Milnaran®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MİLNA RAN® (MILNARAN®)

Composition:

Active substance: milnacipran hydrochloride;

1 hard capsule contains milnacipran hydrochloride 25 mg or 50 mg;

Excipients: calcium hydrogen phosphate dihydrate, calcium carmellose, povidone K30, colloidal anhydrous silicon dioxide, talc, magnesium stearate;

Capsule shell: iron oxide red (E 172), titanium dioxide (E 171), iron oxide yellow (E 172), gelatin.

Medicinal form. Hard capsules.

Main physicochemical properties:

25 mg capsules: hard, opaque gelatin capsules size №4 of caramel color, containing white to almost white powder;

50 mg capsules: hard, opaque gelatin capsules size №3 of red-caramel color, containing white to almost white powder.

Pharmacotherapeutic group. Drugs acting on the nervous system. Psychoanaleptics. Antidepressants. Other antidepressants. ATC code N06AX17.

Pharmacological Properties

Pharmacodynamics

Milnacipran is an inhibitor of both serotonin (5-HT) and norepinephrine (NA) reuptake. Unlike most tricyclic antidepressants, milnacipran has no affinity for H1 histaminergic or A1 adrenergic receptors. Receptor binding studies have shown that milnacipran has no significant affinity for cholinergic (muscarinic) receptors. In addition, milnacipran also lacks affinity for dopaminergic D1 and D2 receptors, benzodiazepine receptors, or opioid receptors. At therapeutic doses, observed plasma concentrations remain consistently at levels corresponding to 50–90% inhibition of norepinephrine and serotonin reuptake. The pharmacological effects observed in the gastrointestinal and genitourinary systems are related to inhibition of norepinephrine reuptake, which may exert an antagonistic effect on acetylcholine (indirect anticholinergic action). Milnacipran does not cause clinically significant changes in cardiac repolarization or conduction, does not affect cognitive functions, and produces only mild sedative effects. Sleep disturbances in patients with depression improve with milnacipran treatment. Sleep latency decreases, as does the frequency of nocturnal awakenings, while the latency to onset of paradoxical sleep increases. Total sleep duration increases.

Pharmacokinetics

Absorption

Milnacipran is well absorbed after oral administration.

Bioavailability is approximately 85%.

Food intake does not affect the drug.

Peak plasma concentration (C_max) is reached approximately 2 hours (T_max) after oral administration.

It is about 120 ng/mL after a single 50 mg dose.

Concentrations increase proportionally with dose up to 200 mg per dose.

After repeated administration, steady state is achieved within 2–3 days, with concentrations increasing by 70% to 100% compared to single dosing (C_max = 216 ng/mL). Inter-individual variability is low.

Distribution

Plasma protein binding is low (13%) and non-saturable.

The volume of distribution of milnacipran is approximately 5 L/kg, with a total clearance of about 40 L/h.

Renal and non-renal clearances are equivalent.

Metabolism

Milnacipran is primarily metabolized via glucuronide conjugation.

Active metabolites are present at very low levels without clinical significance.

Elimination

The elimination half-life from plasma is approximately 8 hours.

Elimination occurs predominantly via the kidneys (90% of the administered dose), with tubular secretion of the unchanged compound.

After repeated dosing, milnacipran is completely eliminated within 2–3 days after discontinuation of therapy.

Preclinical Safety Data

The main target organs are the liver, likely due to an adaptive mechanism, and the nervous system. Milnacipran is neither mutagenic nor carcinogenic.

Milnacipran affected fertility in rats and induced embryonic death; no safety margin was established.

Experimental data show no teratogenic potential of milnacipran.

Administration of milnacipran to rats during the last third of pregnancy and during lactation caused signs of toxicity in the mother and affected fetal viability, growth, and development. The drug affects reproductive parameters in young animals (impaired female fertility) at dose levels causing reduced body weight gain.

In pre- and postnatal development studies, no safety margin for effects on humans has been established.

