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Levomilnacipran

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Last Updated: 23 October 2020

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Levomilnacipran

Chemical and physical data
3D model ( JSmol )Interactive image
FormulaC 15 H 22 N 2 O
Molar mass246.354 gmol 1
Clinical data
AHFS / Drugs.comMonograph
ATC codeNone
Pregnancy categoryUS : N (Not classified yet),
Routes of administrationBy mouth ( capsules )
Trade namesFetzima
Identifiers
CAS Number96847-55-1 Y 175131-60-9 ( hydrochloride )
ChemSpider5293005 N
DrugBankDB08918
IUPHAR/BPS7435
KEGGD10072 N
PubChem CID6917779
UNIIUGM0326TXX
Legal status
Legal statusIn general: (Prescription only)
Pharmacokinetic data
Bioavailability92%
Elimination half-life12 hours
ExcretionRenal
MetabolismHepatic (primarily by CYP3A4 )
Protein binding22%

Major depressive disorder is a common psychiatric disorder with an estimated lifetime prevalence rate in the range of 13% to 16% in the United States population. Patients with MDD often have symptoms such as depressed mood, loss of interest or pleasure in usual activities, changes in eating or sleeping patterns, fatigue, difficulty concentrating and thoughts of suicide. Although many pharmacotherapy treatment options are available for MDD, antidepressants can often cause adverse effects that could affect adherence to medication. Additionally, it is estimated that MDD is unremitting in 15% of patients and 35% can have recurrent episodes. Give high rate of recurrence and adverse effects associated with existing medications, new treatment options for Depression are needed. Both levomilnacipran and vortioxetine are new antidepressants that were approved by the Food and Drug Administration in 2013 for treatment of MDD in adults. Levomilnacipran is a serotonin norepinephrine reuptake inhibitor that was effective in several short - term studies and sustained efficacy and tolerability was demonstrated in a 48-wk extension study. Vortioxetine is a multi-modal antidepressant and it is thought to work via inhibition of serotonin transporter, 5-HT 3A, 5-HT 7 and 5-HT 1D antagonist, 5-HT 1B partial agonist, and 5-HT 1A agonist. Vortioxetine was effective in treatment of MDD in both short-term trials as well as in prevention of relapse in the 24-36 wk trial. Sustain efficacy and tolerability was demonstrated in several long-term open-label trials. Further studies comparing levomilnacipran and vortioxetine to other currently available antidepressants are needed to establish their place in therapy. Major depressive disorder is a common psychiatric disorder with an estimated lifetime prevalence rate in the range of 13% to 16% in the United States population. Patients with MDD often have symptoms such as depressed mood, loss of interest or pleasure in usual activities, changes in eating or sleeping patterns, fatigue, difficulty concentrating and thoughts of suicide. These symptoms persist over a period of at least 2 wk and are not attributable to other disorders such as substance-induce or general medical conditions. Many pharmacotherapy treatment options are available for MDD. They include selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, miscellaneous antidepressants such as bupropion and mirtazapine and antipsychotics such as quetiapine and aripiprazole. Despite the wide variety of antidepressants available, antidepressants can often cause adverse effects such as weight gain, sexual dysfunction, anxiety, headache, nausea, and sleep disturbances which could affect adherence to medication. Additionally, it is estimated that MDD is unremitting in 15% of patients and 35% can have recurrent episodes. If no prophylactic maintenance treatment is provide, risk of recurrence approaches 100% in patients with three or more lifetime depressive episodes. Give high rate of recurrence and adverse effects associated with existing medications, new treatment options for Depression are needed. The objective of this article is to provide an overview of two newest antidepressants, levomilnacipran and vortioxetine, and review safety and efficacy data on these two medications.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Side effects

In deciding to use medicine, risks of taking medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, following should be consider: tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also, tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully. Levomilnacipran is not approved for use in children. Safety and efficacy have not been establish. Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of levomilnacipran in the elderly. However, elderly patients are more likely to have Hyponatremia and age-related kidney problems, which may require adjustment in dose for patients receiving levomilnacipran. There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh potential benefits against potential risks before taking this medication while breastfeeding. Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. Following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive. Using this medicine with any of the following medicines is not recommend. Your doctor may decide not to treat you with this medication or change some of other medicines you take. Furazolidone Iproniazid Isocarboxazid Linezolid Methylene Blue Metoclopramide Moclobemide Phenelzine Procarbazine Rasagiline Safinamide Selegiline Tranylcypromine using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both medicines.


