic enzymes / Delayed / 0-2.0
    hematuria / Delayed / 0-2.0
    proteinuria / Delayed / 0-2.0
    blurred vision / Early / 0-2.0
    teeth grinding (bruxism) / Delayed / 0-2.0
    migraine / Early / 0-2.0
    chest pain (unspecified) / Early / 0-2.0
    angina / Early / Incidence not known
    dysuria / Early / Incidence not known
    impaired cognition / Early / Incidence not known
    hyponatremia / Delayed / Incidence not known
    mania / Early / Incidence not known
    hallucinations / Early / Incidence not known
    depression / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    platelet dysfunction / Delayed / Incidence not known
    hematoma / Early / Incidence not known
    withdrawal / Early / Incidence not known

    Mild

    nausea / Early / 17.0-17.0
    hyperhidrosis / Delayed / 9.0-9.0
    vomiting / Early / 5.0-5.0
    testicular pain / Early / 4.0-4.0
    anorexia / Delayed / 3.0-3.0
    flatulence / Early / 0-2.0
    abdominal pain / Early / 0-2.0
    increased urinary frequency / Early / 0-2.0
    urticaria / Rapid / 0-2.0
    rash (unspecified) / Early / 2.0-2.0
    pruritus / Rapid / 0-2.0
    xerosis / Delayed / 0-2.0
    maculopapular rash / Early / 0-2.0
    xerophthalmia / Early / 0-2.0
    syncope / Early / 0-2.0
    paresthesias / Delayed / 0-2.0
    polydipsia / Early / 0-2.0
    mydriasis / Early / Incidence not known
    drowsiness / Early / Incidence not known
    dizziness / Early / Incidence not known
    yawning / Early / Incidence not known
    agitation / Early / Incidence not known
    epistaxis / Delayed / Incidence not known
    ecchymosis / Delayed / Incidence not known
    petechiae / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be closely monitored for signs and symptoms of bleeding when a platelet inhibitor is administered with an SNRI.
    Acebutolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Acetaminophen; Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Acetaminophen; Dextromethorphan; Doxylamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Acetaminophen; Pentazocine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Acetaminophen; Tramadol: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and tramadol should be discontinued.
    Aliskiren: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents like aliskiren may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Aliskiren; Amlodipine: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents like aliskiren may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including amlodipine, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents like aliskiren may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including amlodipine, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents like aliskiren may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Aliskiren; Valsartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents like aliskiren may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Almotriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like levomilnacipran with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen.
    Alpha-blockers: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including alpha-blockers, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Alprazolam: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Alteplase, tPA: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SNRI.
    Ambrisentan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including ambrisentan, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Amitriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, the tricyclic antidepressant and concurrent serotonergic agents should be discontinued.
    Amitriptyline; Chlordiazepoxide: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, the tricyclic antidepressant and concurrent serotonergic agents should be discontinued. (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Amlodipine: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including amlodipine, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Amlodipine; Atorvastatin: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including amlodipine, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Amlodipine; Benazepril: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including amlodipine, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including amlodipine, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including amlodipine, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Amlodipine; Olmesartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including amlodipine, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Amlodipine; Telmisartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including amlodipine, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Amlodipine; Valsartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including amlodipine, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Amoxapine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have central serotonergic properties such as amoxapine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors such as clarithromycin. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors such as clarithromycin. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Amphetamine; Dextroamphetamine Salts: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as amphetamines. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, the MAOI activity of amphetamines may be of concern with the use of drugs that have serotonergic activity. A man developed marked agitation, anxiety, diaphoresis, shivering, tachycardia, tremor, generalized hypertonia, hyperreflexia, 1 to 2 beats of inducible ankle clonus, frequent myoclonic jerking, and tonic spasm of the right side of his orbicularis oris muscle while taking dexamphetamine and venlafaxine. Cessation of both drugs and administration of cyproheptadine led to a stepwise heart rate reduction and complete symptom resolution. Patients receiving SNRIs and amphetamines should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The SNRI and amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Amprenavir: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Amprenavir and fosamprenavir are considered strong inhibitors of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Anagrelide: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be closely monitored for signs and symptoms of bleeding when a platelet inhibitor is administered with an SNRI.
    Angiotensin II receptor antagonists: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Angiotensin-converting enzyme inhibitors: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Anticoagulants: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Antithrombin III: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Apixaban: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if levomilnacipran and aprepitant, fosaprepitant are used concurrently and monitor for an increase in levomilnacipran-related adverse effects for several days after administration of a multi-day aprepitant regimen. Levomilnacipran is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of levomilnacipran. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Argatroban: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Articaine; Epinephrine: (Major) Due to the effects of levomilnacipran on noradrenergic pathways, paroxysmal hypertension and arrhythmias may occur during concurrent use of epinephrine.
