Milnacipran

Milnacipran (Ixel, Savella, Dalcipran, Toledomin) is a serotonin–norepinephrine reuptake inhibitor (SNRI) used in the clinical treatment of fibromyalgia. It is not approved for the clinical treatment of major depressive disorder in the USA, but it is in other countries.

History
Milnacipran was first approved for the treatment of major depressive episodes in France in December 1996. It is currently marketed (as Ixel) for this indication in over 45 countries worldwide including several European countries such as Austria, Bulgaria, Finland, France, Portugal, and Russia. It is also available in Japan (as Toledomin) and Mexico (as Dalcipran). Cypress Bioscience bought the exclusive rights for approval and marketing of the drug for any purpose in the United States and Canada in 2003 from the manufacturer Pierre Fabre.

In January 2009 the U.S. Food and Drug Administration (FDA) approved milnacipran (under the brand name Savella) only for the treatment of fibromyalgia, making it the third medication approved for this purpose in the United States.

Pharmacology
Milnacipran inhibits the reuptake of serotonin and norepinephrine in an approximately 1:3 ratio, respectively; in practical use this means a relatively balanced action upon both neurotransmitters. Inhibition of both neurotransmitters simultaneously works synergistically to treat both depression and fibromyalgia. Milnacipran exerts no significant actions on H1, α1, D1, D2, and mACh receptors, as well as on benzodiazepine and opioid binding sites.

Clinical results in depression
In a pooled analysis of 7 comparative trials with imipramine, milnacipran and imipramine were shown to have comparable efficacy while milnacipran was significantly better tolerated. A pooled analysis of studies comparing milnacipran and SSRIs concluded a superior efficacy for milnacipran with similar tolerability for milnacipran and SSRIs. A more recent meta-analysis of 6 studies involving more than 1,000 patients showed no distinction between milnacipran and SSRIs in efficacy or discontinuation rates, including discontinuation for side effects or lack of efficacy. A meta-analysis of a total of 16 randomized controlled trials with more than 2200 patients concluded that there were no statistically significant differences in efficacy, acceptability and tolerability when comparing milnacipran with other antidepressant agents. However, compared with TCAs, significantly fewer patients taking milnacipran dropped out due to adverse events. As with other antidepressants, 1 to 3 weeks may elapse before significant antidepressant action becomes clinically evident.

Clinical results in fibromyalgia
During its development for ﬁbromyalgia, milnacipran was evaluated utilizing a composite responder approach. To be considered as a responder for the composite ‘treatment of ﬁbromyalgia’ endpoint, each patient had to show concurrent and clinically meaningful improvements in pain, physical function and global impression of disease status. Using these criteria placebo-controlled trials involving a total of over 2000 patients have shown milnacipran, at both 100 and 200 mg/day, to be significantly more effective than placebo in treating both pain and the broader syndrome of ﬁbromyalgia. Response rates with milnacipran were similar in patients with and without co-morbid depression.

Pharmacokinetics
Milnacipran is well absorbed after oral dosing and has a bioavailability of 85%. Meals do not have an influence on the rapidity and extent 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 glucuronide 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 so that the risk of interactions with drugs metabolized by CYP enzymes is minimal.

Indications and dosage
Milnacipran is indicated for:
 * treatment of major depressive disorder (not in USA)
 * management of fibromyalgia (USA only)

The recommended dose for depression is 100 mg/day (given as 50 mg 2 times daily), with a starting period of 4 days on 25 mg/day. The dose should be decreased in patients with renal disease. The recommended dose for fibromyalgia is 100 mg/day (after an uptitration period ) which may be increased to 200 mg/day based on individual patient response.

After successful treatment of the acute depressive episode, patients should be maintained on milnacipran for several months (normally 9 months) in order to prevent relapse of depression.

Side effects
The most frequently occurring adverse reactions (≥ 5% and greater than placebo) were nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increase, dry mouth, and hypertension [FDA Savella prescribing information]. Milnacipran can have a significant impact on sexual functions, including both a decrease in sexual desire and ability. Milnacipran can cause pain and swelling of the testicles in men as well as blood in the urine and stools. The incidence of cardiovascular and anticholinergic side effects was significantly lower compared to TCAs as a controlled study with over 3,300 patients revealed. 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 (both duration and quality) in depressed patients. In agitated patients or those with suicidal thoughts additive sedative/anxiolytic treatment is usually indicated.

Interactions

 * MAOIs - hyperserotonergia (serotonin syndrome), potentially lethal hypertensive crisis
 * 5-HT1 receptor agonists - coronary vasoconstriction with risk of angina pectoris and myocardial infarction
 * Epinephrine, Norepinephrine (also in local anesthesia) - hypertensive crisis and/or possible cardiac arrhythmia
 * Clonidine - antihypertensive action of clonidine may be antagonized
 * Digitalis - hemodynamic actions increased
 * Alcohol - no interactions known; however, because milnacipran can cause mild elevation of liver enzymes, caution is recommended

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 irreversible MAO inhibitors (e.g. tranylcypromine (Parnate), phenelzine (Nardil), >10 mg L-deprenyl (Selegiline)), digitalis glycosides or 5-HT1D-agonists (e.g. triptan migraine drugs) is an absolute contraindication.

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 (moclobemide, toloxatone).
 * 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 pregnancy 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.