Version May 2024
Milnacipran is a selective serotonin-norepinephrine reuptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders. Antidepressants increased the risk, compared with placebo, of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of such drugs in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults older than 24 years; there was a reduction in risk with antidepressants compared with placebo in adults 65 years and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on milnacipran should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Milnacipran is not approved for use in the treatment of MDD. Milnacipran is not approved for use in pediatric patients.
Fibromyalgia: Oral: 50 mg twice daily.
Titration schedule: 12.5 mg once on day 1, then 12.5 mg twice daily on days 2 to 3, 25 mg twice daily on days 4 to 7, then 50 mg twice daily thereafter. Dose may be increased to 100 mg twice daily, based on individual response. Doses >200 mg daily have not been studied.
Major depressive disorder (off-label use) : Oral: Initial: 25 to 50 mg twice daily; may further increase dose based on response and tolerability up to 100 mg twice daily (Ref).
Discontinuation of therapy: When discontinuing antidepressant treatment that has lasted for >3 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (Ref). Reasons for a slower taper (eg, over 4 weeks) include use of a drug with a half-life <24 hours (eg, paroxetine, venlafaxine), prior history of antidepressant withdrawal symptoms, or high doses of antidepressants (Ref). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Ref). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (Ref). Evidence supporting ideal taper rates is limited (Ref).
Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches, but is contraindicated when switching to or from an MAOI. A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between two SSRIs), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, pharmacodynamics), and the degree of symptom control desired (Ref).
Switching to or from an MAOI:
Allow ≥14 days to elapse between discontinuing an MAOI and initiation of milnacipran.
Allow ≥5 days to elapse between discontinuing milnacipran and initiation of MAOI.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Mild renal impairment: No dosage adjustment necessary.
Moderate renal impairment: Use with caution.
Severe renal impairment (CrCl ≤29 mL/minute): Reduce maintenance dose to 25 mg twice daily; dose may be increased to 50 mg twice daily, based on individual tolerance.
End-stage renal disease (ESRD): Use not recommended.
Mild-to-moderate hepatic impairment: No dosage adjustment necessary.
Severe hepatic impairment: No dosage adjustment necessary; use with caution
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reaction reported in adults.
>10%:
Endocrine & metabolic: Hot flash (11% to 12%)
Gastrointestinal: Constipation (15% to 16%), nausea (35% to 39%)
Nervous system: Dizziness (10% to 11%), headache (17% to 19%), insomnia (12%)
1% to 10%:
Cardiovascular: Chest discomfort (2%), chest pain (3%), flushing (2% to 3%), hypertension (4% to 7%), palpitations (7% to 8%), peripheral edema (≥1%), tachycardia (2% to 3%)
Dermatologic: Hyperhidrosis (8% to 9%), night sweats (≥1%), pruritus (3%), skin rash (3% to 4%)
Endocrine & metabolic: Decreased libido (≥2%), hypercholesterolemia (≥1%), weight changes (≥1%)
Gastrointestinal: Abdominal distention (≥1%), abdominal pain (3%), decreased appetite (1% to 2%), diarrhea (≥1%), dysgeusia (≥1%), dyspepsia (≥1%), flatulence (≥1%), gastroesophageal reflux disease (≥1%), vomiting (6% to 7%), xerostomia (5%)
Genitourinary: Cystitis (≥1%), decreased urine output (≥2%), dysuria (≥2%), ejaculation failure (≥2%), ejaculatory disorder (≥2%), erectile dysfunction (≥2%), prostatitis (≥2%), scrotal pain (≥2%), testicular pain (≥2%), testicular swelling (≥2%), urethral pain (≥2%), urinary hesitancy (≥2%), urinary retention (≥2%), urinary tract infection (≥1%)
Hematologic & oncologic: Bruise (≥1%)
Hepatic: Increased serum alanine aminotransferase (6% to 7%), increased serum aspartate aminotransferase (3% to 5%)
