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Levomilnacipran | CAS No: 96847-54-0 | GMP-certified suppliers
A medication that treats major depressive disorder in adults by selectively inhibiting serotonin and norepinephrine reuptake, enhancing central nervous system neurotransmitter balance.
Therapeutic categories
Primary indications
- Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor indicated for the treatment of major depressive disorder (MDD) in adults
Product Snapshot
- Levomilnacipran is available as oral capsules and extended-release capsules
- It is primarily used for the treatment of major depressive disorder in adults
- The product is approved and marketed in the US and Canada, with investigational status in other regions
Clinical Overview
Pharmacologically, levomilnacipran exhibits potent inhibition of norepinephrine reuptake with an IC50 of approximately 11 nM, and serotonin reuptake inhibition with an IC50 ranging from 16 to 19 nM. It binds selectively to the human serotonin (5-HT) and norepinephrine (NE) transporters without significant affinity for other neurotransmitter receptors, ion channels, or transporters, including monoamine oxidase enzymes. The drug demonstrates over a 15-fold higher selectivity for norepinephrine relative to serotonin reuptake inhibition.
The antidepressant mechanism is attributed to elevated synaptic concentrations of serotonin and norepinephrine in the central nervous system secondary to transporter inhibition. Levomilnacipran does not exhibit clinically relevant effects on cardiac conduction such as QTc prolongation. It is categorized under various CNS agent classes, including combined serotonin/norepinephrine reuptake inhibitors and adrenergic uptake inhibitors.
Absorption, distribution, metabolism, and excretion (ADME) parameters indicate that levomilnacipran is a substrate of multiple cytochrome P450 enzymes, including CYP2C19, CYP2C8, CYP2D6, CYP3A, and CYP3A4, and is mainly eliminated renally. Due to its involvement in cytochrome P450 pathways, potential drug-drug interactions should be evaluated. Safety considerations include the monitoring of serotonin syndrome risk when co-administered with other serotonergic agents and vigilance for adverse effects related to increased adrenergic activity, such as tachycardia.
Approved by the FDA in 2013 for MDD, levomilnacipran’s development for stroke treatment was discontinued by the EMA. Key branded formulations include extended-release oral dosage forms.
In sourcing levomilnacipran API, attention should be given to stereochemical purity, as the therapeutic activity resides in the levomilnacipran enantiomer without conversion to the racemate. Compliance with global pharmacopoeial standards and thorough impurity profiling is essential to ensure quality, safety, and consistency for pharmaceutical manufacturing.
Identification & chemistry
| Generic name | Levomilnacipran |
|---|---|
| Molecule type | Small molecule |
| CAS | 96847-54-0 |
| UNII | UGM0326TXX |
| DrugBank ID | DB08918 |
Pharmacology
| Summary | Levomilnacipran is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) primarily targeting sodium-dependent serotonin and norepinephrine transporters. It exhibits higher potency for norepinephrine reuptake inhibition, enhancing synaptic concentrations of these monoamines in the central nervous system. Its pharmacological profile is characterized by minimal off-target receptor activity and absence of monoamine oxidase inhibition. |
|---|---|
| Mechanism of action | Levomilnacipran is a potent and selective selective serotonin and norepinephrine reuptake inhibitor (SNRI). The exact mechanism of the antidepressant action of levomilnacipran is unknown but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system through inhibition of reuptake at serotonin and norepinephrine transporters. Like milnacipran, levomilnacipran is a more potent inhibitor of the norepinephrine transporter than the serotonin transporter: it exhibits over a 15-fold higher selectivity for norepinephrine versus serotonin reuptake inhibition. |
| Pharmacodynamics | Levomilnacipran is an antidepressant that binds with high affinity to human serotonin (5-HT) and norepinephrine (NE) transporters (Ki = 11 and 91 nM, respectively). It potently inhibits 5-HT and NE reuptake (IC50 = 16 - 19 and 11 nM, respectively). Levomilnacipran does not bind to any other receptors, ion channels, or transporters, including serotonergic (5HT1-7), α- and β adrenergic, muscarinic, or histaminergic receptors and Ca<sup>2+</sup>, Na<sup>+</sup>, K<sup>+</sup> or Cl<sup>-</sup> channels to a significant degree.[A261176, A38560, L47946] Levomilnacipran did not inhibit monoamine oxidase (MAO). Furthermore, levomilnacipran does not prolong the QTc interval to a clinically relevant extent. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Sodium-dependent serotonin transporter | Humans | inhibitor |
