Milnacipran
Identification
- Summary
Milnacipran is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) used for the treatment of fibromyalgia and a short-term treatment of major depressive disorder.
- Brand Names
- Savella
- Generic Name
- Milnacipran
- DrugBank Accession Number
- DB04896
- Background
Milnacipran is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) and like many agents in this category was originally developed for and continues to be approved and indicated for the treatment of depression 27,28,15,21. Furthermore, in 2009 the US FDA approved milnacipran for the additional indication of treating fibromyalgia 26, although other regional regulatory authorities like the EMA, among others, have not yet approved the agent for such treatment, citing lack of robust evidence of efficacy, insufficient demonstration of maintenance of effect, and other concerns 27,28. Nevertheless, milnacipran demonstrates a somewhat unique characteristic among SNRIs to elicit a relatively balanced reuptake inhibition of both serotonin and noradrenaline, with a somewhat increased preference for noradrenaline reuptake inhibition - which is potentially a point of interest given the plausible proposal that noradrenaline plays an important role in the mitigation of pain signals in the descending inhibitory pain pathways in the brain and spinal cord 14,18,19.
Moreover, recent research has shown that the levorotatory enantiomer of milnacipran, levomilnacipran, may have the capacity to inhibit the activity of beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1), which has investigationally been associated with β-amyloid plaque formation - making the agent a possible course of treatment for Alzheimer's disease 22.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 246.354
Monoisotopic: 246.173213336 - Chemical Formula
- C15H22N2O
- Synonyms
- (+-)-Milnacipran
- Midalcipran
- Milnacipran
- Milnacipranum
- External IDs
- F-2207
- F2207
Pharmacology
- Indication
Milnacipran is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the management of fibromyalgia in patients that are 18 years old or above 26.
While milnacipran may be used for the treatment of major depressive disorder (MDD), it is only recommended in adult patients who are 18 years old or above 25 due to an increased risk for suicidal ideation, thinking, and behavior in children, adolescents, and young adults taking antidepressants for major depressive disorder (MDD) and other psychiatric disorders. Some regional prescribing information notes that the use of the medication is specifically for the short-term symptomatic relief of MDD 24. Nevertheless, it is important to note that the regulatory approval of and/or indications listed here for milnacipran may or may not exist and/or vary greatly between regions and nations 27,28.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Fibromyalgia •••••••••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
When utilized to treat fibromyalgia, the effect of milnacipran on the QTcF interval in patients was measured in a double-blind placebo-and positive-controlled parallel study in 88 healthy subjects using three to six times the recommended therapeutic dose for fibromyalgia at 600 mg/day 26. After baseline and placebo adjustment, the maximum mean QTcF change was 8 ms - an increase that is generally not considered to be clinically significant 26.
Conversely, when used for treating major depressive disorder (MDD), non-clinical studies have shown that levomilnacipran binds with high affinity to the norepinephrine (NE) and serotonin (5-HT) transporters (Ki = 71-91 nM and 11 nM respectively at human transporters) 24,25,26. Levomilnacipran inhibits the uptake of both NE and 5-HT in vitro and in vivo; preferentially inhibiting reuptake of NE over 5-HT by approximately 2-fold 24,25,26. Levomilnacipran does not directly affect the uptake of dopamine or other neurotransmitters 24,25,26. Levomilnacipran has no significant affinity for serotonergic (5-HT1-7), α- and β-adrenergic, muscarinic (M1-5), histamine (H1-4), dopamine (D1-5), opiate, benzodiazepine, and γ-aminobutyric acid (GABA) receptors in vitro 24,25. Levomilnacipran has no significant affinity for Ca++, K+, Na+, and Cl– channels and does not inhibit the activity of human monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase 24,25,26.
Moreover, in ECG studies with levomilnacipran used to treat MDD, although no clinically significant changes in QTcF interval (QTcF=QT/RR0.33) were noted, it appears that the agent can cause increases in heart rate and blood pressure 24. In particular, it appears that the maximum therapeutic dose of levomilnacipran at 120 mg/day is capable of causing a maximum mean difference in heart rate from placebo of 20.2 bpm and a mean difference in systolic and diastolic blood pressure from placebo ranging from 3.8 to 7.2 mmHg and 6.1 to 8.1 mmHg, respectively 24. Alternatively, a supratherapeutic dose of 300 mg/day is capable of causing a maximum mean difference in heart rate from placebo of 22.1 bpm and a mean difference in systolic and diastolic blood pressure from placebo ranging from 5.4 to 7.9 mmHg and 7.9 to 10.6 mmHg, respectively 24.