Nervous system: Anxiety (5%), chills (1% to 2%), depression (≥1%), drowsiness (≥1%), falling (≥1%), fatigue (≥1%), hypoesthesia (2%), irritability (≥1%), migraine (4% to 6%), paresthesia (3%), stress (≥1%), suicidal ideation (1%), tension headache (2%), tremor (2%)
Ophthalmic: Blurred vision (2%)
Respiratory: Dyspnea (2%), upper respiratory tract infection (7%)
Miscellaneous: Fever (≥1%)
Frequency not defined: Nervous system: Suicidal tendencies
Postmarketing:
Cardiovascular: Cardiomyopathy (takotsubo), hypertensive crisis, Raynaud disease (Khouri 2016; Peiró 2007), supraventricular tachycardia
Dermatologic: Erythema multiforme, Stevens-Johnson syndrome
Endocrine & metabolic: Galactorrhea not associated with childbirth, hyperprolactinemia, hyponatremia
Gastrointestinal: Acute pancreatitis, anorexia
Genitourinary: Abnormal orgasm (absent or delayed)
Hematologic & oncologic: Leukopenia, neutropenia, thrombocytopenia
Hepatic: Hepatitis
Nervous system: Aggressive behavior, anosmia (including hyposmia), delirium, hallucination, homicidal ideation, loss of consciousness, neuroleptic malignant syndrome (Stevens 2008), outbursts of anger, parkinsonism, seizure
Neuromuscular & skeletal: Rhabdomyolysis
Ophthalmic: Accommodation disturbance
Renal: Acute kidney injury
Use of MAOIs intended to treat psychiatric disorders (concurrently or within 5 days of discontinuing milnacipran, or within 2 weeks of discontinuing the MAOI); initiation of milnacipran in a patient receiving linezolid or methylene blue IV
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Major psychiatric warnings:
• Suicidal thinking/behavior: [US Boxed Warning]: Milnacipran is a serotonin/norepinephrine reuptake inhibitor (SNRI) similar to SNRIs used to treat depression and other psychiatric disorders. Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years of age. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with health care provider. A medication guide concerning the use of antidepressants in children and teenagers should be dispensed with each prescription. Milnacipran is not FDA-approved for the treatment of major depressive disorder or for use in children.
• Suicide risk: Suicide risks should be monitored in patients treated with SNRIs regardless of the indication. The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.
• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their health care provider if any of these symptoms or worsening depression occurs.
Concerns related to adverse effects:
• Bleeding risk: May impair platelet aggregation resulting in increased risk of bleeding events, particularly if used concomitantly with aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants due to ulcerogenic potential. Risk of postpartum bleeding may be increased with selective serotonin reuptake inhibitor (SSRI) use, particularly in the month prior to delivery. Bleeding related to SNRI use has been reported to range from bruising, hematoma, epistaxis, and petechiae to life-threatening hemorrhage.
• Cardiovascular effects: May increase blood pressure and heart rate. Preexisting cardiovascular disease (including hypertension and tachyarrhythmias) should be treated prior to initiating therapy. Blood pressure and heart rate should be evaluated prior to initiating therapy and periodically thereafter; consider dose reduction or gradual discontinuation of therapy in individuals with sustained hypertension or tachycardia during therapy. Use with caution in patients with preexisting hypertension, tachyarrhythmias (eg, atrial fibrillation), or other cardiovascular disease, and with concomitant medications known to increase blood pressure or heart rate.
• Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda 2013; Rizzoli 2012).
• Hepatotoxicity: Generally, avoid use in patients with substantial ethanol intake or evidence of chronic liver disease. Cases of increased liver enzymes and severe liver injury (including fulminant hepatitis) have been reported. Discontinue therapy with the presentation of jaundice or other signs of hepatic dysfunction and do not reinitiate therapy unless another source or cause is identified.
• Ocular effects: May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.
