Identification

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Name
Milnacipran
Accession Number
DB04896
Type
Small Molecule
Groups
Approved, Investigational
Description

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].

Structure
Thumb
Synonyms
  • (+-)-Milnacipran
  • Midalcipran
  • Milnacipran
  • Milnacipranum
External IDs
F-2207 / F2207
Product Ingredients
IngredientUNIICASInChI Key
Milnacipran hydrochlorideRNZ43O5WW5101152-94-7XNCDYJFPRPDERF-UHFFFAOYSA-N
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SavellaTablet, film coated12.5 mg/1OralAllergan2009-04-17Not applicableUs00456 1512 60 nlmimage10 313f1888
SavellaTablet, film coated25 mg/1OralRebel Distributors2009-04-17Not applicableUs
SavellaTablet, film coated100 mg/1OralStat Rx USA2009-04-17Not applicableUs
SavellaTablet, film coated50 mg/1OralCardinal Health2009-04-17Not applicableUs00456 1550 60 nlmimage10 0d1c8694
SavellaTablet, film coated25 mg/1OralLake Erie Medical Dba Quality Care Produts Llc2009-04-172016-12-31Us
SavellaTablet, film coated50 mg/1OralStat Rx USA2009-04-17Not applicableUs
SavellaTablet, film coated100 mg/1OralAllergan2009-04-17Not applicableUs00456 1510 60 nlmimage10 011c8094
SavellaTablet, film coated50 mg/1OralAllergan2009-04-17Not applicableUs0456 155020180913 8702 1gh427g
SavellaTablet, film coated25 mg/1OralStat Rx USA2009-04-17Not applicableUs
SavellaTablet, film coated25 mg/1OralUnit Dose Services2009-04-17Not applicableUs50436 999320180913 8702 10yh6em
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Milnacipran HClTablet12.5 mg/1OralAmneal Pharmaceuticals2014-01-31Not applicableUs
Milnacipran HClTablet100 mg/1OralAmneal Pharmaceuticals2014-01-31Not applicableUs
Milnacipran HClTablet50 mg/1OralAmneal Pharmaceuticals2014-01-31Not applicableUs
Milnacipran HClTablet25 mg/1OralAmneal Pharmaceuticals2014-01-31Not applicableUs
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
SavellaMilnacipran hydrochloride (12.5 mg/1) + Milnacipran hydrochloride (25 mg/1) + Milnacipran hydrochloride (50 mg/1)KitOralAllergan2009-04-17Not applicableUs
SavellaMilnacipran hydrochloride (12.5 mg/1) + Milnacipran hydrochloride (25 mg/1) + Milnacipran hydrochloride (50 mg/1)KitOralAllergan2009-04-17Not applicableUs
SavellaMilnacipran hydrochloride (12.5 mg/1) + Milnacipran hydrochloride (25 mg/1) + Milnacipran hydrochloride (50 mg/1)KitOralAllergan2009-04-17Not applicableUs
International/Other Brands
Dalcipran / Ixel / Toledomin
Categories
UNII
G56VK1HF36
CAS number
92623-85-3
Weight
Average: 246.354
Monoisotopic: 246.173213336
Chemical Formula
C15H22N2O
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

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]. At the same time, levomilnacipran is indicated for the treatment of major depressive disorder (MDD) in patients that are 18 years old or above [25], although some regional prescribing information notes that 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].

Associated Conditions
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].

TargetActionsOrganism
ASodium-dependent serotonin transporter
inhibitor
Humans
ASodium-dependent noradrenaline transporter
inhibitor
Humans
UNMDA receptor
inhibitor
Humans
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].

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].

