Levomilnacipran - Uses, Dosage, Administration, Warning and Precautions, and Contraindications

Overview:

This drug is a serotonin and norepinephrine reuptake inhibitor (SNRI). Adults with major depressive disorder (MDD) are prescribed to take this drug. This drug is the 1S, 2R isomer of Milnacipran, which is also an SNRI. Studies done in the lab on Levomilnacipran have shown that it blocks norepinephrine reuptake about twice as well as it blocks serotonin reuptake. It is the fourth SNRI (serotonin and norepinephrine reuptake inhibitor) to be approved in the US. The drug can be taken once a day in a sustained-release form.

Generic Name:

Levomilnacipran.

Drug Class:

Serotonin-norepinephrine reuptake inhibitors.

Drug Development and Approval:

In July 2013, the US Food and Drug Administration (FDA) approved Levomilnacipran as a treatment for adults with major depressive disorder (MDD).

Indications:

Major depressive disorder (MDD).

Contraindications:

Sensitivity to Levomilnacipran, Milnacipran HCl, or any other ingredient in the drug.

MAOIs (monoamine oxidase inhibitors) used to treat psychiatric disorders should not be taken with Levomilnacipran hydrochloride or within seven days of stopping treatment with Levomilnacipran hydrochloride because they increase the risk of serotonin syndrome. It is also not a good idea to take Levomilnacipran hydrochloride within 14 days of stopping an MAOI used to treat mental disorders.

Starting Levomilnacipran hydrochloride in a patient being treated with MAOIs like Linezolid or intravenous methylene blue is also not a good idea because of the increased risk of serotonin syndrome.

Dosage:

Normal adult dosage:

Initial dose: 20 mg orally once daily for two days, then 40 mg orally once daily.

Daily maintenance dose: 40 to 120 mg orally.

Maximum dose: 120 mg/day.

For Patients:

What Is Major Depressive Disorder?

The World Health Organization (WHO) put major depressive disorder (MDD) as the third leading cause of disease burden around the world in 2008. They think that by 2030, MDD will be the leading cause of disease burden. It is diagnosed when a person has a low or depressed mood that lasts for a long time, anhedonia or less interest in fun things, feelings of guilt or worthlessness, lack of energy, poor concentration, changes in appetite, psychomotor retardation or agitation, trouble sleeping, or suicidal thoughts.

What Is Levomilnacipran?

Levomilnacipran is an antidepressant that blocks the reuptake of serotonin and norepinephrine (SNRI). Major depressive disorder is treated with Levomilnacipran. Depression is treated with Levomilnacipran. It works by helping the brain's natural chemicals (serotonin and norepinephrine) get back into balance. Levomilnacipran is a serotonin-norepinephrine reuptake inhibitor, which is a type of drug (SNRI). It might help them feel better, sleep better, eat better, and get back into the swing of daily living. A similar drug called Milnacipran is used to treat fibromyalgia, a condition that causes pain to last for a long time. Levomilnacipran should not be used to treat fibromyalgia.

Warnings:

People who are depressed or have a mental illness may think about ending their lives when they initially start taking medicine for depression, and some people may have more thoughts of killing themselves.

Tell the doctor immediately if one's mood or behaviour changes suddenly or if anyone encounters repeated episodes of suicidal thoughts.

Do not stop taking Levomilnacipran unless the doctor asks to discontinue the drug.

How to Use Levomilnacipran?

Instructions of Use:

Before starting Levomilnacipran therapy and before getting a refill, read the medication guide and, if available, the patient information leaflet that the pharmacist provides.

Take this medicine by mouth as the doctor prescribes, usually once daily.

This medicine can be taken with or without food.

Take the pills as a whole. Do not open the capsules, crush them, or chew them. Doing this, the drug could all come out at once, which could lead to more side effects.

The right dose depends on one's health, how well the treatment works, and any other medicines one may take. Make sure the doctor and pharmacist know about all other medications taken (including prescription, nonprescription, and herbal products).

To reduce the chance of side effects, the doctor may tell the patient to start with a low dose of this medicine and slowly increase it. Listen carefully to what the doctor advises and do it the same way without any deviation.

