Milnacipran
Encyclopedia
Milnacipran 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.
in December 1996. It is currently marketed (as Ixel) for this indication in over 45 countries worldwide including several Europe
an 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.
s the reuptake
of serotonin
and norepinephrine
in an approximately 1:3 ratio, respectively; in practical use this means a relatively balanced action upon both neurotransmitter
s. 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 receptor
s, as well as on benzodiazepine and opioid
binding site
s.
, 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.
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 was significantly lower compared to TCA
s 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.
Administration of milnacipran should be done with caution in individuals with the following:
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.
Fibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
. 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 FranceFrance
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
in December 1996. It is currently marketed (as Ixel) for this indication in over 45 countries worldwide including several Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
an countries such as Austria
Austria
Austria , officially the Republic of Austria , is a landlocked country of roughly 8.4 million people in Central Europe. It is bordered by the Czech Republic and Germany to the north, Slovakia and Hungary to the east, Slovenia and Italy to the south, and Switzerland and Liechtenstein to the...
, Bulgaria
Bulgaria
Bulgaria , officially the Republic of Bulgaria , is a parliamentary democracy within a unitary constitutional republic in Southeast Europe. The country borders Romania to the north, Serbia and Macedonia to the west, Greece and Turkey to the south, as well as the Black Sea to the east...
, Finland
Finland
Finland , officially the Republic of Finland, is a Nordic country situated in the Fennoscandian region of Northern Europe. It is bordered by Sweden in the west, Norway in the north and Russia in the east, while Estonia lies to its south across the Gulf of Finland.Around 5.4 million people reside...
, France
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
, Portugal
Portugal
Portugal , officially the Portuguese Republic is a country situated in southwestern Europe on the Iberian Peninsula. Portugal is the westernmost country of Europe, and is bordered by the Atlantic Ocean to the West and South and by Spain to the North and East. The Atlantic archipelagos of the...
, and Russia
Russia
Russia or , officially known as both Russia and the Russian Federation , is a country in northern Eurasia. It is a federal semi-presidential republic, comprising 83 federal subjects...
. It is also available in Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
(as Toledomin) and Mexico
Mexico
The United Mexican States , commonly known as Mexico , is a federal constitutional republic in North America. It is bordered on the north by the United States; on the south and west by the Pacific Ocean; on the southeast by Guatemala, Belize, and the Caribbean Sea; and on the east by the Gulf of...
(as Dalcipran). Cypress Bioscience bought the exclusive rights for approval and marketing of the drug for any purpose in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
and Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...
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
Fibromyalgia
Fibromyalgia is a medical disorder characterized by chronic widespread pain and allodynia, a heightened and painful response to pressure. It is an example of a diagnosis of exclusion...
, making it the third medication approved for this purpose in the United States.
Pharmacology
Milnacipran inhibitReuptake inhibitor
A reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
s the reuptake
Reuptake
Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse....
of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
in an approximately 1:3 ratio, respectively; in practical use this means a relatively balanced action upon both neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s. Inhibition of both neurotransmitters simultaneously works synergistically to treat both depression and fibromyalgia. Milnacipran exerts no significant actions on H1
H1 receptor
The H1 receptor is a histamine receptor belonging to the family of Rhodopsin like G-protein-coupled receptors. This receptor, which is activated by the biogenic amine histamine, is expressed throughout the body, to be specific, in smooth muscles, on vascular endothelial cells, in the heart, and in...
, α1
Alpha-1 adrenergic receptor
The alpha-1 adrenergic receptor is a G protein-coupled receptor associated with the Gq heterotrimeric G-protein. It consists of three highly homologous subtypes, including α1A-, α1B-, and α1D-adrenergic...
, D1, D2, and mACh receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s, as well as on benzodiazepine and opioid
Opioid receptor
Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...
binding site
Binding site
In biochemistry, a binding site is a region on a protein, DNA, or RNA to which specific other molecules and ions—in this context collectively called ligands—form a chemical bond...
s.