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].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of hemorrhage can be increased when Milnacipran is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of hemorrhage can be increased when Milnacipran is combined with (S)-Warfarin.
2,4-thiazolidinedioneThe risk or severity of hypoglycemia can be increased when Milnacipran is combined with 2,4-thiazolidinedione.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of serotonin syndrome can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Milnacipran.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylthioamphetamine is combined with Milnacipran.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Milnacipran.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Milnacipran.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Milnacipran.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Milnacipran.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Milnacipran.
Food Interactions
Not Available

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
  1. 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. [PubMed:16869117]
  2. 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. [PubMed:16958942]
  3. Simon LS: Is milnacipran effective in treating pain in patients with fibromyalgia? Nat Clin Pract Rheumatol. 2006 Mar;2(3):126-7. [PubMed:16932669]
  4. 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. [PubMed:16830129]
  5. 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. [PubMed:16814690]
  6. 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. [PubMed:16758367]
  7. 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. [PubMed:3005901]
  8. Briley M, Prost JF, Moret C: Preclinical pharmacology of milnacipran. Int Clin Psychopharmacol. 1996 Sep;11 Suppl 4:9-14. [PubMed:8923122]
  9. Puozzo C, Panconi E, Deprez D: Pharmacology and pharmacokinetics of milnacipran. Int Clin Psychopharmacol. 2002 Jun;17 Suppl 1:S25-35. [PubMed:12369608]
  10. 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. [PubMed:9421348]
  11. 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. [PubMed:16762534]
  12. 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. [PubMed:17300859]
  13. 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. [PubMed:23506481]
  14. 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. [PubMed:26482422]
  15. 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. [PubMed:22419330]
  16. 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. [PubMed:19608694]
  17. Nutt DJ: Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry. 2008;69 Suppl E1:4-7. [PubMed:18494537]
  18. 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. [PubMed:17030082]
  19. 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. [PubMed:28798976]
  20. 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. [PubMed:22653299]
  21. 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. [PubMed:10086481]
  22. 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. [PubMed:25345508]
  23. Brain Uses Serotonin To Perpetuate Chronic Pain Signals In Local Nerves [Link]
  24. Fetzima (levomilnacipran extended-release capsules) Canadian Product Monograph [File]
  25. Fetzima (levomilnacipran) FDA Label [File]
  26. Savella (milnacipran HCl) FDA Label [File]
  27. Australian Public Assessment Report for Milnacipran hydrochloride [File]
  28. EMEA REFUSAL ASSESSMENT REPORT FOR Milnacipran Pierre Fabre Medicament [File]
  29. Serotonin Noradrenaline Reuptake Inhibitors (SNRIs) by Ipek Komsuoglu Celikyurt, Oguz Mutlu, and Guner Ulak [File]
External Links
Human Metabolome Database
HMDB0015602
KEGG Drug
D08222
PubChem Compound
65833
PubChem Substance
46506141
ChemSpider
9797657
BindingDB
86420
ChEBI
135005
ChEMBL
CHEMBL259209
Therapeutic Targets Database
DAP001155
PharmGKB
PA164752812
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Milnacipran
ATC Codes
N06AX17 — Milnacipran
FDA label
Download (332 KB)
MSDS
Download (83.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceFibromyalgia1
2CompletedTreatmentBack Pain Lower Back1
2CompletedTreatmentFibromyalgia Syndrome1
2RecruitingTreatmentPain, Neuropathic1
2TerminatedTreatmentFibromyalgia Syndrome, Primary1
2TerminatedTreatmentFibromyalgia, Primary1
2TerminatedTreatmentIrritable Bowel Syndrome (IBS)1
2Unknown StatusTreatmentFibromylagia1
2, 3CompletedTreatmentFibromyalgia1
2, 3RecruitingTreatmentDepression1
3CompletedTreatmentDepression1
3CompletedTreatmentFibromyalgia3
3CompletedTreatmentFibromyalgia Syndrome2
