Lafaxin® xr asino: detailed information

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LAFAXIN® XR ACINO (LAFAXIN XR ACINO)

Composition:

Active substance: venlafaxine hydrochloride;

One tablet contains 84.85 mg of venlafaxine hydrochloride, equivalent to 75 mg of venlafaxine base;

Excipients: microcrystalline cellulose, hypromellose 2208, ethylcellulose, magnesium stearate, colloidal anhydrous silicon dioxide, coating (aqueous dispersion of ethylcellulose, dibutyl sebacate, hypromellose, macrogol 400).

Pharmaceutical form. Extended-release tablets.

Main physicochemical properties: white, convex, capsule-shaped tablets coated with a film.

Pharmacotherapeutic group.
Antidepressants. ATC code: N06AX16.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

The mechanism of the antidepressant effect of venlafaxine in humans is believed to be related to its potentiation of neurotransmitter activity in the central nervous system (CNS). Preclinical studies have shown that venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV), are serotonin-norepinephrine reuptake inhibitors (SNRIs). Venlafaxine also weakly inhibits dopamine reuptake. Venlafaxine and its active metabolite reduce β-adrenergic responsiveness after both single (single-dose administration) and long-term drug administration. Venlafaxine and ODV are very similar in their overall effects on neurotransmitter reuptake and receptor binding.

Venlafaxine has virtually no affinity for muscarinic, cholinergic, H1-histaminergic, and α1-adrenergic receptors in rat brain in vitro. Pharmacological activity at these receptors may be associated with various adverse effects observed with other antidepressants, such as anticholinergic, sedative, and cardiovascular side effects.

Venlafaxine does not exhibit inhibitory activity against monoamine oxidase (MAO).

In vitro studies have shown that venlafaxine has negligible affinity for opioid or benzodiazepine-sensitive receptors.

Clinical efficacy and safety

Major depressive episodes

The efficacy of immediate-release venlafaxine in the treatment of major depressive episodes was demonstrated in five randomized, double-blind, placebo-controlled, short-term studies lasting 4 to 6 weeks, using doses up to 375 mg/day. The efficacy of extended-release venlafaxine in the treatment of major depressive episodes was established in two placebo-controlled, short-term studies lasting 8 to 12 weeks, using doses of 75 to 225 mg/day. In one longer-term study, adult outpatients who responded to venlafaxine during an 8-week open-label study with extended-release venlafaxine (75 mg, 150 mg, or 225 mg) were randomized to continue treatment with venlafaxine at the same dose or to switch to placebo, with observation for possible relapse over a period of up to 26 weeks.

In a second longer-term study, the efficacy of venlafaxine in preventing relapse of depressive episodes over 12 months was established in a placebo-controlled, double-blind clinical trial involving adult outpatients with recurrent depressive episodes who had responded to venlafaxine treatment (100–200 mg/day, administered twice daily) during a previous depressive episode.

Generalized anxiety disorder

The efficacy of extended-release venlafaxine in the treatment of generalized anxiety disorder (GAD) was established in two 8-week fixed-dose (75–225 mg/day) placebo-controlled studies, one 6-month fixed-dose (75–225 mg/day) placebo-controlled study, and one 6-month variable-dose (37.5 mg/day, 75 mg/day, and 150 mg/day) placebo-controlled study in adult outpatients.

Despite evidence of benefit compared to placebo at the 37.5 mg/day dose, this dose was not as consistently effective as higher doses.

Social anxiety disorder

The efficacy of extended-release venlafaxine in the treatment of social anxiety disorder was established in four 12-week, double-blind, multicenter, parallel-group, placebo-controlled studies with variable dosing, and in one 6-month, double-blind, placebo-controlled, parallel-group study with fixed/variable dosing in adult outpatients. Patients received doses of the drug ranging from 75 to 225 mg/day. No evidence of greater efficacy was observed in the 150–225 mg/day dose group compared to the 75 mg/day dose group over the 6-month study period.

Panic disorder

The efficacy of extended-release venlafaxine in the treatment of panic disorder was established in two 12-week, double-blind, multicenter, placebo-controlled studies in adult outpatients with panic disorder, with or without agoraphobia. The initial dose of the drug in the panic disorder treatment studies was 37.5 mg/day for 7 days. After this, patients received fixed doses of 75 or 150 mg/day in one study and 75 or 225 mg/day in the other study. Efficacy was also demonstrated in one long-term, double-blind, placebo-controlled study evaluating long-term safety, efficacy, and prevention of relapse in parallel groups of adult outpatients who responded to treatment in an open-label phase. Patients continued to receive the same dose of extended-release venlafaxine that they were taking at the end of the open-label phase (75 mg, 150 mg, or 225 mg).