Excretion of milnacipran and/or its metabolites into milk occurs after administration to lactating rats.

Patients in Risk Groups

Patients with hepatic impairment

Hepatic impairment does not cause significant changes in the pharmacokinetics of milnacipran.

Patients with renal impairment. In renal impairment, elimination of milnacipran is slowed proportionally to the degree of renal function impairment (see section "Special Warnings and Precautions for Use").

Patients over 65 years of age. Pharmacokinetic parameters of milnacipran are not significantly altered in elderly patients. However, physiological changes in renal function should be taken into account (see section "Special Warnings and Precautions for Use").

Clinical characteristics.

Indications.

Treatment of major depressive episodes in adults.

Contraindications.

The drug is contraindicated in the following cases:

• Hypersensitivity to the active substance or to any of the excipients;
• Concomitant use with irreversible monoamine oxidase inhibitors (MAOIs), selective MAO-B inhibitors, digitalis glycosides, and 5HT1D agonists (e.g., sumatriptan, etc.);
• Breastfeeding;
• Uncontrolled hypertension, severe or unstable ischemic heart disease, since these underlying conditions may be exacerbated by increased blood pressure or heart rate.

Interaction with other medicinal products and other forms of interaction.

Drug interaction studies have been conducted only in adult patients.

Serotonin syndrome

As with other serotonergic agents, potentially life-threatening serotonin syndrome may occur during treatment with milnacipran, particularly when used concomitantly with other medicinal products that may affect the serotonergic neurotransmitter system (such as irreversible MAO inhibitors (iproniazid, tranylcypromine), selective MAO inhibitors (linezolid, moclobemide, methylene blue), St. John's wort (Hypericum perforatum), buprenorphine, meperidine, tramadol, and most antidepressants).

Symptoms of serotonin syndrome may include:

• Gastrointestinal symptoms (diarrhea);
• Psychiatric and behavioral changes (agitation, confusion, hypomania);
• Motor disturbances (tremor, rigidity, myoclonus, hyperreflexia, and ataxia);
• Autonomic nervous system dysfunction (labile blood pressure, tachycardia, shivering, hyperthermia, possibly coma).

Contraindicated combinations

With irreversible MAO inhibitors (iproniazid, tranylcypromine)

Risk of serotonin syndrome.

A two-week interval must elapse between discontinuation of MAO inhibitor therapy and initiation of milnacipran treatment. Similarly, at least one week should elapse between discontinuation of milnacipran and initiation of MAO inhibitor therapy.

Not recommended combinations

With alpha- and beta-sympathomimetics (intramuscular and intravenous routes)

Paroxysmal hypertension with possible arrhythmia (due to inhibition of adrenaline or noradrenaline uptake into sympathetic nerve fibers).

With selective MAO-A inhibitors (linezolid, moclobemide, methylene blue)

Risk of serotonin syndrome.

If this combination cannot be avoided, close monitoring of the patient is required. Such combination therapy should be initiated at the lowest recommended dose.

Combinations requiring caution

Adrenaline (intravenous and subcutaneous routes)

Severe ventricular arrhythmias due to increased cardiac excitability.

Dosage should be limited, e.g., less than 0.1 mg of adrenaline within 10 minutes or 0.3 mg per hour in adult patients.

With oral anticoagulants and agents affecting blood coagulation

Medicinal products affecting platelet function, such as NSAIDs and aspirin, or other agents that may increase the risk of bleeding.

Special precautions for use.

Sexual dysfunction

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section "Adverse reactions"). Cases of persistent sexual dysfunction have been reported, in which symptoms continued despite discontinuation of SSRIs/SNRIs.

Suicide/suicidal thoughts or worsening of clinical symptoms

Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicide-related events). This risk persists until significant remission occurs. Since improvement may not occur during the first few weeks of treatment or longer, patients should be closely monitored until clinical improvement ensues. Clinical experience indicates that the risk of suicide may increase during the early stages of recovery.