    Aspirin, ASA: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Carisoprodol: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Dipyridamole: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be closely monitored for signs and symptoms of bleeding when a platelet inhibitor is administered with an SNRI.
    Aspirin, ASA; Omeprazole: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Oxycodone: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Aspirin, ASA; Pravastatin: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Atenolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Atenolol; Chlorthalidone: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Atomoxetine: (Moderate) Levomilnacipran is a serotonin norepinephrine reuptake inhibitor (SNRI) and atomoxetine selectively inhibits norepinephrine reuptake; the drugs have some additive pharmacology that may lead to increases in blood pressure or heart rate.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Azilsartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Azilsartan; Chlorthalidone: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Benazepril: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Bendroflumethiazide; Nadolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Benzodiazepines: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Benzphetamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as amphetamines. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, the MAOI activity of amphetamines may be of concern with the use of drugs that have serotonergic activity. A man developed marked agitation, anxiety, diaphoresis, shivering, tachycardia, tremor, generalized hypertonia, hyperreflexia, 12 beats of inducible ankle clonus, frequent myoclonic jerking, and tonic spasm of the right side of his orbicularis oris muscle while taking dexamphetamine and venlafaxine. Cessation of both drugs and administration of cyproheptadine led to a stepwise heart rate reduction and complete symptom resolution. Patients receiving an SNRI and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The SNRI and amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Beta-adrenergic blockers: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Betaxolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Betrixaban: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Bismuth Subsalicylate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Bisoprolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Bivalirudin: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Boceprevir: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Boceprevir is considered a strong inhibitor of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Bosentan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of bosentan may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Brimonidine; Timolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Bromocriptine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as bromocriptine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Buprenorphine: (Major) Concurrent use of opioids, such as buprenorphine, with other drugs that modulate serotonergic function, such as levomilnacipran or other SNRIs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected.
    Buprenorphine; Naloxone: (Major) Concurrent use of opioids, such as buprenorphine, with other drugs that modulate serotonergic function, such as levomilnacipran or other SNRIs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected.
    Buspirone: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as buspirone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Cabergoline: (Moderate) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties, such as cabergoline. Cabergoline has minimal affinity for serotonin receptors, possibly reducing the risk of this interaction compared to the chemically related ergot alkaloids. However, patients receiving cabergoline with an SNRI should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Candesartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Captopril: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Carteolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Carvedilol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Celecoxib: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Chloramphenicol: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Chloramphenicol is considered a strong inhibitor of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Chlordiazepoxide: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Chlordiazepoxide; Clidinium: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Chlorpheniramine; Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Chlorthalidone; Clonidine: (Major) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of clonidine may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. In addition, because levomilnacipran inhibits the reuptake of norepinephrine, it may antagonize the antihypertensive and other pharmacologic effects of clonidine, a centrally-acting antihypertensive that decreases noradrenergic activity. Use of another antidepressant would be preferable in patients taking clonidine.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Cilostazol: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be closely monitored for signs and symptoms of bleeding when a platelet inhibitor is administered with an SNRI.
    Citalopram: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of levomilnacipran with other drugs that have serotonergic properties, such as selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Clarithromycin: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors such as clarithromycin. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Clomipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, the tricyclic antidepressant and concurrent serotonergic agents should be discontinued.
    Clonazepam: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Clonidine: (Major) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of clonidine may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. In addition, because levomilnacipran inhibits the reuptake of norepinephrine, it may antagonize the antihypertensive and other pharmacologic effects of clonidine, a centrally-acting antihypertensive that decreases noradrenergic activity. Use of another antidepressant would be preferable in patients taking clonidine.
    Clopidogrel: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be closely monitored for signs and symptoms of bleeding when a platelet inhibitor is administered with an SNRI.
    Clorazepate: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Conivaptan: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Conivaptan is considered a strong inhibitor of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Cyclobenzaprine: (Major) Cautious use of cyclobenzaprine and drugs that increase serotonin concentrations such as serotonin norepinephrine reuptake inhibitors (SNRIs) is advised because of the possibility of serotonin syndrome. If these drugs must be used together, closely monitor the patient for signs and symptoms of serotonin syndrome. If such a reaction develops, immediately discontinue cyclobenzaprine and the SSRI. A suspected case of serotonin syndrome was noted in a man who took duloxetine, opiates, and cyclobenzaprine. The man developed worsening confusion, hallucinations, diaphoresis, tachycardia, tremors, marked agitation, spontaneous sustained clonus, and multifocal myoclonus.but recovered after duloxetine and cyclobenzaprine discontinuation and cyproheptadine initiation. In addition, cyclobenzaprine is structurally similar to tricyclic antidepressants (TCAs) and like TCAs, is associated with a possible risk of QT prolongation and torsades de pointes (TdP), particularly in the event of acute overdose. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with cyclobenzaprine include venlafaxine and potentially other SNRIs.