Cardiac electrophysiology

It is known from a dedicated QTc study in healthy volunteers that venlafaxine did not prolong the QT interval to any clinically significant extent at a supratherapeutic dose of 450 mg/day (225 mg twice daily). However, cases of QTc prolongation/TdP and ventricular arrhythmia have been reported, particularly in cases of overdose or in patients with other risk factors for QTc/TdP prolongation (see sections "Special precautions for use", "Overdose", and "Adverse reactions").

Pharmacokinetics

Venlafaxine is extensively metabolized, primarily to the active metabolite ODV. Mean elimination half-life values ± standard deviation (SD) for venlafaxine and ODV in plasma are 5 ± 2 hours and 11 ± 2 hours, respectively. Steady-state concentrations of venlafaxine and ODV are achieved within 3 days of multiple oral dosing. Venlafaxine and ODV exhibit linear kinetics over the dose range of 75 to 450 mg/day.

Absorption

At least 92% of venlafaxine is absorbed following a single oral dose of immediate-release venlafaxine. Absolute bioavailability is 40–45%, which is attributed to presystemic metabolism. After administration of an immediate-release venlafaxine dose, peak plasma concentrations of venlafaxine and ODV are observed at 2 and 3 hours, respectively. After administration of an extended-release venlafaxine dose, peak plasma concentrations of venlafaxine and ODV are reached at approximately 5.5 and 9 hours, respectively. When equivalent daily doses of immediate-release or extended-release venlafaxine are administered, the extended-release formulation provides a slower rate of absorption with a similar extent of absorption compared to immediate-release tablets. Food intake does not affect the bioavailability of venlafaxine and ODV.

Distribution

Venlafaxine and ODV exhibit minimal plasma protein binding in humans at therapeutic concentrations (27% and 30%, respectively). The volume of distribution of venlafaxine at steady state is 4.4 ± 1.6 L/kg after intravenous administration.

Biological transformation

Venlafaxine undergoes extensive hepatic metabolism. In vitro and in vivo studies indicate that venlafaxine is biotransformed by the CYP2D6 enzyme to form its major active metabolite, ODV. In vitro and in vivo studies show that venlafaxine is metabolized by the CYP3A4 enzyme to form its minor, less active metabolite, N-desmethylvenlafaxine. In vitro and in vivo studies indicate that venlafaxine is a weak inhibitor of the CYP2D6 enzyme. Venlafaxine does not inhibit the CYP1A2, CYP2C9, or CYP3A4 isoenzymes.

Elimination

Venlafaxine and its metabolites are primarily excreted by the kidneys. Approximately 87% of the venlafaxine dose is excreted in urine within 48 hours, either as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Mean values ± SD for steady-state plasma clearance of venlafaxine and ODV are 1.3 ± 0.6 L/h/kg and 0.4 ± 0.2 L/h/kg, respectively.

Special populations

Age and sex

Patient age and sex do not significantly affect the pharmacokinetics of venlafaxine and ODV.

Poor/intermediate metabolizers of the CYP2D6 isoenzyme

Plasma concentrations of venlafaxine are higher in poor metabolizers of CYP2D6 compared to extensive metabolizers. However, since total exposure (AUC) of venlafaxine and ODV is similar in poor and extensive metabolizers, no different dosing regimens of venlafaxine are required for these two patient groups.

Hepatic impairment

In patients with Child-Pugh class A (mild hepatic impairment) and class B (moderate hepatic impairment) liver disease, the elimination half-life of venlafaxine and ODV is prolonged compared to patients with normal liver function. Oral clearance of venlafaxine and ODV is reduced, with considerable variability in these parameters among patients. Data on the use of the drug in patients with severe hepatic impairment are limited.

Renal impairment

In patients undergoing dialysis, the elimination half-life of venlafaxine is prolonged by approximately 180%, and clearance is reduced by approximately 57%, compared to patients with normal renal function. The elimination half-life of ODV is prolonged by approximately 142%, and clearance is reduced by approximately 56%. Dose adjustment is required for patients with severe renal impairment and for patients requiring hemodialysis (see section "Dosage and administration").

Clinical characteristics.

Indications.

Treatment of major depressive episodes.
Prevention of recurrence of major depressive episodes.
Treatment of generalized anxiety disorder.
Treatment of social anxiety disorder (social phobia).
Treatment of panic disorder with or without agoraphobia.

Contraindications.

Hypersensitivity to venlafaxine or to any of the excipients of the medicinal product.

Concomitant use with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serotonin syndrome, which may present with symptoms such as agitation, tremor, and hyperthermia. Venlafaxine therapy must not be initiated within at least 14 days after discontinuation of irreversible MAOIs.

Venlafaxine treatment must be discontinued at least 7 days prior to starting therapy with irreversible MAOIs.

Interaction with other medicinal products and other types of interactions.