Patients with a history of suicide-related events or those who exhibit a significant degree of suicidal intent prior to treatment initiation are at higher risk of suicidal thoughts or suicide attempts and should therefore be carefully observed during treatment.

A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients under the age of 25.

Close monitoring of patients, particularly those at high risk, should accompany pharmacological treatment, especially at the beginning of therapy and after dose adjustments. Patients (and their caregivers) should be informed about the need to monitor for any clinical worsening, suicidal behaviour or thoughts, and unusual changes in behaviour, and to seek immediate medical attention if such symptoms occur.

Children

Milnacipran should not be used for the treatment of children and adolescents under 18 years of age. Suicidality-related behaviours (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour, and anger) were more frequently observed in clinical trials among children and adolescents receiving antidepressants compared to those receiving placebo. If, based on clinical need, a decision to treat is made, the patient should be closely monitored for the emergence of suicidal symptoms. In addition, there are no long-term safety data in children and adolescents regarding growth, maturation, and cognitive and behavioural development.

Serotonin syndrome

As with other serotonergic agents, potentially life-threatening serotonin syndrome may occur during treatment with milnacipran, particularly when used concomitantly with other medicinal products that may affect the serotonergic neurotransmitter system (e.g. irreversible monoamine oxidase inhibitors (MAOIs) (iproniazid), A-selective MAOIs (linezolid, moclobemide, methylene blue), St. John’s wort [Hypericum perforatum], meperidine, tramadol, most antidepressants) (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

If concomitant treatment with other serotonergic drugs is clinically indicated, careful patient monitoring is recommended, especially at the beginning of treatment and when increasing the dose.

Symptoms of serotonin syndrome may include:

• signs of poisoning (diarrhea);
• psychiatric and behavioural changes (agitation, confusion, hypomania);
• motor coordination disturbances (tremor, rigidity, myoclonus, hyperreflexia, and ataxia);
• autonomic nervous system disturbances (labile blood pressure, tachycardia, shivering, hyperthermia, and possibly coma).

If serotonin syndrome is suspected, consideration should be given to reducing the dose or discontinuing therapy depending on the severity of symptoms.

Concomitant use of milnacipran with alpha- and beta-sympathomimetics (intramuscular and intravenous routes) or with selective MAO-A inhibitors (such as linezolid, moclobemide, and methylene blue) is not recommended.

Precautions

Patients experiencing insomnia or nervousness at the beginning of treatment may require temporary symptomatic therapy.

If a patient develops a pronounced manic episode, treatment with Milnaran**®** should be discontinued and, in most cases, a sedative antipsychotic agent should be prescribed.

Patients who develop jaundice or other signs of hepatic dysfunction should discontinue milnacipran. Treatment with milnacipran should not be resumed unless another cause cannot be established. Although no interaction with alcohol has been demonstrated, alcohol consumption should be avoided, as with any psychotropic medication.

Systemic exposure to Milnaran**®** in healthy volunteers increased by 20% when co-administered with levomepromazine. A higher increase may be expected in elderly patients or those with renal impairment when these drugs are combined.

Milnacipran should be used with caution in the following cases:

• patients with renal impairment;

(dose reduction may be necessary due to prolonged elimination half-life (see section "Dosage and administration"));

• patients with a history of urinary retention, particularly those with benign prostatic hyperplasia or other urogenital disorders. Due to the noradrenergic component of milnacipran's mechanism of action, monitoring for urinary retention is required;
• patients with hypertension or cardiovascular disease;

(blood pressure and heart rate monitoring is recommended at the beginning of treatment, after dose increases, and periodically throughout milnacipran therapy for all patients, as well as for patients with known cardiovascular risk. Persistent elevated blood pressure or increased heart rate should prompt consideration of discontinuing milnacipran if clinically justified);

• patients with elevated intraocular pressure or at risk of developing angle-closure glaucoma;
• patients with epilepsy or a history of epilepsy: milnacipran should be used with caution and treatment should be discontinued in any patient who experiences a seizure.