    Dabigatran: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Dalfopristin; Quinupristin: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Dalfopristin; quinupristin is considered a strong inhibitor of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Dalteparin: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Danaparoid: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors such as ritonavir. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention. Additionally, ritonavir could further increase levomilnacipran concentrations by inhibiting its P-glycoprotein (P-gp) metabolism.
    Delavirdine: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Delavirdine is considered a strong inhibitor of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Desipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, the tricyclic antidepressant and concurrent serotonergic agents should be discontinued.
    Desirudin: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Desvenlafaxine: (Severe) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, serotonin norepinephrine reuptake inhibitors (SNRIs), including levomilnacipran and desvenlafaxine, should not be coadministered. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Dexmethylphenidate: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dexmethylphenidate and serotonin norepinephrine reuptake inhibitors (SNRIs). There are rare reports of serotonin syndrome occurring during use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate, a racemic compound containing dexmethylphenidate. There is also a case of a neuroleptic malignant syndrome-like reaction occurring in a child on chronic methylphenidate therapy 45 minutes after ingesting a dose of venlafaxine. It is unclear if the reaction was the result of a drug interaction. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Dextromethorphan; Guaifenesin: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Dextromethorphan; Promethazine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Dextromethorphan; Quinidine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as dextromethorphan. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Diazepam: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Diazoxide: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of diazoxide may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Diclofenac: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Diclofenac; Misoprostol: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Diflunisal: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Digoxin: (Major) Postural hypotension and tachycardia may occur during concurrent use of intravenous digoxin and milnacipran, a racemic mixture containing levomilnacipran. Because the manufacturer of milnacipran recommends against use of milnacipran and intravenous digoxin, use of levomilnacipran with intravenous digoxin should be approached with extreme caution.
    Diltiazem: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of diltiazem may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Diphenhydramine; Ibuprofen: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Diphenhydramine; Naproxen: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Dipyridamole: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be closely monitored for signs and symptoms of bleeding when a platelet inhibitor is administered with an SNRI.
    Diuretics: (Moderate) Patients receiving a diuretic during treatment with venlafaxine may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH may occur during therapy with SNRIs, including venlafaxine. Cases involving serum sodium levels lower than 110 mmol/l have been reported. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of the SNRI should be considered in patients who develop symptomatic hyponatremia.
    Dolasetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering dolasetron with other drugs that have serotonergic properties such as levomilnacipran. If serotonin syndrome is suspected, discontinue dolasetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Dorzolamide; Timolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Doxazosin: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including alpha-blockers, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Doxepin: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, the tricyclic antidepressant and concurrent serotonergic agents should be discontinued.
    Duloxetine: (Severe) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, serotonin norepinephrine reuptake inhibitors (SNRIs) such as levomilnacipran and duloxetine should not be coadministered. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
    Edoxaban: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Elbasvir; Grazoprevir: (Moderate) Administering levomilnacipran with elbasvir; grazoprevir may result in elevated levomilnacipran plasma concentrations. Levomilnacipran is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eletriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like levomilnacipran with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen.
    Enalapril, Enalaprilat: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Enalapril; Felodipine: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of felodipine may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Enoxaparin: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Epinephrine: (Major) Due to the effects of levomilnacipran on noradrenergic pathways, paroxysmal hypertension and arrhythmias may occur during concurrent use of epinephrine.
    Epoprostenol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of epoprostenol may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Eprosartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Eptifibatide: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be closely monitored for signs and symptoms of bleeding when a platelet inhibitor is administered with an SNRI.
    Ergot alkaloids: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as ergot alkaloids. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving these combinations should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Escitalopram: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of levomilnacipran with other drugs that have serotonergic properties, such as selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Esmolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Esomeprazole; Naproxen: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Estazolam: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Etodolac: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Famotidine; Ibuprofen: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Felodipine: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of felodipine may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Fenoldopam: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of fenoldopam may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Fenoprofen: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Fentanyl: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as fentanyl. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Fluoxetine: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of levomilnacipran with other drugs that have serotonergic properties, such as selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Fluoxetine; Olanzapine: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of levomilnacipran with other drugs that have serotonergic properties, such as selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Flurazepam: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Flurbiprofen: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Fluvoxamine: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of levomilnacipran with other drugs that have serotonergic properties, such as selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Fondaparinux: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Fosamprenavir: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Amprenavir and fosamprenavir are considered strong inhibitors of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Fosinopril: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Frovatriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like levomilnacipran with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen.
    Granisetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering granisetron with other drugs that have serotonergic properties such as levomilnacipran. If serotonin syndrome is suspected, discontinue granisetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Guanfacine: (Major) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of clonidine may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. In addition, because levomilnacipran inhibits the reuptake of norepinephrine, it may antagonize the antihypertensive and other pharmacologic effects of guanfacine, a centrally-acting antihypertensive that decreases noradrenergic activity. Use of another antidepressant would be preferable in patients taking guanfacine.
    Heparin: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Hydralazine: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of hydralazine may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of hydralazine may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of hydralazine may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Hydrocodone; Ibuprofen: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Severe) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Ibuprofen: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Ibuprofen; Oxycodone: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Ibuprofen; Pseudoephedrine: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Iloprost: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of iloprost may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Imipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, the tricyclic antidepressant and concurrent serotonergic agents should be discontinued.
    Indinavir: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Indinavir is considered a strong inhibitor of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Indomethacin: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Irbesartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with levomilnacipran may result in increased serum concentrations of levomilnacipran. Levomilnacipran is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH: (Major) Levomilnacipran is a serotonin norepinephrine reuptake inhibitor (SNRI) and concurrent use with drugs with MAOI-activity such as isoniazid, INH should be avoided when possible because the combination may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. A dosage adjustment is recommended during concurrent use of levomilnacipran and strong CYP3A4 inhibitors such as isoniazid. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects. Therefore, the levomilnacipran should not exceed 80 mg/day PO for adults during concurrent use of strong CYP3A4 inhibitors such as isoniazid.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Levomilnacipran is a serotonin norepinephrine reuptake inhibitor (SNRI) and concurrent use with drugs with MAOI-activity such as isoniazid, INH should be avoided when possible because the combination may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. A dosage adjustment is recommended during concurrent use of levomilnacipran and strong CYP3A4 inhibitors such as isoniazid. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects. Therefore, the levomilnacipran should not exceed 80 mg/day PO for adults during concurrent use of strong CYP3A4 inhibitors such as isoniazid.
    Isoniazid, INH; Rifampin: (Major) Levomilnacipran is a serotonin norepinephrine reuptake inhibitor (SNRI) and concurrent use with drugs with MAOI-activity such as isoniazid, INH should be avoided when possible because the combination may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. A dosage adjustment is recommended during concurrent use of levomilnacipran and strong CYP3A4 inhibitors such as isoniazid. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects. Therefore, the levomilnacipran should not exceed 80 mg/day PO for adults during concurrent use of strong CYP3A4 inhibitors such as isoniazid.
    Isradipine: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of isradipine may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Itraconazole: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Itraconazole is considered a strong inhibitor of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Kava Kava, Piper methysticum: (Moderate) The German Commission E and other groups warn that any substances that act on the CNS, including psychopharmacologic agents such as levomilnacipran, may interact with the phytomedicinals kava kava, Piper methysticum. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action.
    Ketoconazole: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors such as ketoconazole. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention. A clinically significant increase in levomilnacipran exposure occurred during co-administration with ketoconazole.
    Ketoprofen: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Ketorolac: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Labetalol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Lansoprazole; Naproxen: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Lepirudin: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of levomilnacipran; monitor for potential reduction in efficacy. Levomilnacipran is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of levomilnacipran; monitor for potential reduction in efficacy. Levomilnacipran is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
    Levobetaxolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Levobunolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Linezolid: (Severe) The use of linezolid with serotonin norepinephrine reuptake inhibitors (SNRIs) such as levomilnacipran is contraindicated due to the potential for serotonin syndrome. Linezolid is an antibiotic that also possesses weak non-selective MAO-inhibiting activity which could have additive effects with SNRIs on central serotonin activity. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In a patient who requires urgent treatment of a psychiatric condition, interventions other than an SNRI, including hospitalization, should be considered. In some cases, a patient already receiving levomilnacipran may require urgent treatment with linezolid. If acceptable alternatives to linezolid are not available and the potential benefits of linezolid are determined to outweigh the risks of serotonin syndrome in an individual patient, levomilnacipran should be stopped promptly, and linezolid can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid, whichever comes first. Therapy with levomilnacipran may be resumed 24 hours after the last dose of linezolid.
    Lisdexamfetamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as lisdexamfetamine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, the MAOI activity of amphetamines may be of concern with the use of drugs that have serotonergic activity. A man developed marked agitation, anxiety, diaphoresis, shivering, tachycardia, tremor, generalized hypertonia, hyperreflexia, 1 to 2 beats of inducible ankle clonus, frequent myoclonic jerking, and tonic spasm of the right side of his orbicularis oris muscle while taking dexamphetamine and venlafaxine. Cessation of both drugs and administration of cyproheptadine led to a stepwise heart rate reduction and complete symptom resolution. Patients receiving SNRIs and amphetamines should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The SNRI and amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Lisinopril: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Lithium: (Major) Lithium is an effective augmenting agent to antidepressants in treatment-resistant depression; however, lithium has been reported to have central serotonin-enhancing effects and may interact pharmacodynamically with levomilnacipran to cause serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients should be informed of the possible increased risk of serotonin syndrome. If serotonin syndrome occurs, levomilnacipran and lithium should be discontinued and symptomatic treatment should be initiated. One systematic review and meta-analysis of lithium augmentation of tricyclic and second generation antidepressants in major depression found no difference in discontinuation rate due to adverse events between the lithium and placebo groups. However, some data indicate that the elderly may have increased susceptibility to neurotoxicity (e.g., fine tremor, ataxia, severe memory impairment, and/or gait disturbances) from concurrent use of lithium and antidepressants, despite therapeutic lithium concentrations.
    Lopinavir; Ritonavir: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors such as ritonavir. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention. Additionally, ritonavir could further increase levomilnacipran concentrations by inhibiting its P-glycoprotein (P-gp) metabolism.
    Lorazepam: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Lorcaserin: (Major) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, serotonin norepinephrine reuptake inhibitors. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms.
    Losartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Magnesium Salicylate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Meclofenamate Sodium: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Mefenamic Acid: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Meloxicam: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Meperidine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as meperidine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Meperidine; Promethazine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as meperidine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Methamphetamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as amphetamines. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, the MAOI activity of amphetamines may be of concern with the use of drugs that have serotonergic activity. A man developed marked agitation, anxiety, diaphoresis, shivering, tachycardia, tremor, generalized hypertonia, hyperreflexia, 1 to 2 beats of inducible ankle clonus, frequent myoclonic jerking, and tonic spasm of the right side of his orbicularis oris muscle while taking dexamphetamine and venlafaxine. Cessation of both drugs and administration of cyproheptadine led to a stepwise heart rate reduction and complete symptom resolution. Patients receiving an SNRI and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The SNRI and amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Severe) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued.
    Methylene Blue: (Severe) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued.
    Methylphenidate: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome has been reported during concurrent use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. There is also a case of a neuroleptic malignant syndrome-like reaction occurring in a child on chronic methylphenidate therapy 45 minutes after ingesting a dose of venlafaxine. It is unclear if the reaction was the result of a drug interaction. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Metoclopramide: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that are dopamine antagonists such as metoclopramide. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, or tardive dyskinesia) and is contraindicated with other drugs that are likely to cause extrapyramidal effects. Dystonia, akathisia, trismus, torticollis, dyskinesia, tardive dyskinesia, pseudo-parkinsonism, and/or extrapyramidal disorder (unspecified) have been reported during use of SNRIs; however, these effects appear uncommon. Patients receiving concurrent treatment with dopamine antagonists may be more predisposed to these reactions. Case reports documenting an interaction between metoclopramide and other serotonergic agents (i.e., SSRIs) suggest that serotonin syndrome and/or movement disorders are possible during combined use of metoclopramide and SNRIs. Patients receiving SNRIs and metoclopramide should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
    Metoprolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Midazolam: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Milnacipran: (Severe) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, serotonin norepinephrine reuptake inhibitors (SNRIs) such as levomilnacipran and milnacipran should not be coadministered. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
    Minoxidil: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of minoxidil may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Mirtazapine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as mirtazapine and levomilnacipran. Cases of serotonin syndrome have been reported between mirtazapine and other antidepressants such as selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Mitotane: (Minor) Use caution if mitotane and levomilnacipran are used concomitantly. Mitotane is a strong CYP3A4 inducer and levomilnacipran is a CYP3A4 substrate. Coadministration may result in decreased plasma concentrations of levomilnacipran; however, in vivo studies showed no clinically meaningful change in levomilnacipran exposure when coadministered with another strong CYP3A inducer, carbamazepine.
