Drug information of Milnacipran


Drug group:

Milnacipran is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) and like many agents in this category was originally developed for and continues to be approved and indicated for the treatment of depression . Furthermore, in 2009 the US FDA approved milnacipran for the additional indication of treating fibromyalgia. 

Mechanism of effect

The dual ability for milnacipran to inhibit the reuptake of both serotonin (5HT) and norepinephrine (NE) facilitates its treatment of both fibromyalgia and major depressive disorder (MDD).

In particular, it is generally believed that 5HT and NE participate in the modulation of endogenous analgesic mechanisms by way of the descending inhibitory pain pathways in the brain and spinal cord . some studies have proposed that low levels of 5HT may be associated with increased sensitivity to pain - a condition that could subsequently be improved by milnacipran's capacity to enhance the presence of 5HT by inhibiting its reuptake via serotonin transporters at synaptic clefts . Furthermore, in the CNS it is also generally believed that NE released from descending pathways can mitigate pain sensations via eliciting inhibitory effects on alpha-2A-adrenoceptors on central terminals of primary afferent nociceptors, by direct alpha-2-adrenergic action on pain-relay neurons, and by alpha-1-adrenoceptor-mediated activation of inhibitory interneurons.


it appears that the agent can cause increases in heart rate and blood pressure.


Bioavailability: 85-90%

Peak plasma time: 2-4 hr

Protein bound: 13%

Vd: 400 L

Metabolism: Metabolized to several metabolites

Half-life: L-isomer, 6-8 hr; D-isomer, 8-10 hr

Excretion: Urine (55%)




12.5 mg PO once on day 1, then 25 mg/day divided q12hr on days 2-3, then 50 mg/day divided q12hr on days 4-7, then 100 mg/day divided q12hr thereafter; not to exceed 200 mg/day


<17 years: Safety and efficacy not established


Potentially life-threatening serotonin syndrome has been reported with both SNRIs and selective serotonin reuptake inhibitors (SSRIs) when these agents are taken alone, but especially when they are coadministered with other serotonergic agents; thus, patient medications should be thoroughly reviewed for other serotonergic drugs (eg, tryptophan supplements, tramadol, serotonin agonists [triptans], MAOIs, tricyclic antidepressants [TCAs], SSRIs, methylene blue, buspirone, amphetamines, linezolid)

May increase blood pressure (BP) or heart rate (HR); BP should be controlled before initiation of milnacipran; BP and HR should be monitored while patient is taking drug

SSRIs and SNRIs may impair platelet aggregation and increase the risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and GI hemorrhage to life-threatening hemorrhage; concomitant use of aspirin, NSAIDs, warfarin, other anticoagulants, or other drugs known to affect platelet function may add to this risk

Neonates exposed to SNRIs or SSRIs late in third trimester are at risk for complications such as feeding difficulties, irritability, and respiratory problems

Use caution in patients with history of seizures

Moderate renal impairment

Avoid use in severe hepatic impairment

Avoid concomitant use in patients with substantial alcohol use or chronic liver disease

Withdrawal symptoms reported in patients when discontinuing treatment; gradual dose reduction recommended

Pupillary dilation that occurs following use of SNRI drugs including milnacipran may trigger angle closure attack in patients with anatomically narrow angles who do not have a patent iridectomy

Patietns with history of obstructive uropathies may experience higher rates of genitourinary adverse drug reactions (ADRs)

ESRD: Use not recommended

Black Box Warnings

In short-term studies, antidepressants increased risk of suicidal thinking and behavior in children, adolescents, and young (<24 years) adults taking antidepressants for major depressive disorders and other psychiatric illnesses

This increase was not seen in patients aged >24 years; slight decrease in suicidal thinking was seen in adults aged >65 years

In children and young adults, risks must be weighed against benefits of taking antidepressants

Patients should be monitored closely for changes in behavior, clinical worsening, and suicidal tendencies; this should be done during initial 1-2 months of therapy and dosage adjustments

Patient’s family should communicate any abrupt behavioral changes to healthcare provider

Worsening behavior and suicidal tendencies that are not part of presenting symptoms may necessitate discontinuance of therapy

Drug is not approved for use in pediatric patients

Points of recommendation

  • Tell all of your health care providers that you take milnacipran. This includes your doctors, nurses, pharmacists, and dentists.
  • Avoid driving and doing other tasks or actions that call for you to be alert until you see how milnacipran affects you.
  • Do not stop taking milnacipran all of a sudden without calling your doctor. You may have a greater risk of signs of withdrawal. If you need to stop milnacipran, you will want to slowly stop it as ordered by your doctor.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Check blood pressure and heart rate as the doctor has told you. Talk with the doctor.
  • Avoid drinking alcohol while taking milnacipran.
  • Talk with your doctor before you use other drugs and natural products that slow your actions.
  • If you are on a low-salt or salt-free diet, talk with your doctor.
  • It may take several weeks to see the full effects.
  • This medicine may raise the chance of bleeding. Sometimes, bleeding can be life-threatening. Talk with the doctor.
  • A very bad and sometimes deadly health problem called serotonin syndrome may happen. The risk may be greater if you take milnacipran with drugs for depression, migraines, or certain other drugs. Call your doctor right away if you have agitation; change in balance; confusion; hallucinations; fever; fast or abnormal heartbeat; flushing; muscle twitching or stiffness; seizures; shivering or shaking; sweating a lot; very bad diarrhea, upset stomach, or throwing up; or very bad headache.
  • This medicine can cause low sodium levels. Very low sodium levels can be life-threatening, leading to seizures, passing out, trouble breathing, or death. Talk with the doctor.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using milnacipran while you are pregnant.
  • Taking milnacipran in the third trimester of pregnancy may lead to some health problems in the newborn. Talk with the doctor.
  • Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.
  • Take with or without food. Take with food if it causes an upset stomach.
  • To gain the most benefit, do not miss doses.
  • Keep taking milnacipran as you have been told by your doctor or other health care provider, even if you feel well.
  • Skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.

Pregnancy level

Group c - Not adequate studies in pregnant women

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