To reap the greatest benefits from this drug, take it consistently. Take this medication simultaneously every day, which helps them remember and reduce the chance of missing a dose.

Use this medication just as directed, and never increase the dosage, frequency, or duration of use. The condition won't get better any faster, and the chance of experiencing negative effects will rise.

It might take more months before one can fully experience the benefits of this drug.

Continue to take this medication even if one feels normal. Do not discontinue taking this drug without the doctor's approval. Some problems may worsen upon abrupt discontinuation of this medication. In addition, patients may have symptoms such as mood fluctuations, headaches, fatigue, altered sleep patterns, and occasional electric shock-like sensations.

The doctor may gradually reduce the dosage to minimize these symptoms when discontinuing this medication. Report immediately any new or worsening symptoms. Inform the physician if the problem persists or worsens.

What Are the Possible Side Effects of This Medication?

Constipation, throwing up, sweating more, dizziness, or nosebleeds could happen. Inform the doctor or pharmacist immediately if any of these effects happen or worsen.

Remember that the doctor gave the person this medicine because they think the benefits outweigh the risks. A lot of people who take this drug do not actually have serious side effects.

This drug could make the blood pressure go up. Maintain a healthy blood pressure and get their blood pressure checked frequently, and if it is high, then inform the physician.

Tell the doctor right away if the patient has any serious side effects, such as

• A pounding heartbeat.
• Signs of stomach or intestinal bleeding (such as black or bloody stools, vomiting that looks like coffee grounds, or feeling dizzy).
• Easy bleeding or bruising.
• Decreased interest in sex.
• Changes in sexual ability.
• Problems starting the flow of urine.
• Painful or difficult urination.
• Signs of low blood sodium levels (such as drowsy and frequent mood changes).

The individuals should get medical help immediately if they experience serious side effects like seizures, eye irritation, redness, swelling, dilated pupils, or vision changes (such as seeing rainbows around lights at night or blurred vision).

This medicine might increase serotonin levels, sometimes leading to a hazardous condition called serotonin syndrome or toxicity. The risk increases even more if the patient takes other drugs that raise serotonin. Informing the physician or pharmacist about all the medicines the patient takes is mandatory.

Rarely does this drug cause a very bad allergic reaction. But one should see a doctor immediately if they have a serious allergic reaction, such as a rash, itching or swelling (especially in the face, tongue, or throat), severe dizziness, or trouble breathing.

What Precautions Should Be Followed Before Taking This Medicine?

Before patients take Levomilnacipran, inform the physician or pharmacist if the individuals are allergic to it, or Milnacipran, or if one has any other allergies. This product may have inactive ingredients that can cause allergic reactions or other problems. Know in detail about the contents of the drug.

Before taking this medicine, Inform the physician of all the information regarding the medical history, especially kidney problems, a history of glaucoma (angle-closure type), a history of a certain mental or mood disorder (bipolar disorder), a history of suicide attempts by self or a family member, high blood pressure, heart problems (such as chest pain, heart attack, fast or irregular heartbeat), poor blood flow to the brain, urinary retention, or trouble urinating (low level of sodium in the blood).

This drug might make them feel sick or make it hard to see. Alcohol or marijuana (cannabis) can make one more dizzy. Do not drive, use machinery, or do anything else that requires the person to be alert or see well until the individuals are sure they can do it safely.

Stay away from alcoholic drinks, and in case one is habituated, please inform the physician.

Inform the physician or dentist about everything before any surgical procedure (including prescription drugs, nonprescription drugs, and herbal products).

When taking this drug, especially if they are also taking water pills(diuretics), older people may be more likely to have a mineral imbalance (a low level of sodium in the blood).

This medicine should only be taken when it is clearly needed. It could hurt a baby in the womb. Also, babies whose mothers used this drug in the last three months of pregnancy may have withdrawal symptoms like trouble feeding or breathing, seizures, stiff muscles, or constant crying. Tell the doctor right away if the newborn shows any of these signs.

Since mental or mood problems, like depression, that are not treated can be dangerous, don't stop taking this medicine unless the doctor tells them to. If the individuals are planning to get pregnant or think they might be pregnant, talk to the doctor immediately about the pros and cons of using this drug while pregnant.