| Sodium-dependent noradrenaline transporter | Humans | inhibitor |
ADME / PK
| Absorption | The steady-state concentration of levomilnacipran was dose-proportional when administered at a dose ranging from 25 mg to 300 mg (2.5 times the maximum recommended dosage of levomilnacipran) once daily. After daily dosing of 120 mg levomilnacipran, the mean C<sub>max</sub> value was 341 ng/mL, and the mean steady-state AUC value was 5196 ng x h/mL. The relative bioavailability of oral levomilnacipran extended-release capsules was 92% when compared to oral solution. The median time to peak concentration (T<sub>max</sub>) of levomilnacipran ranges from six to eight hours after oral administration. Levomilnacipran concentration was not significantly affected when it was administered with food. |
|---|---|
| Half-life | The apparent terminal elimination half-life of extended-release levomilnacipran is approximately 12 hours. |
| Protein binding | Levomilnacipran is 22% bound to plasma proteins over the concentration range of 10 to 1000 ng/mL. |
| Metabolism | Levomilnacipran undergoes desethylation to form desethyl levomilnacipran (or N-desethyl levomilnacipran) and hydroxylation to form p-hydroxy-levomilnacipran, which are pharmacologically inactive. Both oxidative metabolites can undergo further glucuronidation. Desethylation is primarily catalyzed by CYP3A4 with minor contributions by CYP2C8, 2C19, 2D6, and 2J2.[A38560, L47946] |
| Route of elimination | Levomilnacipran and its metabolites are eliminated primarily by renal excretion. Following oral administration of <sup>14</sup>C-levomilnacipran solution, approximately 58% of the dose is excreted in urine as unchanged levomilnacipran. N-desethyl levomilnacipran was the major metabolite excreted in the urine, accounting for approximately 18% of the dose. Other identifiable metabolites excreted in the urine were levomilnacipran glucuronide (4%), desethyl levomilnacipran glucuronide (3%), p-hydroxy levomilnacipran glucuronide (1%), and p-hydroxy levomilnacipran (1%). |
| Volume of distribution | Levomilnacipran is widely distributed, with an apparent volume of distribution ranging from 387 to 473 L. |
| Clearance | Following oral administration, the mean apparent total clearance of levomilnacipran is 21-29 L/h. |
Formulation & handling
- Levomilnacipran is a small molecule API formulated exclusively for oral administration, primarily in extended-release capsule form.
- The compound has moderate water solubility and logP, supporting oral delivery without significant food effect on absorption.
- Handling considerations include avoiding concomitant use with alcohol and strong CYP3A4 inhibitors to maintain extended-release integrity and dosing safety.
Regulatory status
| Lifecycle | The active pharmaceutical ingredient is marketed primarily in the US and Canada, with patent protections expiring between 2023 and 2032 in the United States, indicating a staggered market exclusivity period. Product lifecycle is transitioning from early maturity toward full generic competition as patent expirations progress. |
|---|
| Markets | US, Canada |
|---|
Supply Chain
| Supply chain summary | Levomilnacipran is primarily marketed in the US and Canadian markets with a limited number of originator companies supplying branded products under the name Fetzima. Multiple patents protect the drug in the United States, with expiration dates extending to 2031 and 2032, indicating that generic competition is not expected in the near term. The supply landscape is therefore characterized by a strong patent protection status supporting brand exclusivity in North America. |
|---|
Safety
| Toxicity | The oral LD<sub>50</sub> in rats was 238 mg/kg. There is limited clinical experience with levomilnacipran overdose in humans. In clinical studies, cases of ingestions up to 360 mg daily were reported with none being fatal. As there is no known specific antidote, levomilnacipran overdose should be managed with supportive measures, including close medical supervision and monitoring, with the consideration of possible multiple drug involvement. The high volume of distribution of levomilnacipran suggests that dialysis will not be effective in reducing levomilnacipran plasma concentrations. |
|---|
- Oral LD50 in rats is 238 mg/kg, indicating moderate acute toxicity
- No specific antidote available
- Overdose management requires supportive care and monitoring
Levomilnacipran is a type of Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)
Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) belong to a vital subcategory of pharmaceutical active pharmaceutical ingredients (APIs) that have gained significant popularity in the treatment of various medical conditions. SNRIs work by modulating the levels of two essential neurotransmitters in the brain, namely serotonin and norepinephrine.