    Moexipril: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Monoamine oxidase inhibitors: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with serotonin norepinephrine reuptake inhibitors (SNRIs). MAOIs should not be used within 5 days of discontinuing treatment with duloxetine or within 7 days of discontinuing treatment with other SNRIs. Conversely, SNRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Morphine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the SNRI should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Morphine; Naltrexone: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the SNRI should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Nabumetone: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Nadolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Naproxen: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Naproxen; Pseudoephedrine: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Naproxen; Sumatriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like levomilnacipran with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen. (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Naratriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like levomilnacipran with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen.
    Nebivolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Nebivolol; Valsartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Nefazodone: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as nefazodone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Netupitant; Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as levomilnacipran. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, discontinue palonosetron and levomilnacipran and initiate appropriate medical treatment.
    Nicardipine: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of nicardipine may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Nifedipine: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of nifedipine may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Nisoldipine: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of nisoldipine may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Nitroprusside: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of sodium nitroprusside may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Nonsteroidal antiinflammatory drugs: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Norepinephrine: (Major) Due to the effects of levomilnacipran on noradrenergic pathways, paroxysmal hypertension and arrhythmias may occur during concurrent use of norepinephrine.
    Nortriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, the tricyclic antidepressant and concurrent serotonergic agents should be discontinued.
    Olmesartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors such as ritonavir. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention. Additionally, ritonavir could further increase levomilnacipran concentrations by inhibiting its P-glycoprotein (P-gp) metabolism.
    Ondansetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as levomilnacipran. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Oxaprozin: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Oxazepam: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as levomilnacipran. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, discontinue palonosetron and levomilnacipran and initiate appropriate medical treatment.
    Paroxetine: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of levomilnacipran with other drugs that have serotonergic properties, such as selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Penbutolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Pentazocine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Pentazocine; Naloxone: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Pentosan: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Perindopril: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Perindopril; Amlodipine: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including amlodipine, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Perphenazine; Amitriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, the tricyclic antidepressant and concurrent serotonergic agents should be discontinued.
    Phenoxybenzamine: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including alpha-blockers, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Phentermine: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report describes adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal therapies.
    Phentermine; Topiramate: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report describes adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal therapies.
    Phentolamine: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including alpha-blockers, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Pindolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Piroxicam: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Platelet Inhibitors: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be closely monitored for signs and symptoms of bleeding when a platelet inhibitor is administered with an SNRI.
    Posaconazole: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Posaconazole is considered a strong inhibitor of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Prasugrel: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be closely monitored for signs and symptoms of bleeding when a platelet inhibitor is administered with an SNRI.
    Prazosin: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including alpha-blockers, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Prilocaine; Epinephrine: (Major) Due to the effects of levomilnacipran on noradrenergic pathways, paroxysmal hypertension and arrhythmias may occur during concurrent use of epinephrine.
    Procarbazine: (Major) Concurrent use of procarbazine and serotonin norepinephrine reuptake inhibitors (SNRIs) should be avoided if possible. Procarbazine is a weak monoamine oxidase inhibitor (MAOI). Since monoamine oxidase type A deaminates serotonin, administration of a non-selective MAO inhibitor concurrently with an SNRI can lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If combination therapy is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Propranolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Protriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, the tricyclic antidepressant and concurrent serotonergic agents should be discontinued.
    Quazepam: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Quinapril: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Ramipril: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Rasagiline: (Major) It is recommended to avoid concurrent use of rasagiline and antidepressants, including serotonin norepinephrine reuptake inhibitors (SNRIs). Severe CNS toxicity with hyperpyrexia has been reported during concurrent use of antidepressants and selective or non-selective MAOIs. During post-marketing use of rasagiline, non-fatal cases of serotonin syndrome have been reported during concomitant antidepressant administration. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. At least 2 weeks should elapse between stopping rasagiline treatment and beginning therapy with any antidepressant. Conversely, when discontinuing the antidepressant, it is advisable to wait the length of 4 to 5 half lives of the individual agent being discontinued prior to initiation with rasagiline.
    Remifentanil: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Reserpine: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of reserpine may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Reteplase, r-PA: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SNRI.
    Ribociclib: (Moderate) Use caution if coadministration of ribociclib with levomilnacipran is necessary, as the systemic exposure of levomilnacipran may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and levomilnacipran is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Moderate) Use caution if coadministration of ribociclib with levomilnacipran is necessary, as the systemic exposure of levomilnacipran may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and levomilnacipran is a CYP3A4 substrate.
    Ritonavir: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors such as ritonavir. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention. Additionally, ritonavir could further increase levomilnacipran concentrations by inhibiting its P-glycoprotein (P-gp) metabolism.
    Rivaroxaban: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Rizatriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like levomilnacipran with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen.