3CompletedTreatmentFibromyalgia / Neurocognition1
3CompletedTreatmentVestibulodynia / Vulvodynia1
3TerminatedTreatmentFibromyalgia2
3WithdrawnTreatmentBack Pain1
4CompletedBasic ScienceFibromyalgia1
4CompletedTreatmentAsperger's Syndrome / Aspergers Syndrome / Autism Spectrum Conditions/Disorders1
4CompletedTreatmentDegenerative Joint Disease / Knee Osteoarthritis (Knee OA) / Pain, Chronic1
4CompletedTreatmentFibromyalgia3
4CompletedTreatmentFibromyalgia / Sleep / Sleep disorders and disturbances1
4CompletedTreatmentKnee Pain After Total Knee Arthroplasty / Osteoarthritis Pain1
4CompletedTreatmentRadicular Pain Related to Lumbosacral Disc Disease1
4CompletedTreatmentRheumatoid Arthritis2
4CompletedTreatmentShoulder Pain Chronic1
4Unknown StatusPreventionChronic Migraine / Migraine With Aura / Migraine Without Aura1
4Unknown StatusTreatmentFibromyalgia1
4Unknown StatusTreatmentOsteoarthritis (OA)1
4WithdrawnTreatmentFibromyalgia / Systemic Lupus Erythematosus (SLE) / Widespread Pain1
Not AvailableActive Not RecruitingTreatmentDepression2
Not AvailableCompletedPreventionChronic Migraine1
Not AvailableRecruitingTreatmentAdverse Reaction to Drug / Depression1
Not AvailableRecruitingTreatmentDepression / Depressive Symptoms1
Not AvailableRecruitingTreatmentFibromyalgia, Primary1
Not AvailableRecruitingTreatmentPain, Chronic / Post Treatment Lyme Syndrome (PTLS)1
Not AvailableTerminatedTreatmentIdiopathic Peripheral Neuropathy1
Not AvailableUnknown StatusPreventionDepression / Stroke, Ischemic1
Not AvailableUnknown StatusTreatmentMajor Depressive Disorder (MDD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Forest Laboratories Inc.
  • Forest Pharmaceuticals
  • Physicians Total Care Inc.
Dosage forms
FormRouteStrength
TabletOral100 mg/1
TabletOral12.5 mg/1
TabletOral25 mg/1
TabletOral50 mg/1
KitOral
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral12.5 mg/1
Tablet, film coatedOral25 mg/1
Tablet, film coatedOral50 mg/1
Prices
Unit descriptionCostUnit
Savella 100 mg tablet2.13USD tablet
Savella 12.5 mg tablet2.13USD tablet
Savella 25 mg tablet2.13USD tablet
Savella 50 mg tablet2.13USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6602911No2003-08-052023-01-14Us
US6992110No2006-01-312021-11-05Us
US7888342No2011-02-152021-11-05Us
US7994220No2011-08-092029-09-19Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
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 solubility19 mg/mLMSDS
Predicted Properties
PropertyValueSource
Water Solubility1.23 mg/mLALOGPS
logP1.72ALOGPS
logP1.42ChemAxon
logS-2.3ALOGPS
pKa (Strongest Basic)9.83ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area46.33 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity73.81 m3·mol-1ChemAxon
Polarizability28.25 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9889
Caco-2 permeable+0.5914
P-glycoprotein substrateSubstrate0.5928
P-glycoprotein inhibitor INon-inhibitor0.902
P-glycoprotein inhibitor IINon-inhibitor0.8787
Renal organic cation transporterNon-inhibitor0.8119
CYP450 2C9 substrateNon-substrate0.8494
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.6514
CYP450 1A2 substrateNon-inhibitor0.6383
CYP450 2C9 inhibitorNon-inhibitor0.7697
CYP450 2D6 inhibitorNon-inhibitor0.7718
CYP450 2C19 inhibitorNon-inhibitor0.8587
CYP450 3A4 inhibitorNon-inhibitor0.6327
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7004
Ames testNon AMES toxic0.8013
CarcinogenicityNon-carcinogens0.5456
BiodegradationNot ready biodegradable0.9972
Rat acute toxicity2.6162 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.993
hERG inhibition (predictor II)Non-inhibitor0.6823
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

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
  1. 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. [PubMed:16869117]
  2. 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. [PubMed:3005901]
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
  1. 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. [PubMed:16869117]
  2. 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. [PubMed:3005901]
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
  1. 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. [PubMed:22716121]
  2. 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. [PubMed:7636857]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
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
  1. 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. [PubMed:19608694]

Drug created on October 21, 2007 16:23 / Updated on April 10, 2019 22:39