No one knows if this medicine gets into breast milk or not. But other drugs that work the same way get into breast milk. Talk to the doctor before breastfeeding.

What Other Medications Interact with Levomilnacipran?

Combining Levomilnacipran with other sedative medications can intensify this effect. Before taking narcotic medications, sleeping pills, muscle relaxants, or medications for anxiety or seizures, consult the doctor.

Inform the doctor about all additional medications they are taking, especially:

• Alternative antidepressants.
• Sibutramine.
• The herb St. John's wort.
• Tryptophan, also known as L-tryptophan.
• Laxatives.
• Water pills (diuretics).
• Anticoagulants (Warfarin).
• Amphetamine and dextroamphetamine combination and methylphenidate hydrochloride like stimulants or medications used to treat attention deficit hyperactivity disorder (ADHD).
• The painkillers like Fentanyl and Tramadol.
• Buspirone, lithium, and a number of other anti-anxiety, mood, thinking, or mental illness medications.
• Migraine and headache medications, including Sumatriptan, Rizatriptan, and Zolmitriptan.

What Should Be Done on Missing a Dose?

Inform the physician about the missed dose and follow their instructions, and only take a double dose with instructions from the doctor.

For Doctors

Pharmacologic Class of Drug:

Serotonin-norepinephrine reuptake inhibitors.

Generic Name:

Levomilnacipran

Therapeutic Indications:

Major Depressive Disorder

The serotonin and norepinephrine reuptake inhibitor (SNRI) Levomilnacipran hydrochloride is approved for the treatment of the major depressive disorder (MDD).

Contraindications:

Hypersensitivity to any excipient in the formulation, including milnacipran HCl and Levomilnacipran.

Due to the increased risk of serotonin syndrome, using MAOIs designed to treat psychiatric disorders in combination with Levomilnacipran hydrochloride or within seven days of terminating treatment with this drug is not recommended.

Levomilnacipran hydrochloride should not be used within 14 days of finishing an MAOI used to treat psychiatric problems.

Due to an elevated risk of serotonin syndrome, starting Levomilnacipran hydrochloride in a patient being treated with MAOIs such as Linezolid or intravenous methylene blue is also prohibited.

Limitation of Use:

Levomilnacipran hydrochloride has not been authorized for the treatment of fibromyalgia. Levomilnacipran hydrochloride's efficacy and safety for treating fibromyalgia have not been established.

Dosage Form and Strength:

Levomilnacipran extended-release capsules come in strengths of 20 mg, 40 mg, 80 mg, and 120 mg.

Mechanism of Action:

The precise mechanism of Levomilnacipran's antidepressant activity is unknown. However, it is assumed to be connected to the central nervous system potentiation of serotonin and norepinephrine via inhibition of reuptake at serotonin and norepinephrine transporters. Have demonstrated that Levomilnacipran is a powerful and selective inhibitor of serotonin and norepinephrine reuptake (SNRI).

Pharmacodynamics:

Levomilnacipran binds to the human serotonin (5-HT) and norepinephrine (NE) transporters with high affinity (Ki = 11 and 91 nM, respectively) and inhibits 5-HT and NE reuptake potently (IC50 = 16-19 and 11 nM, respectively). Levomilnacipran does not bind to any of the other receptors, ion channels, or transporters evaluated in vitro, including serotonergic (5HT1-7), - and adrenergic, muscarinic, or histaminergic receptors, and Ca2+, Na+, K+, or Cl- channels. Levomilnacipran had no effect on monoamine oxidase (MAO).

Electrophysiology of the Cardiovascular System:

Levomilnacipran does not extend QTc to any clinically meaningful level at a dose 2.5 times the maximum recommended dose.

Pharmacokinetics:

When taken from 25 to 300 mg once daily, the steady-state concentration of Levomilnacipran is proportional to the dose. The mean apparent total clearance of Levomilnacipran after oral dosing is 21-29 L/h. Single-dose data predict steady-state Levomilnacipran concentrations. Levomilnacipran has an apparent terminal elimination half-life of about 12 hours. The mean Cmax value after a daily dose of Levomilnacipran 120 mg is 341 ng/mL, while the mean steady-state AUC value is 5196 ng/mL. In humans, there is no interconversion between Levomilnacipran and its stereoisomer.