Uses

In addition to use list above, Fetzima may be used off-label. Off-label drug use is when a drug that is approved for one use is used for different one that is not approve. And you may wonder if Fetzima is used for certain other conditions. Fetzima isnt approved for treating anxiety, but sometimes it is used off-label for this condition. Fetzima belongs to a class of drugs called serotonin-norepinephrine reuptake inhibitors. These drugs are recommended as first-choice treatment option for generalized anxiety disorder by the Anxiety and Depression Association of America. For information about symptoms of anxiety and how Fetzima works to treat it, see section Fetzima and Anxiety above. Fetzima isnt approved to treat fibromyalgia. The effectiveness and safety of Fetzima to treat this condition hasnt been shown in clinical studies. With fibromyalgia, you have widespread pain in your muscles. This pain can affect your energy levels, quality of sleep, memory, and moods. Fetzima belongs to a class of drugs called serotonin-norepinephrine reuptake inhibitors. Some studies have shown that two other SNRIs, duloxetine and milnacipran, can help reduce pain caused by fibromyalgia. Levomilnacipran, active drug in Fetzima, is very similar to milnacipran. In these studies, 31% of people taking either duloxetine or milnacipran had at least 50% less pain after treatment. Of those taking placebo, 21% had the same result. If youre interested in using Fetzima to treat fibromyalgia, talk with your doctor. They can discuss all your treatment options with you.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Pharmacology

Relative to other SNRIs, levomilnacipran, as well as milnacipran, differ in that they are much more balanced reuptake inhibitors of serotonin and norepinephrine. To demonstrate, serotonin: norepinephrine ratios of SNRIs are as follow: venlafaxine = 30: 1, duloxetine = 10: 1, desvenlafaxine = 14: 1, milnacipran = 1. 6: 1, and levomilnacipran = 1: 2. Clinical implications of more balanced elevations of serotonin and norepinephrine are unclear, but may include improved effectiveness, though also increased side effects. Levomilnacipran is selective for serotonin and norepinephrine transporters, lacking significant affinity for over 23 off-target sites. However, it does show some affinity for dizocilpine site of NMDA receptor, and has been found to inhibit NR2A and NR2B subunit-containing NMDA receptors with respective IC 50 values of 5. 62 and 4. 57 M. As such, levomilnacipran is an NMDA receptor antagonist at high concentrations. Levomilnacipran has recently been found to act as an inhibitor of beta-site amyloid precursor protein cleaving enzyme-1, which is responsible for-amyloid plaque formation, and hence may be a potentially useful drug in treatment of Alzheimer's disease.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Clinical Results

Although antidepressants clearly have been significantly effective in treatment of major depressive disorder, they have also been disappointing, in that many patients fail to respond, only have partial response, cannot continue treatment due to intolerable side effects, or relapse despite continuing initially successful antidepressant treatment. 2 3 This was highlighted in STAR * D study in which only approximately 30% of patients had remission and 50% had clinical response to 12-to 14-week course of citalopram, selective serotonin reuptake inhibitor. 2 3 in addition, over 40% of patients had significant side effects. 3 Lastly, even for patients who initially respond to treatment with citalopram, approximately 40% relapse within one year of continued treatment. 2-4 Thus, there is a need for alternative antidepressants that are more effective and better tolerated than currently approved antidepressants. Recently, levomilnacipran, was approved by the US Food and Drug Administration for Treatment of MDD. It is an enantiomer of the racemic drug, milnacipran, which is approved for treatment of MDD in Europe and Japan and for fibromyalgia in the USA. 5-7 Preclinical studies have found that LVM is more potent inhibitor of norepinephrine and serotonin than the less active enantiomer, F2696. Furthermore, it has a better pharmacokinetic profile than F2696, having a longer elimination half-life with higher maximal concentration and area under curve. 8 Thus, LVM is a dual neurotransmitter reuptake inhibitor of norepinephrine and serotonin. It is unique amongst other dual neurotransmitter reuptake inhibitors in that it predominantly potentiates norepinephrine over serotonin; it has over 15-fold higher selectivity for norepinephrine versus serotonin reuptake inhibition compared with duloxetine, desvenlafaxine, or venlafaxine. 8-10 Interestingly, both in vitro and in vivo animal studies suggest that, at higher doses, serotonergic activity increases so that inhibition of norepinephrine reuptake approaches that of inhibition of serotonin reuptake. Lvm lacks affinity for other receptors, including dopaminergic, adrenergic, histaminic, muscarinic, and opioid receptors. 8 pharmacokinetics of LVM follow linear dynamics between 25 mg / day and 300 mg / day. Lvm has a half-life of approximately 12 hours, with time to peak concentration of 6-8 hours. Absorption is not affected by food intake, and the drug is 22% bound to protein. Metabolism is primarily through cytochrome 3A4. The latter can contribute to potential drug-drug interactions if the concomitant drug is a strong inhibitor of cytochrome 3A4, such as ketoconazole, clarithromycin, or ritonavir. Therefore, in these situations, maximum dose of 80 mg is recommend. Excretion of LVM is predominantly via kidney. Thus, package insert suggests reducing the maximal dose to 80 mg if moderate renal impairment exists and 40 mg if severe renal impairment exists. Lvm should not be used in patients with end-stage renal disease. The purpose of this paper is to review the status of LVM, which was approved by the US Food and Drug Administration in July 2014, presenting an overview of its effectiveness, safety, and tolerability. Some speculation as to where the LVM might fit in clinically is also present.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Message for the clinic