These APIs are commonly prescribed for managing a range of mental health disorders, including depression, anxiety disorders, and certain chronic pain conditions. By inhibiting the reuptake of serotonin and norepinephrine, SNRIs enhance their availability in the brain, leading to improved mood, increased energy levels, and reduced pain perception.
SNRIs exhibit a unique dual mechanism of action, making them distinct from other classes of antidepressant medications. By targeting both serotonin and norepinephrine reuptake, SNRIs provide a broader spectrum of therapeutic effects, making them effective in treating patients who do not respond well to other medications.
Due to their widespread usage and effectiveness, SNRIs have become a preferred choice for healthcare professionals. Some commonly prescribed SNRIs include duloxetine, venlafaxine, and desvenlafaxine. These APIs are typically available in oral formulations and are well-tolerated by most patients, with a favorable side effect profile.
In summary, SNRIs represent a significant subcategory of pharmaceutical APIs that play a crucial role in the management of mental health disorders and chronic pain conditions. Their unique dual mechanism of action and effectiveness make them a valuable treatment option for healthcare providers, ensuring improved patient outcomes and quality of life.
Levomilnacipran (Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)), classified under Antidepressants
Antidepressants are a category of pharmaceutical Active Pharmaceutical Ingredients (APIs) widely used in the treatment of depression and other mood disorders. These medications work by balancing the levels of certain chemicals in the brain called neurotransmitters, such as serotonin, norepinephrine, and dopamine.
There are several types of antidepressants available, each with its own mechanism of action and efficacy. Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed as a first-line treatment for depression. They prevent the reabsorption of serotonin, resulting in increased serotonin levels in the brain. Examples of popular SSRIs include fluoxetine, sertraline, and escitalopram.
Tricyclic antidepressants (TCAs) are another class of antidepressants that work by blocking the reuptake of both serotonin and norepinephrine. They are generally used when SSRIs are ineffective or not well-tolerated. Amitriptyline, nortriptyline, and imipramine are commonly prescribed TCAs.
Other antidepressants include serotonin-norepinephrine reuptake inhibitors (SNRIs), atypical antidepressants, and monoamine oxidase inhibitors (MAOIs). SNRIs, such as venlafaxine and duloxetine, inhibit the reuptake of both serotonin and norepinephrine. Atypical antidepressants, including bupropion and mirtazapine, have diverse mechanisms of action, targeting multiple neurotransmitters. MAOIs, such as phenelzine and tranylcypromine, work by inhibiting the enzyme monoamine oxidase, which breaks down neurotransmitters.
It is important to note that antidepressants may have various side effects and require close monitoring by healthcare professionals. Dosages and treatment duration vary based on individual needs and response. Antidepressants are typically prescribed as part of a comprehensive treatment plan that may include psychotherapy and lifestyle modifications.
In conclusion, antidepressants are a vital category of pharmaceutical APIs used to manage depression and related mood disorders. They act on neurotransmitters in the brain to alleviate symptoms and improve overall well-being. It is crucial to consult with a healthcare provider to determine the most suitable antidepressant and monitor its effects.
Levomilnacipran API manufacturers & distributors
Compare qualified Levomilnacipran API suppliers worldwide. We currently have 9 companies offering Levomilnacipran API, with manufacturing taking place in 4 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Centaur Pharma | Producer | India | India | CoA, USDMF | 40 products |
| Cosma | Producer | Italy | Italy | CoA, USDMF | 20 products |
| Hetero Labs | Producer | India | India | CoA, USDMF | 90 products |
| Micro Labs | Producer | India | India | CoA, USDMF | 38 products |
| MSN Life Sciences | Producer | India | India | CoA, USDMF, WC | 46 products |
| MSN Pharma | Producer | India | India | CoA, GMP, USDMF, WC | 31 products |
| Pierre Fabre Medi. | Producer | France | France | CoA, USDMF | 4 products |
| Quimica Sintetica | Producer | Spain | Unknown | CoA, USDMF | 51 products |
| Raks Pharma | Producer | India | India | CoA, USDMF | 58 products |
When sending a request, specify which Levomilnacipran API quality you need: for example EP (Ph. Eur.), USP, JP, BP, or another pharmacopoeial standard, as well as the required grade (base, salt, micronised, specific purity, etc.).
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