Cases of hyponatraemia have been reported in patients receiving serotonin reuptake inhibitors, possibly due to syndrome of inappropriate antidiuretic hormone secretion (SIADH). Caution is advised in elderly patients, patients taking diuretics or other treatments that may cause hyponatraemia, and patients with liver cirrhosis or nutritional disturbances.

Cases of bleeding, sometimes serious, have been reported with the use of serotonin reuptake inhibitors. SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see sections "Use during pregnancy or breastfeeding" and "Adverse reactions").

Caution is advised in patients receiving concomitant oral anticoagulants, agents affecting platelet function (e.g. NSAIDs and aspirin), or other drugs that may increase the risk of bleeding. Caution is also required in patients with pre-existing coagulation disorders.

The safety and efficacy of milnacipran for the treatment of major depressive episodes in adults at doses higher than 100 mg per day have not been established. For patients who do not experience clinical benefit at a dose of 100 mg per day, treatment should be discontinued.

Discontinuation of treatment.

The risk of withdrawal symptoms associated with SSRIs and SNRIs may depend on several factors, including duration and dose of treatment, and the rate of dose reduction. Typically, withdrawal symptoms may range from mild to moderate; however, in some patients, they may be severe. These symptoms usually occur within the first few days after discontinuation of treatment, although very rarely such symptoms have been reported in patients who have accidentally missed a dose.

These symptoms are usually self-limiting and resolve within two weeks, although in some individuals they may persist for a longer period (2–3 months). Therefore, it is recommended that milnacipran dosage be gradually reduced when discontinuing treatment, rather than abruptly stopped after prolonged use (see sections "Dosage and administration" and "Adverse reactions").

Use during pregnancy or breastfeeding.

Pregnancy

There are no data on the use of milnacipran in pregnant women.

Animal studies have shown reproductive toxicity (see section "Pharmacological properties"). There are reports of increased risk to newborns following treatment with serotonin reuptake inhibitors during pregnancy, which may be related to withdrawal syndrome or serotonergic toxicity: tachypnoea, feeding difficulties, tremor, hypertension or hypotension, sleep disturbances, increased irritability, or less commonly, persistent crying. These signs typically appear in the first days of life and are usually transient and not severe.

Therefore, as a precautionary measure, it is advisable to avoid the use of milnacipran during pregnancy and in women of reproductive potential who are not using contraception.

Breastfeeding

Since a small amount of milnacipran passes into breast milk, breastfeeding is contraindicated.

Fertility

Milnacipran affected fertility in rats and induced embryolethality; a safety margin was not established (see section "Pharmacological properties"). There are no data on the effect of milnacipran on human fertility.

Ability to affect reaction speed when driving or operating machinery.

In studies conducted in healthy volunteers, no changes in cognitive or psychomotor functions were reported. However, when using the medicinal product, a reduction in mental and physical abilities required for potentially hazardous activities that require high concentration and rapid reaction may occur.

Dosage and administration

The medication should be taken orally.

Adults

The recommended daily dose is 100 mg, divided into two doses of 50 mg each—1 capsule in the morning and 1 capsule in the evening, preferably with meals.

Elderly patients

Dose adjustment is not required if renal function is normal.

Patients with renal impairment

Dose adjustment is necessary. It is recommended to reduce the dose to 50 mg or 25 mg depending on the degree of renal function impairment. In such cases, Milnaran**®** 25 mg capsules are recommended.

The following dose adjustments are recommended:

Duration of treatment

Treatment with an antidepressant is symptomatic.

As with any other antidepressants, the efficacy of milnacipran is achieved only after 1–3 weeks. For a single episode, treatment should last several months (typically about

6 months) to prevent relapse. Treatment with Milnaran**®** should be discontinued gradually.

Concomitant psychotropic medications

Concurrent administration of a sedative or anxiolytic therapy may be beneficial at the beginning of treatment to prevent the occurrence or worsening of anxiety symptoms. However, anxiolytics do not always protect patients from suicide attempts.