- Mechanism of action
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 14,18,19. 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 19,29,23. 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 18. 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 29.
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 17.
Target Actions Organism ASodium-dependent serotonin transporter inhibitorHumans ASodium-dependent noradrenaline transporter inhibitorHumans UNMDA receptor inhibitorHumans - Absorption
Racemic milnacipram demonstrates an absolute bioavailability of about 85-90% following oral administration 26. 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 26.
Conversely, the relative bioavailability of levomilnacipram has been documented as 92% 24,25. The median time to peak concentration Tmax for levomilnacipram is about 6-8 hours after oral administration 24,25. 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 26,24,25.
- Volume of distribution
The mean volume of distribution recorded for racemic milnacipran following a single intravenous dose to healthy subjects was approximately 400 L 26. Alternatively, levomilnacipran is widely distributed with an apparent volume of distribution of 387-473 L 24,25.
- Protein binding
The protein binding determined for racemic milnacipran is 13% 26. Conversely, the plasma protein binding documented for levomilnacipran is 22% over a concentration range of 10 to 1000 ng/mL 24,25.
- Metabolism
It has been determined that levomilnacipran undergoes desethylation and hydroxylation to generate desethyl levomilnacipran and p-hydroxy-levomilnacipran, respectively 24,25,20. Both oxidative metabolites undergo further conjugation with glucuronide to form the conjugate milnacipran carbamoyl-O-glucuronide 24,25,26,20. The desethylation is catalyzed primarily by CYP3A4 with minor contribution by CYP2C8, 2C19, 2D6, and 2J2 24,25. Additionally, it is the general understanding that there is no interconversion between the enantiomers of milnacipran in the body 24,25,26,27.
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- Route of elimination
Levomilnacipran and its metabolites are eliminated primarily by renal excretion 24,25. Following oral administration of 14C-levomilnacipran solution, approximately 58% of the dose is excreted in urine as unchanged levomilnacipran 24,25. N-desethyl levomilnacipran is the major metabolite excreted in the urine and accounted for approximately 18% of the dose 24,25. 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%) 24,25.
- 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 26. Alternatively, the terminal elimination half-life determined specifically for levomilnacipran formulations is about 12 hours 24,25.
- Clearance
The total plasma clearance determined for milnacipran is approximately 40 L/h 27.
- Adverse Effects
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- 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 26. In postmarketing experience, fatal outcomes have been reported for acute overdoses primarily involving multiple drugs but also with milnacipran only 26. 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 24,25,26.
There are no adequate and well-controlled studies in pregnant women 24,25,26. In fact, milnacipram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus 24,25,26.
Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding 24,25,26. 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 24,25,26. These features are consistent with either a direct toxic effect of SNRI class drugs like milnacipran or, possibly, a drug discontinuation syndrome 24,25,26. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome 24,25,26.
The effect of milnacipran on labor and delivery in humans is unknown 24,25,26. Milnacipran should be used during labor and delivery only if the potential benefits outweigh the potential risks 24,25,26.
There are no adequate and well-controlled studies in nursing mothers 24,25,26. It is not known if milnacipran is excreted in human milk 24,25,26. Studies have shown that levomilnacipran is excreted into the milk of lactating rats 24,25,26. Subsequently, possible excretion into human milk possesses the potential for serious adverse reactions in nursing infants 24,25,26. As a consequence, breastfeeding by women treated with levomilnacipran should be considered only if the potential benefits outweigh the potential risks to the child 24,25,26.
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 24,25,26.
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 24,25,26.
Levomilnacipran was not mutagenic when evaluated in vitro in a bacterial mutagenicity study (Ames test) and not genotoxic in a mouse lymphoma study 24,25,26. It was not clastogenic in an in vivo micronucleus assay in rats 24,25,26.
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 24,25,26. The NOAEL was 100 mg/kg/day based on reductions in body weight gain and food consumption 24,25,26. There were no levomilnacipran effects on male and female fertility parameters 24,25,26.