• Serotonin syndrome: Potentially life-threatening serotonin syndrome (SS) has occurred with serotonergic agents (eg, SSRIs, SNRIs) when used alone, but also particularly when used in combination with other serotonergic agents (eg, triptans, tricyclic antidepressants, fentanyl, lithium, meperidine, methadone, tramadol, buspirone, amphetamines, St John's wort, tryptophan) or agents that impair metabolism of serotonin (eg, monoamine oxidase inhibitors [MAOIS] intended to treat psychiatric disorders, other MAOIs [ie, linezolid and intravenous methylene blue]). Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.
• Sexual dysfunction: SNRIs have been associated with symptoms of sexual dysfunction. In males, symptoms include ejaculatory delay/failure, decreased libido, and erectile dysfunction. Decreased libido and absent/delayed orgasm have occurred in women. Evaluate patients’ sexual function prior to initiating therapy; rule out any underlying causes.
• SIADH and hyponatremia: SSRIs and SNRIs have been associated with the development of SIADH; hyponatremia has been reported rarely (including severe cases with serum sodium <110 mmol/L), predominately in elderly patients. Volume depletion and/or concurrent use of diuretics likely increases risk.
• Urinary hesitancy: May cause increased urinary resistance; advise patient to report symptoms of urinary hesitation/difficulty. Use caution in patients with a history of dysuria, especially males with prostatic hypertrophy, prostatitis, or other lower urinary tract disorders.
Disease-related concerns:
• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Combination therapy with an antidepressant and a mood stabilizer should also be avoided in acute mania or mixed episodes, as well as maintenance treatment in bipolar disorder due to the mood-destabilizing effects of antidepressants (CANMAT [Yatham 2018]; WFSBP [Grunze 2018]). Patients presenting with depressive symptoms should be screened for bipolar disorder. Milnacipran is not FDA approved for the treatment of bipolar disorder.
• Seizure disorders: Use caution with a previous seizure disorder or condition predisposing to seizures such as brain damage or alcoholism.
Special populations:
• Older adult: Use caution in older adult patients; may cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion or hyponatremia.
Other warnings/precautions:
• Discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, light-headedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010; Fava 2006; Haddad 2001; Shelton 2001; Warner 2006).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Miscellaneous, Oral:
Savella Titration Pack: 12.5 & 25 & 50 mg (55 ea) [contains fd&c blue #2 (indigo carm) aluminum lake]
Tablet, Oral:
Savella: 12.5 mg [contains fd&c blue #2 (indigo carm) aluminum lake]
Savella: 25 mg, 50 mg
Savella: 100 mg [contains fd&c red #40(allura red ac)aluminum lake]
No
Misc (Savella Titration Pack Oral)
12.5 & 25 & 50 mg (per each): $9.75
Tablets (Savella Oral)
12.5 mg (per each): $9.75
25 mg (per each): $9.75
50 mg (per each): $9.75
100 mg (per each): $9.75
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Oral: Administer with or without food; food may improve tolerability.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/022256s028lbl.pdf#page=31, must be dispensed with this medication.
Fibromyalgia: Management of fibromyalgia
Major depressive disorder
Milnacipran may be confused with levomilnacipran
Savella may be confused with cevimeline, sevelamer
Beers Criteria: Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) (milnacipran) are identified in the Beers Criteria as a potentially inappropriate medication to be used with caution in patients 65 years and older due to their potential to cause or exacerbate syndromes of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium concentration closely when initiating or adjusting the dose in older adults (Beers Criteria [AGS 2023]).