MAOIs

Irreversible non-selective MAOIs

Venlafaxine must not be used in combination with irreversible non-selective MAOIs. Venlafaxine therapy must not be initiated within at least 14 days after discontinuation of irreversible non-selective MAOIs. Venlafaxine treatment must be discontinued at least 7 days prior to starting therapy with irreversible non-selective MAOIs (see sections "Contraindications" and "Special precautions").

Reversible selective MAO-A inhibitor (moclobemide)

Concomitant use of venlafaxine with reversible selective MAOIs such as moclobemide is not recommended due to the risk of serotonin syndrome. After discontinuation of a reversible MAO inhibitor, a shorter washout period (less than 14 days) may be considered before initiating venlafaxine therapy. It is recommended to discontinue venlafaxine at least 7 days prior to starting treatment with a reversible MAO inhibitor (see section "Special precautions").

Reversible non-selective MAOI (linezolid)

The antibiotic linezolid is a weak reversible non-selective MAOI and should not be prescribed to patients receiving venlafaxine (see section "Special precautions").

Severe adverse reactions have been reported in patients who recently discontinued MAOIs and started venlafaxine therapy, or who recently discontinued venlafaxine prior to initiating MAOI therapy. These reactions included tremor, myoclonus, profuse sweating, nausea, vomiting, flushing, dizziness, and hyperthermia with features resembling neuroleptic malignant syndrome (NMS), seizures, and fatal outcomes.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome—a potentially life-threatening condition—may occur during treatment with venlafaxine, particularly when used concomitantly with other medicinal products that may affect the serotonergic neurotransmitter system (including triptans, selective serotonin reuptake inhibitors (SSRIs), SNRIs, tricyclic antidepressants, amphetamines, lithium, sibutramine, St. John’s wort (Hypericum perforatum), opioids [e.g., fentanyl and its analogs, tramadol, dextromethorphan, tapentadol, meperidine, methadone, pentazocine, buprenorphine, and buprenorphine/naloxone combination]) and with agents that interfere with serotonin metabolism, such as MAO inhibitors (e.g., methylene blue), or with serotonin precursors (such as tryptophan supplements), or with antipsychotics or other dopamine antagonists (see sections "Contraindications" and "Special precautions").

If there is a clinical need for concomitant use of venlafaxine with SSRIs, SNRIs, or a serotonin receptor agonist (a triptan), careful patient monitoring is recommended, particularly at the beginning of treatment and when increasing the dose. Concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended (see section "Special precautions").

Substances affecting the CNS

The risk of using venlafaxine in combination with other CNS-active substances has not been systematically studied. Therefore, caution is recommended when taking venlafaxine in combination with other CNS-active substances.

Ethanol

Patients should be advised to avoid alcohol consumption due to its CNS effects and potential for clinical worsening of psychiatric disorders, as well as the possibility of developing an unfavorable interaction with venlafaxine, including CNS depressant effects.

Medicinal products that prolong the QT interval

The risk of QTc prolongation and/or development of ventricular arrhythmia (e.g., TdP) increases when venlafaxine is used concomitantly with other medicinal products that prolong the QTc interval. Concomitant use of such medicinal products should be avoided (see section "Special precautions").

These include:

Class Ia and III antiarrhythmics (e.g., quinidine, amiodarone, sotalol, dofetilide);
Certain antipsychotics (e.g., thioridazine);
Certain macrolides (e.g., erythromycin);
Certain antihistamines;
Certain quinolone antibiotics (e.g., moxifloxacin).

The list of medicinal products above is not exhaustive. Avoid concomitant use of other known individual medicinal products that significantly prolong the QT interval.

Effect of other medicinal products on venlafaxine

Ketoconazole (CYP3A4 inhibitor)

A pharmacokinetic study of ketoconazole use in rapid metabolizers (RM) and poor metabolizers (PM) of CYP2D6 showed increased AUC of venlafaxine (70% and 21% in PM and RM CYP2D6 subjects, respectively) and O-desmethylvenlafaxine (ODV) (33% and 23% in PM and RM CYP2D6 subjects, respectively) after ketoconazole administration. Concomitant use of CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, voriconazole, posaconazole, ketoconazole, nelfinavir, ritonavir, saquinavir, telithromycin) and venlafaxine may increase levels of venlafaxine and ODV. Therefore, caution is recommended if a patient's therapy includes concomitant use of a CYP3A4 inhibitor and venlafaxine.

Effect of venlafaxine on other medicinal products

Lithium

Concomitant use of venlafaxine and lithium may lead to serotonin syndrome (see section on serotonin syndrome).

Diazepam

Venlafaxine does not affect the pharmacokinetics and pharmacodynamics of diazepam and its active metabolite desmethyldiazepam. Diazepam is unlikely to affect the pharmacokinetics of either venlafaxine or ODV. It is unknown whether there is a pharmacokinetic and/or pharmacodynamic interaction with other benzodiazepines.

