Milnacipran

Uses

Milnacipran is used for the management of fibromyalgia. Milnacipran is not approved for use in pediatric patients

Milnacipran is also used to associated treatment for these conditions: Fibromyalgia

How Milnacipran works

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 . Although the specific mechanism of action remains unclear, 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 . Such NE pain mitigation is consequently also enhanced by milnacipran's ability to enhance the presence of NE by inhibiting its reuptake via norepinephrine transporters at synaptic clefts .

Concurrently, milnacipran's capacity to inhibit the reuptake of both 5HT and NE also facilitates its treatment of MDD. Given the monoamine hypothesis' assertion that decreased 5HT can be associated with anxiety, obsessions, compulsions, and decreased NE can result in lowered alertness, energy, attention, and general interest in life, it is proposed that milnacipran's basic activities as a serotonin and norepinephrine reuptake inhibitor could assist in treating such symptoms of MDD by increasing the presence of both 5HT and NE in the body by inhibiting their reuptake .

Dosage

Milnacipran dosage

The recommended dose of Milnacipranis 100 mg/day (50 mg twice daily). Based on efficacy and tolerability dosing may be titrated according to the following schedule:

Day 1:12.5 mg once

Days 2-3:25 mg/day (12.5 mg twice daily)

Days 4-7:50 mg/day (25 mg twice daily)

After Day 7:100 mg/day (50 mg twice daily)

Based on individual patient response, the dose may be increased to 200 mg/day (100 mg twice daily). Doses above 200 mg/day have not been studied.

Should be taken with food. Preferably taken during meals.

Side Effects

Increased heart rate, HTN, increased liver enzymes, severe liver injury, hyponatraemia, abnormal bleeding, dysuria, mydriasis, nausea, vomiting, constipation, headache, insomnia, dizziness, hot flushes, hyperhidrosis, palpitations, dry mouth, migraine.

Toxicity

There is limited clinical experience with milnacipran overdose in humans. In clinical trials, cases of acute ingestions up to 1000 mg daily were reported with none being fatal . In postmarketing experience, fatal outcomes have been reported for acute overdoses primarily involving multiple drugs but also with milnacipran only . The most common signs and symptoms of overdose included increased blood pressure, cardio-respiratory arrest, changes in the level of consciousness (ranging from somnolence to coma), confusional state, dizziness, and increased hepatic enzymes .

There are no adequate and well-controlled studies in pregnant women . In fact, milnacipram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus .

Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding . Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying . These features are consistent with either a direct toxic effect of SNRI class drugs like milnacipran or, possibly, a drug discontinuation syndrome . It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome .

The effect of milnacipran on labor and delivery in humans is unknown . Milnacipran should be used during labor and delivery only if the potential benefits outweigh the potential risks .

There are no adequate and well-controlled studies in nursing mothers . It is not known if milnacipran is excreted in human milk . Studies have shown that levomilnacipran is excreted into the milk of lactating rats . Subsequently, possible excretion into human milk possesses the potential for serious adverse reactions in nursing infants . As a consequence, breastfeeding by women treated with levomilnacipran should be considered only if the potential benefits outweigh the potential risks to the child .

Milnacipran is not indicated for use in children under 18 years of age due to concerns over the potential for agitation-type emotional and behavioral changes, as well as suicidal ideation and/or behavior .

SNRIs like milnacipran have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event .

Levomilnacipran was not mutagenic when evaluated in vitro in a bacterial mutagenicity study (Ames test) and not genotoxic in a mouse lymphoma study . It was not clastogenic in an in vivo micronucleus assay in rats .

The potential effects of levomilnacipran on gonadal function, mating behavior, reproductive performance and early pregnancy were evaluated in rats at oral doses of 0, 10, 30, or 100 mg/kg/day . The NOAEL was 100 mg/kg/day based on reductions in body weight gain and food consumption . There were no levomilnacipran effects on male and female fertility parameters .

In the rat and rabbit embryo/fetal development studies, decreases in maternal body weight gain and food consumption were noted . In the fetuses, increases in the incidence of ossification anomalies were noted but were of no toxicological significance . In both species, the NOAEL was determined to be 100 mg/kg/day, a dose which represents a rat or rabbit animal-to-human exposure margin of 9-fold and 4-fold, respectively relative to the human exposure from 120 mg/day of levomilnacipran .

Material safety data for milnacipran has documented the LD50 oral value in the rat model as being 213 mg/kg .

Precaution

Patient with major depressive disorder or other psychiatric disorders, history of dysuria, controlled narrow-angle glaucoma, pre-existing HTN, tachyarrhythmias or other CV disease, history of seizure disorder or condition predisposing to seizures (e.g. brain damage, alcoholism). Avoid abrupt withdrawal. Severe hepatic and moderate to severe renal impairment including ESRD. Pregnancy and lactation.

Interaction

Increased risk of bleeding with aspirin, NSAIDs, warfarin and other drugs that affect coagulation. Increased CNS effects with centrally-acting drugs (e.g. clomipramine). Increased risk of serotonin syndrome and NMS-like reactions with serotonergic drugs (e.g. tramadol), SSRIs, other selective serotonin-norepinephrine reuptake inhibitors, 5-HT1 receptor agonists (e.g. sumatriptan), antipsychotic agents and other dopamine antagonists. May inhibit antihypertensive effect of clonidine. May potentiate adverse haemodynamic effects with digoxin. Paroxysmal HTN and cardiac arrhythmia may occur when taken concurrently with epinephrine or norepinephrine.