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Abrocitinib: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Abrocitinib. Risk X: Avoid combination
Acalabrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the hepatotoxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Particularly duloxetine and milnacipran. Management: Consider advising patients to avoid concomitant use of alcohol with SNRIs, particularly those using extended-release SNRI formulations, due to the risk of accelerated drug release. Heavy alcohol use has been associated with overdose and hepatotoxicity. Risk D: Consider therapy modification
Almotriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Alosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Alpha-/Beta-Agonists: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the tachycardic effect of Alpha-/Beta-Agonists. Serotonin/Norepinephrine Reuptake Inhibitors may enhance the vasopressor effect of Alpha-/Beta-Agonists. Management: If possible, avoid coadministration of direct-acting alpha-/beta-agonists and serotonin/norepinephrine reuptake inhibitors. If coadministered, monitor for increased sympathomimetic effects (eg, increased blood pressure, chest pain, headache). Risk D: Consider therapy modification
Alpha2-Agonists: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the therapeutic effect of Alpha2-Agonists. Risk C: Monitor therapy
Amphetamines: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed. Risk C: Monitor therapy
Anagrelide: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy
Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Antiplatelet Agents (P2Y12 Inhibitors): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). Risk C: Monitor therapy
Antipsychotic Agents: Serotonergic Agents (High Risk) may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
Apixaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Risk C: Monitor therapy
Aspirin: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy
Bemiparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin with antiplatelet agents. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Brexanolone: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Bromopride: May enhance the adverse/toxic effect of Serotonin/Norepinephrine Reuptake Inhibitors. Risk X: Avoid combination
BusPIRone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Caplacizumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Caplacizumab. Specifically, the risk of bleeding may be increased. Management: Avoid coadministration of caplacizumab with antiplatelets if possible. If coadministration is required, monitor closely for signs and symptoms of bleeding. Interrupt use of caplacizumab if clinically significant bleeding occurs. Risk D: Consider therapy modification
Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy
Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and or bleeding may be increased. Risk C: Monitor therapy
Cyclobenzaprine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Dabigatran Etexilate: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Risk C: Monitor therapy
Dapoxetine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Risk X: Avoid combination
Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy
Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Dexmethylphenidate-Methylphenidate: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Dextromethorphan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Digoxin: Milnacipran may enhance the adverse/toxic effect of Digoxin. The risk of postural hypotension and tachycardia may be increased. Risk X: Avoid combination
Edoxaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Risk C: Monitor therapy
Eletriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Enoxaparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue antiplatelet agents prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Ergot Derivatives: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Fenfluramine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
FentaNYL: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor therapy
Gepirone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy
Heparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or agents with antiplatelet properties if coadministration is required. Risk D: Consider therapy modification
Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Risk C: Monitor therapy
Ibritumomab Tiuxetan: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Risk C: Monitor therapy
Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Icosapent Ethyl: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Inotersen: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Iobenguane Radiopharmaceutical Products: Serotonin/Norepinephrine Reuptake Inhibitors may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer these drugs until at least 7 days after each iobenguane dose. Risk X: Avoid combination
Lasmiditan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Lecanemab: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of hemorrhage may be increased. Risk C: Monitor therapy
Levomethadone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Linezolid: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination
Lipid Emulsion (Fish Oil Based): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Lorcaserin (Withdrawn From US Market): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Meperidine: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor therapy
Metaxalone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Methadone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Methylene Blue: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
Metoclopramide: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Consider monitoring for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Mirtazapine: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors (Antidepressant): May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination
Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Nefazodone: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Nonselective): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Topical): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Topical). Risk C: Monitor therapy
Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy
Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Ondansetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Opioid Agonists: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Opioid Agonists (metabolized by CYP3A4 and CYP2D6): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Opioid Agonists (metabolized by CYP3A4): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Oxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Ozanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Risk C: Monitor therapy
Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Pirtobrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Ramosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Rasagiline: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination
Rivaroxaban: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Rivaroxaban. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Risk C: Monitor therapy
Safinamide: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination
Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of Serotonin/Norepinephrine Reuptake Inhibitors. Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Risk C: Monitor therapy
Selegiline: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Risk X: Avoid combination
Selumetinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Serotonergic Agents (High Risk, Miscellaneous): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Serotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the antiplatelet effect of other Serotonin/Norepinephrine Reuptake Inhibitors. Serotonin/Norepinephrine Reuptake Inhibitors may enhance the serotonergic effect of other Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, mental status changes) when these agents are combined. In addition, monitor for signs and symptoms of bleeding. Risk C: Monitor therapy
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
St John's Wort: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of Serotonergic Agents (High Risk). Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Syrian Rue: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
TraMADol: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the adverse/toxic effect of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and seizures when these agents are combined. Risk C: Monitor therapy
TraZODone: May enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Tricyclic Antidepressants: Serotonin/Norepinephrine Reuptake Inhibitors may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes when these agents are combined. Risk C: Monitor therapy
Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Risk X: Avoid combination
Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Serotonin/Norepinephrine Reuptake Inhibitors may enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy
Zanubrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy
Milnacipran is associated with sexual dysfunction in males and females. Evaluate sexual function prior to and during therapy; rule out any underlying causes if changes in sexual function occur.