    Rofecoxib: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Sacubitril; Valsartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Safinamide: (Severe) Safinamide is contraindicated for use with serotonin norepinephrine reuptake inhibitors (SNRIs) due to the risk of serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least 14 days should elapse between the discontinuation of safinamide and the initiation of an SNRI.
    Salicylates: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Salsalate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
    Selective serotonin reuptake inhibitors: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of levomilnacipran with other drugs that have serotonergic properties, such as selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Serotonin-Receptor Agonists: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like levomilnacipran with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen.
    Sertraline: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of levomilnacipran with other drugs that have serotonergic properties, such as selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Sibutramine: (Major) Sibutramine is a serotonin reuptake inhibitor. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering sibutramine with other drugs that have serotonergic properties such as serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving sibutramine in combination with an SNRI should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    St. John's Wort, Hypericum perforatum: (Major) Due to possible additive effects on serotonin concentrations, it is advisable to avoid combinations of St. John's wort, Hypericum perforatum with serotonin norepinephrine reuptake inhibitors (SNRIs). Interactions between SNRIs and serotonergic agents can lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Streptogramins: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Dalfopristin; quinupristin is considered a strong inhibitor of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Streptokinase: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SNRI.
    Sulindac: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Sumatriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like levomilnacipran with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen.
    Tapentadol: (Major) Caution is advised when tapentadol is coadministered with serotonin norepinephrine reuptake inhibitors as this combination may result in excessive concentrations of serotonin and/or norepinephrine and increase the potential for adverse cardiac events and serotonin syndrome development. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage adjustments (increases) of either agent.
    Tedizolid: (Minor) Use caution with the concurrent use of tedizolid and serotonin norepinephrine reuptake inhibitors (SNRIs) due to the theoretical risk of serotonin sydrome. Animal studies did not predict serotonergic effects; however, patients on concurrent SNRIs were excluded from clinical trials. Additionally, tedizolid is an antibiotic that is also a weak reversible, non-selective MAO inhibitor and monoamine oxidase type A deaminates serotonin; therefore, coadministration theoretically could lead to serious reactions including serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Telaprevir: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Telaprevir is considered a strong inhibitor of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Telithromycin: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Telithromycin is considered a strong inhibitor of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Telmisartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Telotristat Ethyl: (Minor) Use caution if coadministration of telotristat ethyl and levomilnacipran is necessary, as theoretically, the systemic exposure of levomilnacipran may be decreased resulting in reduced efficacy. Levomilnacipran is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. In vivo studies showed no clinically meaningful change in levomilnacipran exposure when coadministered with the CYP3A4 inducer carbamazepine.
    Temazepam: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Tenecteplase, TNK-tPA: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SNRI.
    Terazosin: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of antihypertensive agents, including alpha-blockers, may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Thrombolytic Agents: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SNRI.
    Ticagrelor: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be closely monitored for signs and symptoms of bleeding when a platelet inhibitor is administered with an SNRI.
    Ticlopidine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be closely monitored for signs and symptoms of bleeding when a platelet inhibitor is administered with an SNRI.
    Timolol: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of beta-blockers may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Tinzaparin: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Tipranavir: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors. Tipranavir is considered a strong inhibitor of CYP3A4. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention.
    Tirofiban: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be closely monitored for signs and symptoms of bleeding when a platelet inhibitor is administered with an SNRI.
    Tolmetin: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Tramadol: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and tramadol should be discontinued.
    Trandolapril: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Trandolapril; Verapamil: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin-converting enzyme inhibitors may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary. (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of verapamil may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Trazodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as trazodone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and trazodone should be discontinued.
    Treprostinil: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of treprostinil may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Triazolam: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
    Tricyclic antidepressants: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, the tricyclic antidepressant and concurrent serotonergic agents should be discontinued.
    Trimipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, the tricyclic antidepressant and concurrent serotonergic agents should be discontinued.
    Urokinase: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SNRI.
    Valdecoxib: (Moderate) Platelet aggregation may be impaired by SNRIs such as levomilnacipran due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Monitor for signs and symptoms of bleeding in patients taking levomilnacipran and NSAIDs.
    Valsartan: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of angiotensin II receptor antagonists may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Venlafaxine: (Severe) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, serotonin norepinephrine reuptake inhibitors (SNRIs) such as levomilnacipran and venlafaxine should not be coadministered. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
    Verapamil: (Moderate) Levomilnacipran has been associated with an increase in blood pressure. The effectiveness of verapamil may be diminished during concurrent use of levomilnacipran. It is advisable to monitor blood pressure if the combination is necessary.