Clinical results in depression
In a pooled analysis of 7 comparative trials with imipramineImipramine
Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
, 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 anticholinergicAnticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
side effects was significantly lower compared to TCA
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s 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
Mania
Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
has also been seen and dictates termination of treatment. In psychotic patients emergence of delirium
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
has been noticed. Milnacipran has a low incidence of sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
but improves sleep
Sleep
Sleep is a naturally recurring state characterized by reduced or absent consciousness, relatively suspended sensory activity, and inactivity of nearly all voluntary muscles. It is distinguished from quiet wakefulness by a decreased ability to react to stimuli, and is more easily reversible than...
(both duration and quality) in depressed patients. In agitated
Psychomotor agitation
Psychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
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 infarctionMyocardial infarctionMyocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
- EpinephrineEpinephrineEpinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
, NorepinephrineNorepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(also in local anesthesia) - hypertensive crisis and/or possible cardiac arrhythmia - ClonidineClonidineClonidine is a sympatholytic medication used to treat medical conditions, such as high blood pressure, some pain conditions, ADHD and anxiety/panic disorder...
- antihypertensive action of clonidine may be antagonized - DigitalisDigitalisDigitalis is a genus of about 20 species of herbaceous perennials, shrubs, and biennials that are commonly called foxgloves. This genus was traditionally placed in the figwort family Scrophulariaceae, but recent reviews of phylogenetic research have placed it in the much enlarged family...
- hemodynamic actions increased - AlcoholAlcoholIn chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
- 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. tranylcypromineTranylcypromineTranylcypromine is a drug of the substituted phenethylamine and amphetamine classes which acts as a monoamine oxidase inhibitor —it is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase...
(Parnate), phenelzinePhenelzinePhenelzine is a non-selective and irreversible monoamine oxidase inhibitor of the hydrazine class which is used as an antidepressant and anxiolytic...
(Nardil), >10 mg L-deprenyl (Selegiline)), digitalisDigitalisDigitalis is a genus of about 20 species of herbaceous perennials, shrubs, and biennials that are commonly called foxgloves. This genus was traditionally placed in the figwort family Scrophulariaceae, but recent reviews of phylogenetic research have placed it in the much enlarged family...
glycosideGlycosideIn chemistry, a glycoside is a molecule in which a sugar is bound to a non-carbohydrate moiety, usually a small organic molecule. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. These can be activated by enzyme...
s or 5-HT1D-agonists (e.g. triptanTriptanTriptans are a family of tryptamine-based drugs used as abortive medication in the treatment of migraines and cluster headaches. They were first introduced in the 1990s...
migraine drugs) is an absolute contraindication.
Administration of milnacipran should be done with caution in individuals with the following:
- Concomitant treatment with parenteral epinephrineEpinephrineEpinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
, norepinephrineNorepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
, with clonidineClonidineClonidine is a sympatholytic medication used to treat medical conditions, such as high blood pressure, some pain conditions, ADHD and anxiety/panic disorder...
and reversible MAO-A Inhibitors (moclobemideMoclobemideMoclobemide is a monoamine oxidase inhibitor drug primarily used to treat depression and social anxiety. Although clinical trials with the medicine began in 1977, it is not approved for use in the United States...
, toloxatoneToloxatoneToloxatone is an antidepressant launched in 1984 for the treatment of depression. It acts as a selective reversible inhibitor of MAO-A .- References :...
). - 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.
External links
- http://www.savella.com
- Scientific Information on Ixel (German)
- http://www.highbeam.com/library/doc0.asp?docid=1G1:131710212&dtype=0~0&dinst=&author=&title=Cypress%20Bioscience%20Revises%20Milnacipran%20License%20With%20Pierre%20Fabre%20Medicament%20to%20Improve%20Economic%20Terms%20and%20Expand%20the%20Licensed%20Field.&date=06/09/2003&refid=ency_botnm License Agreement Cypress - Pierre Fabre.
- Agreement on Study in Fibromyalgia
- Israeli prescribing information for milnacipran (English)