Nonteratogenic adverse events have been observed with milnacipran or other SNRIs/SSRIs when used during pregnancy. Cyanosis, apnea, respiratory distress, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypo- or hypertonia, hyper-reflexia, jitteriness, irritability, constant crying, and tremor have been reported in the neonate immediately following delivery after exposure to SSRIs, or SNRIs late in the third trimester.
Prolonged hospitalization, respiratory support, or tube feedings may be required. Some symptoms may be due to the toxicity of the SNRIs/SSRIs or a discontinuation syndrome and may be consistent with serotonin syndrome associated with treatment.
SNRI exposure late in pregnancy may increase the risk of bleeding, including postpartum hemorrhage.
Data collection to monitor pregnancy and infant outcomes following exposure to milnacipran is ongoing. Health care providers are encouraged to enroll patients exposed to milnacipran during pregnancy in the Savella Pregnancy Registry (877-643-3010 or http://www.savellapregnancyregistry.com).
Milnacipran is present in breast milk.
According to product labeling, data related to the presence of milnacipran in breast milk are available from 8 lactating women given a single dose of oral milnacipran 50 mg. Patients were ≥ 12 weeks postpartum. The estimated exposure of milnacipran via breast milk was reported to be 5% of the maternal dose, calculated using peak breast milk concentration
Agitation, irritability, poor feeding, and poor weight gain have been reported in infants exposed to SNRIs/SSRIs via breast milk. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Monitor infants exposed to milnacipran via breast milk.
BP and heart rate should be regularly monitored; renal function should be monitored for dosing purposes; mental status for suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased); intraocular pressure should be monitored in those with baseline elevations or a history of glaucoma; signs of sexual dysfunction; signs of serotonin syndrome such as mental status changes (eg, agitation, hallucinations, delirium, coma), autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia, incoordination), neuromuscular changes (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), GI symptoms (eg, nausea, vomiting, diarrhea), and/or seizures.
Potent inhibitor of norepinephrine and serotonin reuptake (3:1). Milnacipran has no significant activity for serotonergic, alpha- and beta-adrenergic, muscarinic, histaminergic, dopaminergic, opiate, benzodiazepine, and GABA receptors. It does not possess MAO-inhibitory activity.
Absorption: Well absorbed.
Distribution: IV: Vd: ~400 L.
Protein binding: 13%.
Metabolism: Hepatic to inactive metabolites.
Bioavailability: ~85% to 90%.
Half-life elimination: ~6 to 8 hours.
Time to peak, plasma: Oral: 2 to 4 hours.
Excretion: Urine (~55% as unchanged drug).
Altered kidney function: The AUC increased by 16%, 52%, and 199%, and terminal half-life increased by 38%, 41%, and 122% in patients with mild, moderate, and severe renal impairment, respectively.
Hepatic function impairment: AUC and half-life are similar in healthy subjects and subjects with mild and moderate hepatic impairment. In subjects with severe hepatic impairment, the AUC and half-life are increased 31% and 55%, respectively, compared with healthy subjects.
Older adult: Because of age-related decreases in renal function, Cmax and AUC are ~30% higher in those >65 years of age compared with younger subjects.
Sex: Cmax and AUC of milnacipran were ~20% higher in women compared with men.
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