mil-na-SIP-ran

Therapeutic Classification: antifibromyalgia agents

Pharmacologic Classification: selective norepinephrine reuptake inhibitors

• Fibromyalgia.

• Inhibits neuronal reuptake of norepinephrine and serotonin.

• Decreased pain associated with fibromyalgia.

Absorption: 85–90% absorbed following oral administration.

Distribution: Unknown.

Metabolism/Excretion: Mostly excreted in urine as unchanged drug (55%) and inactive metabolites.

Half-life: D: isomer 8–10 hr; L: isomer 4–6 hr.

(↓ in pain)

Contraindicated in:

• Concurrent use of MAO inhibitors or MAO-like drugs (linezolid or methylene blue)
• End-stage renal disease
• Significant history of alcohol use/abuse
• Chronic liver disease
• Lactation: Lactation.

Use Cautiously in:

• History of suicide risk or attempt
• History of seizures
• Moderate to severe renal impairment (↓ dose if CCr <30 mL/min)
• Hypertension
• Severe hepatic impairment
• Obstructive uropathy (↑ risk of adverse genitourinary effects)
• Angle-closure glaucoma
• OB: Use during pregnancy only if potential maternal benefit justifies potential fetal risk
• Pedi: ↑risk of suicidal thinking and behavior (suicidality) in adolescents and young adults up to 24 yr with major depressive disorder and other psychiatric disorders
• Geri: Appears on Beers list. May worsen or cause syndrome of inappropriate antidiuretic hormone (SIADH) secretion and/or hyponatremia in older adults. Use with caution in older adults and closely monitor sodium concentrations when starting therapy or ↑ dose

CV: hypertension, tachycardia.

Derm: ↑sweating, hot flush.

Endo: SIADH.

F and E: hyponatremia.

GI: ↑liver enzymes, constipation, dry mouth, nausea, PANCREATITIS, vomiting.

GU: ↓libido, delayed/absent orgasm, ejaculatory delay/failure, erectile dysfunction.

Hemat: BLEEDING.

Neuro: dizziness, headache, insomnia, NEUROLEPTIC MALIGNANT SYNDROME, SUICIDAL THOUGHTS.
Misc: SEROTONIN SYNDROME.

Drug-Drug:

• Concurrent use with MAO inhibitors may result in serious, potentially fatal reactions; wait at least 14 days following discontinuation of MAO inhibitor before initiation of milnacipran. Wait at least 5 days after discontinuing milnacipran before initiation of MAO inhibitor.
• Concurrent use with MAO-inhibitor-like drugs, such as linezolid or methylene blue may ↑ risk of serotonin syndrome; concurrent use contraindicated; do not start therapy in patients receiving linezolid or methylene blue; if linezolid or methylene blue need to be started in a patient receiving milnacipran, immediately discontinue milnacipran and monitor for signs/symptoms of serotonin syndrome for 5 days or until 24 hr after last dose of linezolid or methylene blue, whichever comes first (may resume milnacipran therapy 24 hr after last dose of linezolid or methylene blue)
• Drugs that affect serotonergic neurotransmitter systems, including tricyclic antidepressants, SNRIs, fentanyl, lithium, buspirone, tramadol, meperidine, methadone, amphetamines, and triptans↑ risk of serotonin syndrome
• ↑risk of bleeding with NSAIDs, aspirin, clopidogrel, prasugrel, ticagrelor, dabigatran, apixaban, edoxaban, rivaroxaban, or warfarin.
• May ↓ antihypertensive effectiveness of clonidine.
• ↑risk of hypertension and arrhythmias with epinephrine or norepinephrine.
• ↑risk of euphoria and hypotension when switching from clomipramine.
• Concurrent use with digoxin may result in adverse hemodynamics, including hypotension and tachycardia; avoid concurrent use with IV digoxin.

Drug-Natural Products:

• Use with St. John's wort↑ serotonin syndrome.

• PO (Adults): Day 1: 12.5 mg; Day 2–3: 12.5 mg twice daily; Day 4–7: 25 mg twice daily; After Day 7: 50 mg twice daily. Some patients may require up to 100 mg twice daily depending on response.

(Generic available)

• Tablets (contain tartrazine): 12.5 mg; 25 mg; 50 mg; 100 mg;

• Assess intensity, quality, and location of pain periodically during therapy. May require several wk for effects to be seen.
• Monitor BP and heart rate before and periodically during therapy. Treat pre-existing hypertension and cardiac disease prior to therapy. Sustained hypertension may be dose related; decrease dose or discontinue therapy if this occurs.
• Monitor closely for changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.
• Monitor for development of neuroleptic malignant syndrome (fever, respiratory distress, tachycardia, convulsions, diaphoresis, hypertension or hypotension, pallor, tiredness, severe muscle stiffness, loss of bladder control). Report symptoms immediately.
• Assess sexual function before starting milnacipran. Assess for changes in sexual function during treatment, including timing of onset; patient may not report.

• May cause ↑ ALT, AST, and bilirubin.
  • May cause hyponatremia.

• PO: May be administered without regard to meals; may be more tolerable if taken with food.

• Instruct patient to take milnacipran as directed at the same time each day. Take missed doses as soon as possible unless time for next dose. Do not stop abruptly; must be decreased gradually. Advise patient to read the Medication Guide prior to therapy and with each Rx refill in case of changes.
• Encourage patient and family to be alert for emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression and suicidal ideation, especially during early antidepressant therapy. Assess symptoms on a day-to-day basis as changes may be abrupt. If these symptoms occur, notify health care professional.
• May cause dizziness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
• Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's wort. Avoid use of aspirin, NSAIDs, and warfarin due to increased risk for bleeding.
• Instruct patient to notify health care professional if signs of liver damage (pruritus, dark urine, jaundice, right upper quadrant tenderness, unexplained "flu-like" symptoms) or hyponatremia (headache, difficulty concentrating, memory impairment, confusion, weakness, unsteadiness, falls), rash, or serotonin syndrome (mental status changes: agitation, hallucinations, coma; autonomic instability: tachycardia, labile BP, hyperthermia; neuromuscular aberrations: hyperreflexia, incoordination; and/or GI symptoms: nausea, vomiting, diarrhea) occur.
• Advise patient to avoid taking alcohol during milnacipran therapy.
• Inform patient that milnacipran may cause symptoms of sexual dysfunction. In males, ejaculatory delay or failure, decreased libido, and erectile dysfunction may occur. In female patients, may result in decreased libido and delayed or absent orgasm. Advise patient to notify health care professional if symptoms occur.
• May cause fetal harm. Instruct patient to notify health care professional if pregnancy is planned or suspected or if breastfeeding. May be associated with an increased risk of postpartum hemorrhage. Neonates exposed to milnacipran late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding; can arise immediately upon delivery. Symptoms may include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. Monitor infants exposed to milnacipran for agitation, irritability, poor feeding and poor weight gain. Encourage patients who become pregnant while taking milnacipran to enroll in the Savella pregnancy registry by calling 1-800-643-3010 or at .
• Encourage patient to maintain routine follow-up visits with health care provider to determine effectiveness.

• Reduction in pain and soreness associated with fibromyalgia.

Savella