Milran

Approved Indications

• Fibromyalgia in Adults:
  Milnacipran is approved for the management of fibromyalgia, a chronic condition characterized by widespread musculoskeletal pain, fatigue, sleep disturbances, and cognitive difficulties.

Important Off-label or Clinically Accepted Uses

• Major Depressive Disorder (MDD):
  Although not FDA-approved in the U.S. for depression, milnacipran is widely used in other countries (e.g., Japan, parts of Europe) as an antidepressant for moderate to severe major depressive disorder, especially in patients unresponsive to SSRIs or those with pain-predominant symptoms.
• Chronic Fatigue Syndrome (CFS):
  Used off-label in some cases to address fatigue and functional impairment in CFS.

Adults (Fibromyalgia)

• Initial dose: 12.5 mg orally once on Day 1
• Titration Schedule:
• Days 2–3: 12.5 mg twice daily (BID)
• Days 4–7: 25 mg BID
• Day 8 onward: 50 mg BID (maintenance dose)
• Maximum dose: 100 mg/day (50 mg BID)
• Administration: With or without food; swallow tablets whole.

Adults (Off-label for MDD)

• 50 mg to 100 mg per day in divided doses. Dosing varies depending on country-specific approval.

Pediatric Use

• Not recommended; safety and efficacy not established in patients under 18 years of age.

Elderly

• Use with caution due to possible reduced renal function and increased sensitivity to CNS side effects.
• No dosage adjustment solely based on age, but renal function should guide dosing.

Renal Impairment

• Mild (CrCl 50–79 mL/min): No adjustment needed.
• Moderate (CrCl 30–49 mL/min): Max dose 50 mg BID
• Severe (CrCl 5–29 mL/min): Max dose 25 mg BID
• End-stage renal disease (ESRD): Use not recommended.

Hepatic Impairment

• No dose adjustment required.
• Use with caution in severe hepatic impairment due to potential for increased exposure.

Milnacipran is a serotonin-norepinephrine reuptake inhibitor (SNRI). It selectively inhibits the reuptake of norepinephrine (NE) and serotonin (5-HT) by presynaptic neurons in the central nervous system. By increasing the synaptic availability of these neurotransmitters, it helps modulate central pain pathways and mood regulation. The drug has approximately a 3:1 affinity for norepinephrine over serotonin reuptake inhibition, which may contribute to its analgesic effect in fibromyalgia independent of antidepressant activity.

• Absorption:
  Rapid oral absorption with high bioavailability (~85%); Tmax ≈ 2–4 hours after dosing.
• Distribution:
  Volume of distribution: 400 L
  Protein binding: ~13%
• Metabolism:
  Minimal hepatic metabolism (~10%); major pathways include glucuronidation.
  Minor involvement of CYP450 enzymes (CYP1A2 and CYP2C19).
• Excretion:
  ~90% excreted in urine (55% unchanged)
  Elimination half-life: 6–8 hours
  Renal clearance is the main route of elimination.

• Pregnancy:
  Former FDA Category C
  Animal studies show adverse effects on the fetus (e.g., fetal growth reduction), but there are no adequate human studies. Use only if the potential benefit justifies the risk.
• Lactation:
  Milnacipran is excreted in human breast milk.
  Use with caution in breastfeeding women, as the effects on the nursing infant are unknown.
  Consider alternative treatments or discontinue breastfeeding if needed.

• Primary Class: Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)
• Subclass: Non-tricyclic antidepressant; centrally acting analgesic (for fibromyalgia)

• Hypersensitivity to milnacipran or any component of the formulation
• Concomitant use with or within 14 days of MAO inhibitors (risk of serotonin syndrome)
• Uncontrolled narrow-angle glaucoma
• Use in patients with untreated or unstable hypertension or severe cardiac arrhythmias

• Suicidality Risk (Black Box Warning):
  Increased risk of suicidal thoughts and behavior in children, adolescents, and young adults (18–24 years) with major depressive disorder.
• Serotonin Syndrome:
  Risk increases with co-administration of serotonergic agents (e.g., SSRIs, triptans, MAOIs).
• Hypertension & Tachycardia:
  May increase blood pressure and heart rate; monitor especially in patients with pre-existing hypertension or cardiac disease.
• Seizure Risk:
  Use with caution in individuals with a seizure history.
• Urinary Retention:
  May cause difficulty urinating, particularly in men with prostatic hypertrophy.
• Withdrawal Symptoms:
  Taper gradually upon discontinuation to minimize withdrawal (e.g., dizziness, nausea, headache, irritability).
• Clinical Monitoring:
• BP and heart rate at baseline and periodically
• Signs of mood or behavior changes, especially early in treatment

Common Adverse Effects:

• Central Nervous System:
  Headache, dizziness, insomnia, anxiety, fatigue
• Gastrointestinal:
  Nausea, constipation, dry mouth, vomiting
• Cardiovascular:
  Increased blood pressure, palpitations, tachycardia
• Genitourinary:
  Urinary hesitation or retention, erectile dysfunction

Less Common/Serious Effects:

• Serotonin syndrome (especially when combined with serotonergic drugs)
• Suicidal thoughts or behavior (especially in young adults)
• Liver enzyme elevation (rare)
• Hyponatremia (in elderly or volume-depleted patients)
• Severe allergic reactions (e.g., angioedema – rare)

• MAO Inhibitors:
  Contraindicated due to risk of hypertensive crisis or serotonin syndrome
• SSRIs/SNRIs/Triptans/Tramadol:
  Additive serotonergic effect → increased risk of serotonin syndrome
• Alcohol:
  May worsen CNS side effects (e.g., sedation, dizziness)
• Digoxin:
  No clinically significant interaction, but monitor ECG in high-risk cardiac patients
• Enzyme systems:
  Weak involvement with CYP1A2 and CYP2C19 – not a major substrate or inhibitor of CYP450 enzymes

• FDA:
  No recent changes in labeling, but milnacipran remains under post-marketing surveillance for long-term safety in fibromyalgia.
• ACR 2024 Guidelines for Fibromyalgia:
  Milnacipran continues to be listed as a recommended option alongside duloxetine and pregabalin for fibromyalgia management.
• EMA & NICE:
  Milnacipran is not widely recommended in UK clinical guidelines due to limited approval status for fibromyalgia or depression.

• Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Permitted excursions: 15°C to 30°C (59°F to 86°F)
• Humidity & Light: Store in original container; protect from moisture
• Handling: Do not split or crush tablets
• Reconstitution: Not applicable; no refrigeration needed