Milnacipran
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Trade names | Ixel, Joncia, Savella |
AHFS/Drugs.com | Monograph |
MedlinePlus | a609016 |
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Routes of administration | By mouth (tablets), capsules) |
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Chirality | Racemic mixture |
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Milnacipran (trade names 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 US, but it is in other countries.
Medical uses
Depression
In a pooled analysis of 7 comparative trials with imipramine,[2] milnacipran and imipramine were shown to have comparable efficacy while milnacipran was significantly better tolerated. A pooled analysis of studies comparing milnacipran and SSRIs[3] 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.[4] A meta-analysis of a total of 16 randomized controlled trials with more than 2200 patients[5] 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.
Impulse Control
Milnacipran was found to improve impulse control in rats, which has been linked to its activation of D1-like receptors in the infralimbic cortex.[6] Depression has been associated with increased impulsivity.
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. A systematic review in 2015 showed moderate relief for a minority of people with fibromyalgia. Milnacipran was associated with increased adverse events when discontinuing use of the drug.[7]
Social anxiety
There is some evidence that milnacipran may be effective for social anxiety.[8]
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 selegiline) or digitalis glycosidesis an absolute contraindication.
Administration of milnacipran should be done with caution in individuals with the following:
- Concomitant treatment with parenteral migraine drugs)
- 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.
Side effects
The most frequently occurring adverse reactions (≥ 5% and greater than placebo) were nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhydrosis, 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[
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
- Triptans — there have been rare postmarketing reports of hyperserotonergia (serotonin syndrome). If concomitant treatment of milnacipran with a triptan is clinically warranted, careful observation of patient is advised when starting or increasing dosages.[13]
- Alcohol — no interactions known; however, because milnacipran can cause mild elevation of liver enzymes, caution is recommended; the FDA advises against the concomitant use of alcohol and milnacipran
Pharmacology
Pharmacodynamics
Milnacipran
Recently,
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.[16]
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 Laboratoires Pierre Fabre.
In January 2009 the
References
- ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
- S2CID 27199308.
- S2CID 31546691.
- S2CID 27679241.
- PMID 19588396.
- S2CID 12806222.
- PMID 26482422.
- PMID 19300537.
- ^ "www.accessdata.fda.gov" (PDF).
- PMID 22247614.
- PMID 19721721.
- S2CID 173746.
- ^ "SAVELLA - milnacipran hydrochloride tablet, film coated". DailyMed. National Institute of Health.
- S2CID 46629043.
- S2CID 37407165.
- ^ S2CID 45279690.
- PMID 25345508.
- PMID 25100992.
- ^ European Medicines Agency. "Questions and answers on the recommendati on for the refusal of the marketing authorisation for Milnacipran Pierre Fabre Médicament/Impulsor" (PDF). European Medicines Agency. Archived from the original (PDF) on 22 February 2014. Retrieved 30 May 2013.
External links
- "Milnacipran". Drug Information Portal. U.S. National Library of Medicine.
- "Milnacipran hydrochloride". Drug Information Portal. U.S. National Library of Medicine.