Children

Milnacipran is not recommended for use in children and adolescents under 18 years of age (see section "Special precautions for use").

During clinical trials, suicidal behavior (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behavior, and anger) were observed more frequently in children and adolescents receiving antidepressants compared to those receiving placebo. If, based on clinical need, a decision to treat is made, patients should be closely monitored for the emergence of suicidal symptoms. In addition, long-term safety data regarding growth, puberty, cognitive, and behavioral development in children and adolescents are lacking.

Overdose

Cases of overdose have been reported with milnacipran.

With high doses, the emetic effect may significantly limit the risk of overdose.

When a dose of 200 mg is administered, the following symptoms are usually observed (> 10%): nausea, excessive sweating, and constipation.

When doses between 800 mg and 1 g are administered in monotherapy, the main observed symptoms are: vomiting, respiratory disturbances (episodes of apnea), and tachycardia.

After a large dose (1.9–2.8 g) in combination with other drugs (particularly benzodiazepines), additional symptoms occur: drowsiness, hypercapnia, and impaired consciousness.

Treatment of overdose

There is no specific antidote for milnacipran.

Treatment is symptomatic; gastric lavage and administration of activated charcoal are recommended as soon as possible after ingestion.

Medical monitoring should be continued for at least 24 hours.

Adverse reactions

Adverse reactions observed during milnacipran treatment for depression occur mainly during the first week or first two weeks of treatment and subsequently regress, concomitantly with improvement in depressive symptoms.

The following table lists adverse reactions with a causality assessment not rated as "excluded", observed in 13 clinical studies, including 5 placebo-controlled clinical trials (involving a total of 3059 patients—2557 on milnacipran and 502 on placebo) in patients with depression.

The most commonly reported adverse reactions in patients with depression receiving milnacipran in clinical studies were nausea and headache.

Adverse reactions are systematized by system organ classes and listed according to the following frequency categories: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), and frequency not known (isolated reports, frequency cannot be estimated from the available data).

Adverse reaction table:

(1) Expected frequency of adverse effects reported during post-marketing surveillance; these were not observed in placebo-controlled clinical trials.

(2) Particularly observed in patients with a history of epilepsy.

(3) See section "Special precautions for use".

(*) Serotonin syndrome, especially when milnacipran is combined with other medicinal products (see section "Interaction with other medicinal products and other forms of interaction"), characterized by at least three symptoms including changes in mental status and behavior (agitation, confusion, anxiety, restlessness, delirium, and nervousness), motor disturbances (tremor, rigidity, myoclonus, hyperreflexia, and ataxia), hypotension or hypertension, and autonomic symptoms such as sweating, fever, tremor, and diarrhea.

(**) This event has been reported for the therapeutic class of SSRIs/SNRI (see sections "Use during pregnancy or breastfeeding" and "Special precautions for use").

Cases of suicidal behavior and suicidal thoughts have been reported during treatment with Milnaran**®** or at the beginning of treatment discontinuation (see section "Special precautions for use").

Withdrawal syndrome

Cases of potential withdrawal syndrome have been reported following discontinuation of Milnaran**®** treatment. In general, for SSRIs and SNRIs, symptoms are mild to moderate and self-limiting; however, in some patients, they may be severe and/or prolonged. Therefore, it is recommended to gradually reduce the dose when treatment with milnacipran is no longer required (see sections "Dosage and administration" and "Special precautions for use").

Additional reactions reported during post-marketing experience for the indication of depression (frequency unknown).

Other adverse reactions reported during post-marketing experience in patients with depression were related to the depressive disorder itself:

• Relief of psychomotor retardation associated with suicidal risk;
• Mood changes with episodes of mania;
• Re-emergence of delusions in psychotic patients;
• Anxiety attacks (for psychostimulant antidepressants).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua/.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of the reach and sight of children.

Packaging. 8 capsules in a blister; 7 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Rivopharm SA.

Manufacturer's address and location of operations.

Centro Insema, 6928 Manno, Switzerland.