In the rat and rabbit embryo/fetal development studies, decreases in maternal body weight gain and food consumption were noted 24,25,26. In the fetuses, increases in the incidence of ossification anomalies were noted but were of no toxicological significance 24,25,26. 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 24,25,26.
Material safety data for milnacipran has documented the LD50 oral value in the rat model as being 213 mg/kg MSDS.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The risk or severity of adverse effects can be increased when 1,2-Benzodiazepine is combined with Milnacipran. Abacavir Abacavir may decrease the excretion rate of Milnacipran which could result in a higher serum level. Abametapir The serum concentration of Milnacipran can be increased when it is combined with Abametapir. Abciximab The risk or severity of hemorrhage can be increased when Milnacipran is combined with Abciximab. Abemaciclib The metabolism of Abemaciclib can be decreased when combined with Milnacipran. - Food Interactions
- 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.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Milnacipran hydrochloride RNZ43O5WW5 101152-94-7 XNCDYJFPRPDERF-UHFFFAOYSA-N - Product Images
- International/Other Brands
- Dalcipran / Ixel / Toledomin
- Brand Name Prescription Products
- Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Milnacipran HCl Tablet 25 mg/1 Oral Amneal Pharmaceuticals LLC 2014-01-31 Not applicable US Milnacipran HCl Tablet 100 mg/1 Oral Amneal Pharmaceuticals LLC 2014-01-31 Not applicable US Milnacipran HCl Tablet 12.5 mg/1 Oral Amneal Pharmaceuticals LLC 2014-01-31 Not applicable US Milnacipran HCl Tablet 50 mg/1 Oral Amneal Pharmaceuticals LLC 2014-01-31 Not applicable US - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Savella Milnacipran hydrochloride (12.5 mg/1) + Milnacipran hydrochloride (25 mg/1) + Milnacipran hydrochloride (50 mg/1) Kit Oral Allergan, Inc. 2009-04-17 Not applicable US Savella Milnacipran hydrochloride (12.5 mg/1) + Milnacipran hydrochloride (25 mg/1) + Milnacipran hydrochloride (50 mg/1) Kit Oral Allergan, Inc. 2009-04-17 Not applicable US Savella Milnacipran hydrochloride (12.5 mg/1) + Milnacipran hydrochloride (25 mg/1) + Milnacipran hydrochloride (50 mg/1) Kit Oral Allergan, Inc. 2009-04-17 Not applicable US
Categories
- ATC Codes
- N06AX17 — Milnacipran
- Drug Categories
- Adrenergic Agents
- Adrenergic Uptake Inhibitors
- Agents producing tachycardia
- Analgesics
- Analgesics, Non-Narcotic
- Antidepressive Agents
- Central Nervous System Agents
- Central Nervous System Depressants
- Combined Inhibitors of Serotonin/Norepinephrine Reuptake
- Cyclopropanes
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (moderate)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Drugs that are Mainly Renally Excreted
- Hypoglycemia-Associated Agents
- Membrane Transport Modulators
- Nervous System
- Neurotransmitter Agents
- Neurotransmitter Uptake Inhibitors
- Norepinephrine Uptake Inhibitors
- Peripheral Nervous System Agents
- Psychoanaleptics
- Psychotropic Drugs
- Selective Serotonin Reuptake Inhibitors
- Sensory System Agents
- Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
- Serotonin Agents
- Serotonin and Noradrenaline Reuptake Inhibitors
- Serotonin Modulators
- Classification
- Not classified
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- G56VK1HF36
- CAS number
- 92623-85-3
- InChI Key
- GJJFMKBJSRMPLA-UHFFFAOYSA-N
- InChI
- InChI=1S/C15H22N2O/c1-3-17(4-2)14(18)15(10-13(15)11-16)12-8-6-5-7-9-12/h5-9,13H,3-4,10-11,16H2,1-2H3
- IUPAC Name
- 2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropane-1-carboxamide
- SMILES
- CCN(CC)C(=O)C1(CC1CN)C1=CC=CC=C1
References
- Synthesis Reference
Jean Deregnaucourt, "Use of the (1S,2R) enantiomer of milnacipran for the preparation of a drug." U.S. Patent US20040259953, issued December 23, 2004.