Levomilnacipran is an oral antidepressant that received regulatory approval on 25 July 2013 by the US Food and Drug Administration for treatment of Major Depressive Disorder. Levomilnacipran is a potent and selective serotonin-norepinephrine reuptake inhibitor with greater potency for inhibition of norepinephrine relative to serotonin reuptake. Approval for treatment of MDD was based on a clinical development program that included one 10week and Four 8week randomise placebocontrolled clinical trials in patients with MDD where levomilnacipran was titrated to target doses ranging from 40 to 120 mg taken once daily. Four of five trials demonstrate efficacy as measured by Montgomery Asberg Depression Rating Scale, with NNT for response vs. Placebo of 9, and for remission, 14. Nnh vs. Placebo for discontinuation because adverse events across all five trials was 19. Most commonly encountered AEs, as identified in product labelling, were nausea, hyperhidrosis, constipation, heart rate increase, erectile dysfunction in men, vomiting, tachycardia and palpitations. Levomilnacipran was not associated with clinically relevant weight change in shortterm trials or in the 48week openlabel extension trial. Mean changes from baseline in systolic blood pressure, diastolic BP and heart rate were + 3. 0 mmHg, + 3. 2 mm Hg and + 7. 4 bpm for levomilnacipran, and 0. 4 mmHg, no change and 0. 3 bpm for placebo, respectively. The Categorical shift in BP from normal or prehypertension at baseline to Stage 1 or Stage 2 hypertension at end of study was 10. 4% for levomilnacipran vs. 7. 1% for placebo, for NNH of 31. Levomilnacipran represents another option for treatment of MDD.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Introduction

Levomilnacipran is a potent and selective serotonin-norepinephrine reuptake inhibitor with greater potency for inhibition of norepinephrine relative to serotonin reuptake 1, and was approved for Treatment of Major depressive disorder by the US Food and Drug Administration on 25 July 2013 2 3. Levomilnacipran is an active enantiomer of racemic drug milnacipran 4 5; Milnacipran itself is approved by US FDA for management of fibromyalgia 6 and in other countries for treatment of MDD 7. Mdd is a common disorder. Estimate lifetime prevalence rates for MDD in epidemiological studies have ranged from approximately 13-16% of the US population, with 12month prevalence rates of 5. 3-6. 6%, and with rates that are higher in women than in men 8. Mdd can be unremitting in 15% of patients and recurrent in 35%; about half of those with firstonset episode recover and have no further episodes 8. Although there are a wide variety of different antidepressant medications, including combinations that are FDAapproved 9, it remains challenging to treat episodes of MDD to remission while simultaneously minimising adverse effects of medications such as sexual dysfunction 10 and weight gain 11. The aim of this review was to synthesise available data regarding the efficacy and safety of Levomilnacipran for Treatment of MDD and to place this new antidepressant into clinical perspective.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