Absorption:

When compared to the oral solution, the relative bioavailability of Levomilnacipran after administration of Levomilnacipran ER was 92 %. When Levomilnacipran was provided with food, the concentration of Levomilnacipran did not change appreciably. The median time to peak concentration (Tmax) of Levomilnacipran after oral treatment is six to eight hours. The apparent volume of distribution of Levomilnacipran is 387-473 L; plasma protein binding is 22 % throughout a concentration range of 10 to 1000 ng/mL.

Metabolism:

Demethylation of Levomilnacipran results in desmethyl Levomilnacipran, and hydroxylation results in p-hydroxy-Levomilnacipran.To create conjugates, both oxidative metabolites are further conjugated with glucuronide. Demethylation is largely catalyzed by CYP3A4, with modest contributions from CYP2C8, 2C19, 2D6, and 2J2.

Elimination:

Levomilnacipran and its metabolites are primarily removed through renal excretion. After taking 14C-Levomilnacipran solution orally, approximately 58 % of the dose is eliminated in urine as unaltered Levomilnacipran.

Warnings:

• In short-term studies, antidepressants raised the risk of suicide ideas and actions in children, adolescents, and young adults. In these studies, antidepressants did not increase the risk of suicidal thoughts and actions in patients over 24, but they did lower it in patients 65 and older.
• When antidepressant therapy is started in patients of all ages, keep a cautious eye out for any worsening of the condition and the onset of suicidal thoughts and actions.
• When antidepressant therapy is started in patients of all ages, keep a cautious eye out for any worsening of the condition and the onset of suicidal thoughts and actions.
• Inform families and caretakers of the importance of close monitoring and regular contact with the prescriber.
• Children are not allowed to take Levomilnacipran hydrochloride.

Administration and Dosage:

• The recommended Levomilnacipran dose range is 40 mg to 120 mg once daily, with or without food.
• Levomilnacipran should be started at 20 mg once daily for two days, then gradually increased to 40 mg once daily.
• Levomilnacipran may then be increased in increments of 40 mg every two or more days based on efficacy and tolerability.
• The maximum recommended daily dose is 120 mg.

Follow-Up or Continuation or Extended Treatment:

• Acute episodes of major depressive disorder, it is generally agreed, necessitate several months or longer of sustained pharmacologic therapy.
• Patients should be reassessed regularly to determine the need for maintenance treatment and the appropriate treatment dose.
• Levomilnacipran efficacy has not been established beyond eight weeks.

Use in Special Populations:

Renal Impairment:

• No dose change is indicated in patients with mild renal impairment (creatinine clearance of 60 to 89 mL/min).
• Patients with moderate renal impairment (creatinine levels). The maintenance dose should be at most 80 mg once daily if the clearance is 30 to 59 mL/min.
• The maintenance dose for patients with severe renal impairment (creatinine clearance of 15-29 mL/min) should not exceed 40 mg once daily.
• Patients with end-stage renal illness should not be prescribed Levomilnacipran.

Treatment Cessation:

Discontinuation showed withdrawal symptoms had been recorded when serotonergic medications, such as Levomilnacipran. When possible, gradual dose reduction is preferred to abrupt withdrawal.

When quitting Levomilnacipran, keep an eye out for these symptoms. Severe symptoms occur when a dose is reduced, or treatment is stopped. Consider restarting the previously prescribed dose and gradually lowering the dose.

Changing a Patient's Monoamine Oxidase Inhibitor (MAOI) Treatment for Psychiatric Disorders:

At least 14 days should elapse between the withdrawal of an MAOI (monoamine oxidase inhibitors) used to treat psychiatric problems and the start of Levomilnacipran therapy. In contrast, at least seven days should elapse after discontinuing Levomilnacipran before beginning an MAOI antidepressant.

Levomilnacipran In Combination with Other MAOIs Such as Linezolid or Methylene Blue:

If a patient is on Linezolid or intravenous methylene blue, do not begin Levomilnacipran since there is an elevated risk of serotonin syndrome. Other measures, including hospitalization, should be considered in a patient who requires more urgent treatment for a psychiatric problem.