US20040259953- General References
- Leo RJ, Brooks VL: Clinical potential of milnacipran, a serotonin and norepinephrine reuptake inhibitor, in pain. Curr Opin Investig Drugs. 2006 Jul;7(7):637-42. [Article]
- Sato S, Yamakawa Y, Terashima Y, Ohta H, Asada T: Efficacy of milnacipran on cognitive dysfunction with post-stroke depression: preliminary open-label study. Psychiatry Clin Neurosci. 2006 Oct;60(5):584-9. [Article]
- Simon LS: Is milnacipran effective in treating pain in patients with fibromyalgia? Nat Clin Pract Rheumatol. 2006 Mar;2(3):126-7. [Article]
- Soya A, Terao T, Nakajima M, Kojima H, Okamoto T, Inoue Y, Iwakawa M, Shinkai K, Yoshimura R, Ueta Y, Nakamura J: Effects of repeated milnacipran administration on brain serotonergic and noradrenergic functions in healthy volunteers. Psychopharmacology (Berl). 2006 Sep;187(4):526-7. Epub 2006 Jul 8. [Article]
- King T, Rao S, Vanderah T, Chen Q, Vardanyan A, Porreca F: Differential blockade of nerve injury-induced shift in weight bearing and thermal and tactile hypersensitivity by milnacipran. J Pain. 2006 Jul;7(7):513-20. [Article]
- Moojen VK, Martins MR, Reinke A, Feier G, Agostinho FR, Cechin EM, Quevedo J: Effects of milnacipran in animal models of anxiety and memory. Neurochem Res. 2006 Apr;31(4):571-7. Epub 2006 May 9. [Article]
- Moret C, Charveron M, Finberg JP, Couzinier JP, Briley M: Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug. Neuropharmacology. 1985 Dec;24(12):1211-9. [Article]
- Briley M, Prost JF, Moret C: Preclinical pharmacology of milnacipran. Int Clin Psychopharmacol. 1996 Sep;11 Suppl 4:9-14. [Article]
- Puozzo C, Panconi E, Deprez D: Pharmacology and pharmacokinetics of milnacipran. Int Clin Psychopharmacol. 2002 Jun;17 Suppl 1:S25-35. [Article]
- Leinonen E, Lepola U, Koponen H, Mehtonen OP, Rimon R: Long-term efficacy and safety of milnacipran compared to clomipramine in patients with major depression. Acta Psychiatr Scand. 1997 Dec;96(6):497-504. [Article]
- Papakostas GI, Fava M: A meta-analysis of clinical trials comparing milnacipran, a serotonin--norepinephrine reuptake inhibitor, with a selective serotonin reuptake inhibitor for the treatment of major depressive disorder. Eur Neuropsychopharmacol. 2007 Jan;17(1):32-6. Epub 2006 Jun 8. [Article]
- Kako Y, Niwa Y, Toyomaki A, Yamanaka H, Kitagawa N, Denda K, Koyama T: A case of adult attention-deficit/hyperactivity disorder alleviated by milnacipran. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Apr 13;31(3):772-5. Epub 2007 Jan 12. [Article]
- Bernstein CD, Albrecht KL, Marcus DA: Milnacipran for fibromyalgia: a useful addition to the treatment armamentarium. Expert Opin Pharmacother. 2013 May;14(7):905-16. doi: 10.1517/14656566.2013.779670. Epub 2013 Mar 19. [Article]
- Cording M, Derry S, Phillips T, Moore RA, Wiffen PJ: Milnacipran for pain in fibromyalgia in adults. Cochrane Database Syst Rev. 2015 Oct 20;(10):CD008244. doi: 10.1002/14651858.CD008244.pub3. [Article]
- Derry S, Gill D, Phillips T, Moore RA: Milnacipran for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2012 Mar 14;(3):CD008244. doi: 10.1002/14651858.CD008244.pub2. [Article]
- Paris BL, Ogilvie BW, Scheinkoenig JA, Ndikum-Moffor F, Gibson R, Parkinson A: In vitro inhibition and induction of human liver cytochrome p450 enzymes by milnacipran. Drug Metab Dispos. 2009 Oct;37(10):2045-54. doi: 10.1124/dmd.109.028274. Epub 2009 Jul 16. [Article]
- Nutt DJ: Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry. 2008;69 Suppl E1:4-7. [Article]
- Pertovaara A: Noradrenergic pain modulation. Prog Neurobiol. 2006 Oct;80(2):53-83. doi: 10.1016/j.pneurobio.2006.08.001. Epub 2006 Oct 9. [Article]