    Vilazodone: (Major) Due to possible additive effects on serotonin concentrations, it is advisable to avoid combining serotonin norepinephrine reuptake inhibitors (SNRIs) with vilazodone. Interactions between vilazodone and serotonergic agents can lead to serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving vilazodone and an SNRI should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. Vilazodone and the SNRI should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Vorapaxar: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be closely monitored for signs and symptoms of bleeding when a platelet inhibitor is administered with an SNRI.
    Vortioxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, vortioxetine should generally not be administered with serotonin norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, desvenlafaxine, duloxetine, and milnacipran. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, vortioxetine and concurrent serotonergic agents should be discontinued.
    Warfarin: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Zolmitriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like levomilnacipran with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen.
    Zolpidem: (Moderate) Disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and some SNRI antidepressants. The duration of the visual hallucinations has ranged from 30 minutes to 7 hours. The interaction is thought to be pharmacodynamic in nature; therefore, a similar reaction is possible with levomilnacipran. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, a decision should be made to discontinue levomilnacipran or discontinue breast-feeding, taking into account the importance of the drug to the mother. It is not known if levomilnacipran is excreted into breast milk. Other serotonergic antidepressants (e.g., fluoxetine) that are excreted in breast milk have caused increased irritability, colic, vomiting, and decreased sleep in infants. The American Academy of Pediatrics has suggested that the use of serotonin reuptake inhibitors during breast-feeding may be of concern. A pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum and, therefore, may be the preferred antidepressants in breast-feeding mothers. Consider the benefits of breast-feeding, the risk of potential drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding baby experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Decreased adrenergic and serotoninergic neurotransmission has been proposed to play a key role in the etiology of depression. It is theorized that the mechanism of action of serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors involves blockade of the central presynaptic reuptake of 5-HT and NE, resulting in an increased sustained level of these neurotransmitters. A change in postsynaptic receptor characteristics with chronic administration is thought to contribute to the efficacy of antidepressants. Serotonin is a neurotransmitter which regulates an extensive modulatory behavioral system in the brain. The serotoninergic system is known to modulate mood, emotion, sleep, and appetite and thus is implicated in the control of numerous behavioral and physiological functions. Norepinephrine is an adrenergic neurotransmitter which appears to be involved in a range of psychological processes, including mood stabilization, sleep regulation, overall alertness and arousal, and in regulating response to stressors which might initiate or exacerbate depressive symptomatology. Levomilnacipran does not possess monoamine oxidase inhibiting activity. In addition, levomilnacipran lacks significant affinity for alpha- and beta-adrenergic, muscarinic, and histaminergic receptors.

    PHARMACOKINETICS

    Levomilnacipran is administered orally. Levomilnacipran is an enantiomer of racemic milnacipran. The drug has a large volume of distribution, and clinically insignificant plasma protein binding (22%). Metabolism occurs through desethylation to form the major metabolite N-desethyl levomilnacipran, and through hydroxylation to form p-hydroxy-levomilnacipran. The metabolites, which are inactive, undergo conjugation with glucuronide to form conjugates. Desethylation occurs primarily by CYP3A4 with minor contributions by CYP2C8, CYP2C19, CYP2D6, and CYP2J2. The half-life of the parent compound is about 12 hours. Levomilnacipran and its metabolites are eliminated primarily by renal excretion. About 58% of a dose is excreted as levomilnacipran, and 18% of a dose is excreted as N-desethyl levomilnacipran. The remaining identifiable metabolites account for 9% of a dose.
     
    Affected cytochrome P450 enzymes: CYP3A4, CYP2C8, CYP2C19, CYP2D6, CYP2J2, P-gp
    The isoenzyme CYP3A4 contributes to the metabolism of levomilnacipran; the drug is also a weak substrate of P-gp. Do not exceed 80 mg/day in adults during the concurrent use of strong CYP3A4 inhibitors. In vitro studies suggest that CYP2C8, CYP2C19, CYP2D6, and CYP2J2 have only minimal contributions to the metabolism; therefore, no dosage adjustments are needed during use of inhibitors of these isoenzymes. In addition, no clinically significant change in levomilnacipran exposure occurred during coadministration with carbamazepine, a strong CYP3A4 inducer, or alprazolam, a primary CYP3A4 substrate. Levomilnacipran is not a substrate of BCRP, OATP1B1, OATP1B3, OAT3, or OCT2.

    Oral Route

    The relative bioavailability of the extended-release formulation of levomilnacipran is about 92% compared to an oral solution of the drug. The time to reach peak plasma concentrations following an oral dose is 6—8 hours. Food does not significantly affect plasma concentrations of levomilnacipran; therefore, the drug can be administered with or without food.