Food Interaction

• Avoid excessive or chronic alcohol consumption. Avoid excessive or chronic alcohol consumption. Milnacipran may worsen liver disease, which is potentially caused by excessive alcohol use.
• Take with or without food. Taking milnacipran with food may improve its tolerability.

[Moderate] GENERALLY AVOID: Use of milnacipran in conjunction with chronic alcohol consumption may potentiate the risk of liver injury.

Milnacipran alone can increase serum transaminase levels.

In placebo-controlled fibromyalgia trials, increases in ALT were more frequently observed in patients treated with milnacipran 100 mg

One patient receiving milnacipran 100 mg

Increases in AST were also more frequently observed in patients treated with milnacipran 100 mg

There have been reported cases of increased liver enzymes and severe liver injury, including fulminant hepatitis, from foreign postmarketing experience with milnacipran.

Significant underlying clinical conditions and
MANAGEMENT: Due to the risk of liver injury, patients prescribed milnacipran should be counseled to avoid excessive use of alcohol.

Milnacipran should generally not be prescribed to patients with substantial alcohol use.

Milnacipran Hypertension interaction

[Moderate] Selective serotonin and norepinephrine reuptake inhibitor antidepressants (SNRIs) have been associated with sustained increases in blood pressure.

Therapy with SNRI antidepressants should be administered cautiously in patients with preexisting hypertension.

Blood pressure should be assessed prior to initiating treatment and monitored regularly.

The dose should be reduced or discontinued if necessary.

Milnacipran Drug Interaction

Major: 5-hydroxytryptophan, duloxetine, fentanyl, fluoxetineModerate: aripiprazole, aspirin, pregabalin, gabapentin, clopidogrel, quetiapineUnknown: zolpidem, thyroid desiccated, lorazepam, loratadine, promethazine, hydroxychloroquine, pantoprazole, ascorbic acid, cholecalciferol, alprazolam

Milnacipran Disease Interaction

Major: liver disease, depression, renal diseaseModerate: glaucoma, hypertension, hyponatremia, mania, seizures, urinary tract obstruction

Volume of Distribution

The mean volume of distribution recorded for racemic milnacipran following a single intravenous dose to healthy subjects was approximately 400 L . Alternatively, levomilnacipran is widely distributed with an apparent volume of distribution of 387-473 L .

Elimination Route

Racemic milnacipram demonstrates an absolute bioavailability of about 85-90% following oral administration . Maximum concentrations of the racemic agent are reached within 2-4 hours after oral dosing, and steady-state levels are obtained by 36-48 hours .

Conversely, the relative bioavailability of levomilnacipram has been documented as 92% . The median time to peak concentration Tmax for levomilnacipram is about 6-8 hours after oral administration . After daily dosing of levomilnacipram 120 mg, the mean Cmax value is 341 ng/mL, and the mean steady-state AUC value is 5196 ng.h/mL.

In general, the administration of either racemic milnacipram or levomilnacipram with food does not affect the medication's oral bioavailability .

Half Life

The terminal elimination half-life documented for racemic milnacipran is approximately 6-8 hours, where d-milnacipran has a longer elimination half-life of 8-10 hours compared to that of the l-enantionmer at 4-6 hours . Alternatively, the terminal elimination half-life determined specifically for levomilnacipran formulations is about 12 hours .

Clearance

The total plasma clearance determined for milnacipran is approximately 40 L/h .

Elimination Route

Levomilnacipran and its metabolites are eliminated primarily by renal excretion . Following oral administration of 14C-levomilnacipran solution, approximately 58% of the dose is excreted in urine as unchanged levomilnacipran . N-desethyl levomilnacipran is the major metabolite excreted in the urine and accounted for approximately 18% of the dose . Other identifiable metabolites excreted in the urine are levomilnacipran glucuronide (4%), desethyl levomilnacipran glucuronide (3%), p-hydroxy levomilnacipran glucuronide (1%), and p-hydroxy levomilnacipran (1%) .

Pregnancy & Breastfeeding use

Pregnancy: Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during Milnacipran therapy. Patients should be encouraged to enroll in the Milnacipran Pregnancy Registry if they become pregnant, preferably before any prenatal testing is done. This registry is collecting information about the safety of milnacipran during pregnancy.

Nursing: Advise patients to notify their physician if they are breast feeding

Contraindication

Uncontrolled narrow-angle glaucoma. Concomitant use with MAOI or within 2 wk after withdrawal of MAOI.

Special Warning

Renal Impairment: Severe (CrCl 5-29 mL/min): 25 mg bid, may increase to 50 mg bid according to response.

End stage renal disease (ESRD): Not recommended.

Pediatric use: Safety and effectiveness of Milnacipran in a fibromyalgia pediatric population below the age of 18 have not been established. The use of Milnacipran is not recommended in pediatric patients.

Acute Overdose

Symptoms: Increased BP, cardio-resp arrest, changes in the level of consciousness (ranging from somnolence to coma), confusional state, dizziness, and increased hepatic enzymes.

Management: Symptomatic treatment with gastric lavage and activated charcoal. Maintain adequate airway, oxygenation and ventilation and monitor cardiac rhythm and vital signs. May give cyproheptadine with adequate temp control to treat serotonin syndrome.

Storage Condition

Store at 25° C.

Innovators Monograph

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