- Martin SL, Power A, Boyle Y, Anderson IM, Silverdale MA, Jones AKP: 5-HT modulation of pain perception in humans. Psychopharmacology (Berl). 2017 Oct;234(19):2929-2939. doi: 10.1007/s00213-017-4686-6. Epub 2017 Aug 10. [Article]
- Li F, Chin C, Wangsa J, Ho J: Excretion and metabolism of milnacipran in humans after oral administration of milnacipran hydrochloride. Drug Metab Dispos. 2012 Sep;40(9):1723-35. doi: 10.1124/dmd.112.045120. Epub 2012 May 31. [Article]
- Gorman JM, Kent JM: SSRIs and SNRIs: broad spectrum of efficacy beyond major depression. J Clin Psychiatry. 1999;60 Suppl 4:33-8; discussion 39. [Article]
- Rizvi SM, Shaikh S, Khan M, Biswas D, Hameed N, Shakil S: Fetzima (levomilnacipran), a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta-site amyloid precursor protein cleaving enzyme-1. CNS Neurol Disord Drug Targets. 2014;13(8):1427-31. [Article]
- Brain Uses Serotonin To Perpetuate Chronic Pain Signals In Local Nerves [Link]
- Fetzima (levomilnacipran extended-release capsules) Canadian Product Monograph [File]
- Fetzima (levomilnacipran) FDA Label [File]
- Savella (milnacipran HCl) FDA Label [File]
- Australian Public Assessment Report for Milnacipran hydrochloride [File]
- EMEA REFUSAL ASSESSMENT REPORT FOR Milnacipran Pierre Fabre Medicament [File]
- Serotonin Noradrenaline Reuptake Inhibitors (SNRIs) by Ipek Komsuoglu Celikyurt, Oguz Mutlu, and Guner Ulak [File]
- External Links
- Human Metabolome Database
- HMDB0254055
- KEGG Drug
- D08222
- PubChem Compound
- 65833
- PubChem Substance
- 46506141
- ChemSpider
- 9797657
- BindingDB
- 50490618
- 588250
- ChEBI
- 135005
- ChEMBL
- CHEMBL259209
- Therapeutic Targets Database
- DAP001155
- PharmGKB
- PA164752812
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Milnacipran
- FDA label
- Download (332 KB)
- MSDS
- Download (83.2 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Basic Science Fibromyalgia 1 4 Completed Treatment Aspergers Syndrome / Autism Disorder 1 4 Completed Treatment Chronic Pain / Degenerative Joint Disease / Osteoarthritis of the Knee 1 4 Completed Treatment Fibromyalgia 5 4 Completed Treatment Fibromyalgia / Sleep / Sleep disorders and disturbances 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Forest Laboratories Inc.
- Forest Pharmaceuticals
- Physicians Total Care Inc.
- Dosage Forms
Form Route Strength Capsule Oral Tablet Oral 100 mg/1 Tablet Oral 12.5 mg/1 Tablet Oral 25 mg/1 Tablet Oral 50 mg/1 Capsule Oral 25 mg Capsule Oral 50 mg Kit Oral Tablet, film coated Oral 100 mg/1 Tablet, film coated Oral 12.5 mg/1 Tablet, film coated Oral 25 mg/1 Tablet, film coated Oral 50 mg/1 - Prices
Unit description Cost Unit Savella 100 mg tablet 2.13USD tablet Savella 12.5 mg tablet 2.13USD tablet Savella 25 mg tablet 2.13USD tablet Savella 50 mg tablet 2.13USD tablet DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US6602911 No 2003-08-05 2023-01-14 US US6992110 No 2006-01-31 2021-11-05 US US7888342 No 2011-02-15 2021-11-05 US US7994220 No 2011-08-09 2029-09-19 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 179°C Bernstein CD, Albrecht KL, Marcus DA: Milnacipran for fibromyalgia: a useful addition to the treatment armamentarium. Expert Opin Pharmacother. 2013 Mar 19. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/23506481 water solubility 19 mg/mL MSDS - Predicted Properties