A patient already getting Levomilnacipran medication may require immediate treatment with Linezolid or intravenous methylene blue. If there are no alternatives to Linezolid or intravenous methylene blue treatment and the potential benefits of Linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a specific patient, Levomilnacipran should be discontinued immediately, and Linezolid or intravenous methylene blue administered.

The patient's symptoms of serotonin syndrome should be evaluated for two weeks or until 24 hours after the last dosage of Linezolid or intravenous methylene blue, whichever comes first.

Levomilnacipran therapy can be continued 24 hours after the previous Linezolid or intravenous methylene blue dosage.

The risk of using Levomilnacipran in non-intravenous methods (such as oral tablets or local injection) or intravenous doses significantly lower than 1 mg/kg is unknown.

However, the doctor should be aware that such use may result in sudden signs of serotonin syndrome.

Use of Levomilnacipran In Conjunction with Cytochrome p450 (cyp3a4) Enzyme Inhibitors:

When combined with powerful CYP3A4 inhibitors, the dose of Levomilnacipran should not exceed 80 mg once daily (e.g. Ketoconazole, Clarithromycin, Ritonavir).

Adverse Reactions:

Hypersensitivity

Hypersensitivity to Levomilnacipran, milnacipran HCl, or any of the formulation's excipients of the formulation is possible.

Suicidal Thoughts and Behaviors in Adolescents and Young Adults

Adult and pediatric patients with major depressive disorder (MDD) may experience worsening depression or the emergence of suicidal ideation and behaviour (suicidality) or unusual behavioural changes, regardless of whether they are taking antidepressant medications, and this risk may persist until significant remission. Suicide is a known risk of depression and other psychiatric diseases, and these conditions are the most accurate predictors of suicidal behaviour. However, there has been a long-standing concern that antidepressants may play a role in generating depression deterioration and the onset of suicidal ideation in specific individuals during the initial period of treatment.

Families and carers of patients receiving antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted to the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Families and carers should conduct daily observations as part of this monitoring.

Serotonin Syndrome

Serotonin syndrome has been reported with SNRIs and SSRIs alone but especially with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort) and drugs that impair serotonin metabolism (in particular, MAOIs, both those intended to treat psychiatric disorders.

Mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms of Serotonin syndrome should be monitored.

Elevated Blood Pressure

Blood pressure rises have been linked to SNRIs, particularly Levomilnacipran. Blood pressure should be checked before starting treatment and at regular intervals during Levomilnacipran treatment. Before starting Levomilnacipran medication, pre-existing hypertension should be managed. Patients with pre-existing hypertension and cardiovascular or cerebrovascular disorders that may cause blood pressure increases may compromise should be treated cautiously. Patients with a sustained rise in blood pressure while taking Levomilnacipran should be considered for cessation of the drug or other appropriate medical action.

Increased Heart Rate

SNRIs, including Levomilnacipran, have been linked to an increase in heart rate. Before starting treatment and regularly during Levomilnacipran treatment, the heart rate should be monitored. Before beginning Levomilnacipran therapy, preexisting tachyarrhythmias and other heart disorders should be treated. Patients who notice a sustained rise in heart rate while taking Levomilnacipran may consider cessation or other appropriate medical intervention.

Glaucoma with Angle Closure

Numerous antidepressant medications cause pupillary dilatation. Levomilnacipran may cause an angle closure attack.

Urinary Retention or Hesitation

SNRIs, including Levomilnacipran, have a noradrenergic impact that can affect urethral resistance. If urinary hesitancy occurred in four per cent, five per cent, and six per cent of Levomilnacipran-treated patients receiving dosages of 40, 80, and 120 mg, respectively, compared to no patients in the control group.

Levomilnacipran should be used with caution in patients prone to obstructive lung disease.

Urinary Problems: If signs of urinary hesitancy, urine retention, or dysuria appear during the procedure, Consideration should be made to the possibility that they may be allergic to Levomilnacipran.

Drug-related issues should be addressed, and cessation or other necessary medical interventions should be explored.

