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Milnacipran
Systematic (IUPAC) name
(1R,2R)-2-(aminomethyl)-N,N-diethyl-1-phenyl-cyclopropane-1-carboxamide
Identifiers
CAS number	92623-85-3
ATC code	N06AX17
PubChem	65833
Chemical data
Formula	C15H22N2O
Mol. weight	246.348
Pharmacokinetic data
Bioavailability	85%
Metabolism	Hepatic
Half life	8 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	X (US)
Legal status	Unscheduled Rx-only (not approved in the US)
Routes	Oral

Milnacipran is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class.

History

Milnacipran has been approved and sold in Austria since September 1998 under the brand name Ixel®. Cypress Bioscience bought the exclusive rights for approval and marketing of the drug for any purpose in the US and Canada in 2003 from the manufacturer Pierre Fabre; the approval procedure in both countries is ongoing.

Pharmacology

Milnacipran inhibits norepinephrine and serotonin reuptake in a 3:1 ratio, in practical use this means a balanced (equal) action upon both transmitters. The serotonin reuptake inhibition is likely to improve depression, while the norepinephrine reuptake inihibition probably improves chronic pain. Milnacipran exerts no significant actions on postynaptic H1, Alpha1, D1, D2 and muscarinic receptors as well as on benzodiazepin/opiate binding sites. In a clinical trial with over 1,000 depressed patients Milnacipran showed results comparable to Imipramine and superior to SSRIs, but proved in a different study inferior to Clomipramine. As with other antidepressants 1 to 3 weeks may elapse before significant antidepressive action becomes clinically evident.

Pharmacokinetics

Milnacipran is well absorbed after oral dosing and has a bioavailability of 85%. Meals do not have an influence on the rapidity and extend of absorption. Peak plasma concentrations are reached 2 hours after oral dosing. The elimination half-life of 8 hours is not increased by liver impairment and old age, but by significant renal disease. Milnacipran is conjugated to the inactive glucuronid and excreted in the urine as unchanged drug and conjugate. Only traces of active metabolites are found. Enzymes of the CYP class do not play a role in the metabolism of Milnacipran.

Indications & Dosage

Milnacipran is used to treat:

• Moderate to severe clinical depression (Major Depression)
• Chronic Pain

The recommended dose for depression is 50mg 2 times daily (after an initial phase of 50mg daily as single dose on days 1 to 4). The dose should be decreased in patients with renal disease. The dosage for the other indications has not been well established so far.

Milnacipran is available in 25mg and 50mg capsules.

After successful treatment of the acute depressive episode, patients should be maintained on Milnacipran for several months (normally 6 months) in order to prevent relapse of depression.

Experimental Uses

In experimental studies Milnacipran showed useful activity as adjunct in the therapy of Fibromyalgia and Lupus, both conditions with potentially devastating effects. In Fibromyalgia the drug improved pain, mood, and fatigue compared to placebo. In Lupus patients pain was alleviated and a sense of well-being was provided.

On January, 5th., 2006, Forest Pharmaceuticals and Cypress Bioscience agreed to commence a phase III multicenter study encompassing 1,200 patients with Fibromyalgia. Early results will be available by mid 2007.

Side effects

Side effects include itching, nausea, vertigo, increased anxiety, sweats, shivering, dysuria and testicle pain. Milnacipran does not seem to have a negative impact on sexual functions. The incidence of cardiovascular and anticholinergic side effects was significantly lower compared to TCAs as a controlled study with over 3,300 patients revealed. Cases of hypertension, hypotension and tachycardia have been noted. Elevation of liver enzymes without signs of symptomatic liver disease has been infrequent. Mood swing to mania has also been seen and dictates termination of treatment. In psychotic patients emergence of delirium has been noticed. Milnacipran has a low incidence of sedation but improves sleep (as well duration and quality) in depressed patients. In agitated patients or those with suicidal thoughts additive sedative/anxiolytic treatment is usually indicated.

Interactions

• MAOIs, Lithium - serotoninergic syndrome, potentially lethal
• 5-HT1AD-Agonists - coronary vasoconstriction with risk of angina pectoris and myocardial infarction
• Epinephrine, Norepinephrine (also in local anesthesia) - hypertensive crisis and possible arrhythmias
• Clonidine - antihypertensive action of Clonidine may be antagonized
• Digitalis - hemodynemic actions increased

Contraindications

Administration of milnacipran should be avoided in individuals with the following:

• Known hypersensitivity to Milnacipran (absolute contraindication)
• Patients under 15 years of age (no sufficient clinical data)
• Concomitant treatment with irreversibe and reversible (MAO-B) MAO-Inhibitors, Digitalis-Glycosids and 5-HT1D-Agonists (e.g. Sumatriptan) - absolute contraindications -

Administration of milnacipran should be done with caution in individuals with the following:

• Concomitant treatment with parenteral Epinephrine, Norepinephrine, with Clonidine and reversible MAO-A-Inhibitors (Moclobemid, Toloxaton).
• Advanced renal disease (decreased dosage required)
• Hypertrophy of the prostate gland (possibly urination hesitancy induced), with hypertension and heart disease (tachycardia may be a problem) as well as with open angle glaucoma

Milnacipran should not be used during pregancy because it may cross the placenta barrier and no clinical data exists on harmful effects in humans and animal studies. Milnacipran is contraindicated during lactation because it is excreted in the milk and it is not known, if it is harmful to the newborn.

References/External Links

• http://www.ixel.at/fachinfo.html#4.5 Scentific Information on Ixel® (German)
• http://www.antiaging-systems.com/a2z/milnacipran.htm
• [1]License Agreement Cypress - Pierre Fabre.
• http://www.freshnews.com/news/biotech-biomedical/article_29042.html?Cypress+Bioscience Agreement on Study in Fibromyalgia.