Property Value Source Water Solubility 1.23 mg/mL ALOGPS logP 1.72 ALOGPS logP 1.42 Chemaxon logS -2.3 ALOGPS pKa (Strongest Basic) 9.83 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 2 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 46.33 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 73.81 m3·mol-1 Chemaxon Polarizability 28.25 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 1.0 Blood Brain Barrier + 0.9889 Caco-2 permeable + 0.5914 P-glycoprotein substrate Substrate 0.5928 P-glycoprotein inhibitor I Non-inhibitor 0.902 P-glycoprotein inhibitor II Non-inhibitor 0.8787 Renal organic cation transporter Non-inhibitor 0.8119 CYP450 2C9 substrate Non-substrate 0.8494 CYP450 2D6 substrate Non-substrate 0.9116 CYP450 3A4 substrate Non-substrate 0.6514 CYP450 1A2 substrate Non-inhibitor 0.6383 CYP450 2C9 inhibitor Non-inhibitor 0.7697 CYP450 2D6 inhibitor Non-inhibitor 0.7718 CYP450 2C19 inhibitor Non-inhibitor 0.8587 CYP450 3A4 inhibitor Non-inhibitor 0.6327 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7004 Ames test Non AMES toxic 0.8013 Carcinogenicity Non-carcinogens 0.5456 Biodegradation Not ready biodegradable 0.9972 Rat acute toxicity 2.6162 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.993 hERG inhibition (predictor II) Non-inhibitor 0.6823
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0002-0690000000-e358699dd4ba3ced536b Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0002-3390000000-4a22ea8684355b17c232 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-000t-3970000000-6a00667afb142f57e896 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-00kb-9360000000-32dc0f23bf29a8d2ba83 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-014i-9700000000-217adea06b61e02741c0 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00fr-9300000000-77df58f97fce227ecf77 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Serotonin:sodium symporter activity
- Specific Function
- Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into t...
- Gene Name
- SLC6A4
- Uniprot ID
- P31645
- Uniprot Name
- Sodium-dependent serotonin transporter
- Molecular Weight
- 70324.165 Da
References
- Leo RJ, Brooks VL: Clinical potential of milnacipran, a serotonin and norepinephrine reuptake inhibitor, in pain. Curr Opin Investig Drugs. 2006 Jul;7(7):637-42. [Article]
- Moret C, Charveron M, Finberg JP, Couzinier JP, Briley M: Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug. Neuropharmacology. 1985 Dec;24(12):1211-9. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Norepinephrine:sodium symporter activity
- Specific Function
- Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
- Gene Name
- SLC6A2
- Uniprot ID
- P23975
- Uniprot Name
- Sodium-dependent noradrenaline transporter
- Molecular Weight
- 69331.42 Da
References
- Leo RJ, Brooks VL: Clinical potential of milnacipran, a serotonin and norepinephrine reuptake inhibitor, in pain. Curr Opin Investig Drugs. 2006 Jul;7(7):637-42. [Article]
- Moret C, Charveron M, Finberg JP, Couzinier JP, Briley M: Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug. Neuropharmacology. 1985 Dec;24(12):1211-9. [Article]
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Voltage-gated cation channel activity
- Specific Function
- NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein plays a key role in synaptic p...
Components:
References
- Kohno T, Kimura M, Sasaki M, Obata H, Amaya F, Saito S: Milnacipran inhibits glutamatergic N-methyl-D-aspartate receptor activity in spinal dorsal horn neurons. Mol Pain. 2012 Jun 19;8:45. doi: 10.1186/1744-8069-8-45. [Article]
- Shuto S, Takada H, Mochizuki D, Tsujita R, Hase Y, Ono S, Shibuya N, Matsuda A: (+/-)-(Z)-2-(aminomethyl)-1-phenylcyclopropanecarboxamide derivatives as a new prototype of NMDA receptor antagonists. J Med Chem. 1995 Jul 21;38(15):2964-8. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Paris BL, Ogilvie BW, Scheinkoenig JA, Ndikum-Moffor F, Gibson R, Parkinson A: In vitro inhibition and induction of human liver cytochrome p450 enzymes by milnacipran. Drug Metab Dispos. 2009 Oct;37(10):2045-54. doi: 10.1124/dmd.109.028274. Epub 2009 Jul 16. [Article]
Drug created at October 21, 2007 22:23 / Updated at January 02, 2024 23:48