Mania or Hypomania Activation

Mania or hypomania symptoms were found in 0.2 % of Levomilnacipran-treated patients.

These disorders are observed in a tiny number of people with mood disorders who received previous treatments with antidepressants.

In patients with a history of depression, use Levomilnacipran with caution, as with all antidepressants or a family history of bipolar disorder, manic or hypomanic episodes.

Seizures

Levomilnacipran has not been thoroughly studied in patients with seizure disorders. Patients with a history of seizures were barred from participating in clinical trials. Levomilnacipran should not be recommended. In patients with seizure disorders, use with caution. In premarketing clinical investigations using Levomilnacipran, one case of seizure was observed.

Animal Study Data

When pregnant rats or rabbits were given oral doses of up to 100 mg/kg/day of Levomilnacipran during the organogenesis stage, no teratogenic effects were detected. On an mg/m2 basis, this dose is 8, and 16 times (in rats and rabbits, respectively) the maximum recommended human dose (MRHD) of 120 mg. Fetal body weights were lowered in rats at this level, and skeletal ossification was delayed in both rats and rabbits; similar effects were not detected in either species at doses up to 30 mg/kg/day, 2.4 times the MRHD in rats or five times the MRHD in rabbits.

There was an increase in early postnatal pup mortality when pregnant rats were given Levomilnacipran at an oral dose of 60 mg/kg/day, five times the MRHD, during organogenesis and throughout pregnancy and lactation; no pup mortality was detected at 20 mg/kg/day, 1.6 times the MRHD. Pre- and post-weaning pup weight increase was reduced in the surviving pups until at least eight weeks; however, physical and functional development, including reproductive performance, was unaffected. At 7 mg/kg/day, 0.6 times the MRHD, no impacts on body weight growth were seen.

Non-Clinical Toxicology (Carcinogenesis, Mutagenesis, and Fertility Impairment):

Carcinogenesis

The oral gavage administration of Levomilnacipran to rats for two years and mice for six months did not increase the incidence of tumors. Levomilnacipran was given to rats at doses of up to 90/70 mg/kg/day (the dose was reduced in males after 45 weeks of administration). On an mg/m2 basis, the 90 mg/kg/day dose is seven times the maximum recommended human dose (MRHD) of 120 mg.

Tg.rasH2 mice were given Levomilnacipran at daily doses of up to 150 mg/kg. This dose is six times higher than the MRHD.

Mutagenesis

Levomilnacipran was found to be non-mutagenic in an in vitro bacterial mutation experiment (Ames test) and non-clastogenic in a rat in vivo micronucleus assay. Furthermore, in the in vitro mouse lymphoma (L5178Y TK+/-) cell forward mutation experiment, Levomilnacipran was not genotoxic.

Fertility Impairment

There were no effects on fertility when Levomilnacipran was given orally to male and female rats before mating, during mating, and up to day 7 of gestation at doses up to 100 mg/kg/day. This dose is eight times higher than the MRHD.

Information on Patient Counseling:

Patient's Information:

Inform patients, their families, and carers on the benefits and hazards of Levomilnacipran treatment, and educate them on its proper usage. Encourage patients, their families, and carers to read the medication guide and help them grasp its contents.

Suicide Danger:

Advise patients and carers to be on the lookout for the appearance of suicidality, particularly early in treatment and when the dose is increased or decreased.

Administration and Dosage:

Inform patients that Levomilnacipran should be ingested whole without being chewed, crushed, or opened.

Inform patients that they can take Levomilnacipran with or without food. Levomilnacipran should be started at 20 mg once a day for two days, then raised to 40 mg once daily. Levomilnacipran may be increased in increments of 40 mg every two or more days based on efficacy and tolerability. The highest suggested daily intake is 120 mg.

Instruct patients to take the missed medication as soon as they remember if they miss a dose. If the next dose is approaching, instruct them to forego the missed dose and take their next medication at the regular time. Tell them not to take two Levomilnacipran dosages at the same time.

Medication Taken Together:

Instruct patients not to use Levomilnacipran in conjunction with an MAOI or within 14 days of discontinuing an MAOI and to wait seven days after stopping Levomilnacipran before beginning an MAOI.