EFFICACY STUDIES, SAFETY AND TOLERABILITY

As reported in the product monograph, safety of Levomilnacipran was evaluated in 2673 MDD Patients aged from 18 to 78 years of age diagnosed with MDD recruit in clinical studies, representing 942 patient-years of exposure. Most frequent adverse events under Levomilnacipran treatment, with an incidence of at least 5% and twice that for placebo, were nausea, hyperhidrosis, constipation, heart rate increase, erectile dysfunction and ejaculation disorders in males, urinary hesitation, vomiting, palpitations and tachycardia in females. Most AEs were from mild to moderate in intensity; nausea and headache generally occur early during treatment and were transient. However, as further reported in product labelling, data from short-term trials show that the presence of at least one AE, most frequently nausea, was the main reason for leaving treatment in 9% of Levomilnacipran patients versus 3% of those receiving placebo. Incidence of AEs was not dose related to Levomilnacipran doses between 40 and 120 mg / day, with only the exception of erectile dysfunction and urinary hesitation; this latter AE, due to increased peripheral noradrenergic tone, was observed in up to 6% of Levomilnacipran-treated patients versus none of patients receiving placebo. Regarding cardiovascular AEs, in short-term studies, small mean changes in blood pressure, sustained systolic or diastolic hypertension were greater for patients in the Levomilnacipran ER group compared with placebo in short-term studies, and presence of both sustained systolic and diastolic hypertension occurred in 0. 3% of Levomilnacipran patients versus 0. 1% of placebo patients; Levomilnacipran-treated patients also exhibited orthostatic hypotension in a higher percentage than patients on placebo. Heart rate result also increased during Levomilnacipran treatment in contrast with a mean decrease of 0. 3 bpm in placebo-treated patients. Treatment with Levomilnacipran was not associated with clinically significant prolongation of QT interval correct for heart rate according to Bazett's or Fridericia's formulas in short term studies; small dose-dependent mean increases in QTcB were report, probably as function of increase in heart rate during Levomilnacipran therapy. In patients on Levomilnacipran, laboratory tests show mean increases in gamma-glutamyl transferase, alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase; in study by Asnis et al., Ast and / or ALT levels three times above the upper limit of normal, thus considered as potentially clinically significant, were found in seven Levomilnacipran-treated patients. Regarding suicidality, short-term studies do not show differences between patients on Levomilnacipran versus those on placebo; nevertheless, as pointed out by Mago et al., Presence of recent suicidal behavior and / or significant suicidal ideation at baseline was considered as an exclusion criterion in cited trials. Lvm has a neutral profile on body weight: four of five short-term LVM trials report mean weight change of-0. 5 kg for LVM-treated patients and 0. 1 kg for placebo-treated patients. In 48-Week, open-label study-0. 55 kg weight change by end of treatment was observe, whereas 24-Week multicenter study report-0. 5 kg weight change for LVM versus 0. 5 kg weight change for placebo. In a 48-Week open-label extension trial by Mago et al.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

CONCLUSIONS, PLACE IN THERAPY

Ahmed Z. Elmaadawi, MD Narendra Singh, MD Jagadeesh Reddy, MD, MPH Adjunct Clinical Assistant Professors department of Psychiatry Indiana University School of Medicine-South Bend Campus South Bend, Indiana disclosures Drs. Elmaadawi, Singh, and Reddy report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Nasr is a member of speakers bureau For Forest Pharmaceuticals and Takeda Pharmaceutical Company limit and H. Lundbeck / S. With prevalence > 17%, Depression is one of the most common Mental Disorders in the United States and the second leading cause of Disability worldwide. 1 2 For decades, primary care and mental health providers have used selective serotonin reuptake inhibitors as first-line treatment for depressionyet remission rate after first trial of antidepressant is < 30%, and continues to decline after first antidepressant failure. 3 That is why clinicians continue to seek effective treatments for depression. That will provide quick and sustainable remissionand why scientists and pharmaceutical manufacturers have been competing to develop more effective antidepressant medications. In the past 4 years, FDA has approved 3 antidepressantsvilazodone, levomilnacipran, and vortioxetinewith hope of increasing options for patients who suffer from major Depression. These 3 antidepressants differ in their mechanisms of action from other available antidepressants, and all have been shown to have acceptable safety and tolerability profiles. In this article, we review these novel antidepressants and present some clinical pearls for their use. We also present our observations that each agent appears to show particular advantage in certain subpopulation of depressed patients who often do not respond, or who do not adequately respond, to other antidepressants. Vilazodone Vilazodone was approved by the FDA in 2011. The drug increases serotonin bioavailability in synapses through strong dual action: blocking serotonin reuptake through serotonin transporter partial agonism of 5-HT1A presynaptic receptor. Vilazodone also has moderate effect on 5-HT4 receptor and on dopamine and norepinephrine uptake inhibition. The unique presynaptic 5-HT1A partial agonism of Vilazodone is similar to that of buspirone, in which both drugs initially inhibit serotonin synthesis and neuronal firing. 4 Researchers therefore expect that Vilazodone would be more suitable for patients who have Depression and comorbid anxiety disorder; current FDA approval, however, is for Depression only. Adverse effects. The 5-HT4 receptor on which Vilazodone acts is present in the gastrointestinal tract, and contributes to regulating symptoms in patients with irritable bowel syndrome 5; Not surprisingly, most frequent adverse effects of Vilazodone are GI in nature. Headache is the most common non-GI side effect of Vilazodone. Depressed patients who took Vilazodone had no significant weight gain and did not report adverse sexual effects, compared with subjects given placebo. 6 following casea of patient with Depression, significant anxiety, and IBS exemplifies the type of patient for whom we find Vilazodone most useful. Case Ms., 19, is a college student with a history of major depressive disorder, social anxiety, and panic attacks for 2 years and IBS for 3 years.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

Sources

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions

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