Imipramine

Venlafaxine did not affect the pharmacokinetics of imipramine or 2-OH-imipramine. A dose-dependent increase in AUC of 2-OH-desipramine by 2.5–4.5 times was observed with venlafaxine doses of 75–150 mg once daily. Imipramine did not affect the pharmacokinetics of venlafaxine or ODV. The clinical significance of this interaction is unknown. Caution is recommended when venlafaxine is used concomitantly with imipramine.

Haloperidol

Pharmacokinetic study results of venlafaxine co-administered with haloperidol showed a 42% decrease in oral clearance, a 70% increase in AUC, and an 88% increase in Cmax of haloperidol, while the elimination half-life remained unchanged. This should be considered in patients receiving concomitant haloperidol and venlafaxine therapy. The clinical significance of this interaction is unknown.

Risperidone

Venlafaxine increased the AUC of risperidone by 50%, but did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). The clinical significance of this interaction is unknown.

Metoprolol

Concomitant administration of venlafaxine and metoprolol in healthy volunteers in a pharmacokinetic interaction study resulted in approximately a 30–40% increase in plasma concentration of metoprolol without changes in plasma concentration of its active metabolite α-hydroxymetoprolol. The clinical significance of these findings in patients with increased sensitivity is unknown. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite ODV. Caution is recommended when venlafaxine and metoprolol are used concomitantly.

Indinavir

Pharmacokinetic data from a study using indinavir showed a 28% decrease in AUC and a 36% decrease in maximum concentration (Cmax) of indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine or ODV. The clinical significance of this interaction is unknown.

Medicinal products metabolized by cytochrome P450

In vivo isoenzyme studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP3A4 (alprazolam and carbamazepine), CYP1A2 (caffeine), CYP2C9 (tolbutamide), or CYP2C19 (diazepam) in vivo.

Oral contraceptives

Post-marketing experience has reported cases of unintended pregnancy in individuals taking oral contraceptives while being treated with venlafaxine. There is no clear evidence that these pregnancies resulted from a drug interaction with venlafaxine. Interaction studies with hormonal contraceptives have not been conducted.

Special precautions for use.

Overdose

Patients should be advised to avoid alcohol consumption due to its CNS effects and potential for clinically worsening psychiatric disorders, as well as the possibility of adverse interactions with venlafaxine, including CNS depressant effects (see section "Interaction with other medicinal products and other forms of interaction").

Overdose with venlafaxine has been reported primarily in combination with alcohol and/or other medicinal products, including cases with fatal outcomes (see section "Overdose").

Venlafaxine should be prescribed in the smallest effective dose appropriate to ensure adequate patient monitoring, in order to minimize the risk of overdose (see section "Overdose").

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal ideation and suicide (suicidal behaviour). The 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 such improvement occurs. Clinical experience indicates that the risk of suicide may increase in the early stages of recovery.

Other psychiatric disorders for which venlafaxine is indicated may also be associated with an increased risk of suicidal behaviour. Additionally, these conditions may accompany major depressive disorder. Precautions taken when treating patients with major depressive disorder should also be followed when treating patients with other psychiatric disorders.

Patients with a history of suicidal behaviour or those exhibiting pronounced suicidal ideation prior to treatment initiation are known to have an increased risk of developing suicidal thoughts or attempts during treatment and should be closely monitored. A meta-analysis of placebo-controlled clinical trials of antidepressant use in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients under 25 years of age.

Close monitoring of patients, especially those at high risk, should be carried out in conjunction with pharmacological treatment, particularly during the initial stages of therapy and after dose adjustments. Patients and caregivers should be alerted to the need to monitor for any clinical worsening, emergence of suicidal thoughts or behaviour, or unusual changes in behaviour, and to seek immediate medical attention if such symptoms occur.

Children

Suicidal behaviour (suicidal thoughts or suicide attempts) and hostility (mainly aggression, oppositional behaviour, and anger) have been observed more frequently in clinical trials among children and adolescents receiving antidepressants compared to those receiving placebo. If, due to clinical necessity, treatment is still initiated, patients should be carefully monitored for the emergence of suicidal symptoms. Furthermore, long-term safety data on the effects of the drug on growth, maturation, and cognitive and behavioural development in children and adolescents are lacking.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome—a potentially life-threatening condition—may occur during treatment with venlafaxine, particularly when used concomitantly with other medicinal products that affect the serotonergic neurotransmitter system (including triptans, SSRIs, SNRIs, tricyclic antidepressants, amphetamines, lithium, sibutramine, St John’s wort (Hypericum perforatum), opioids [e.g., fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, meperidine, methadone, pentazocine, buprenorphine, and buprenorphine/naloxone combination]) or with agents that interfere with serotonin metabolism, such as MAO inhibitors (e.g., methylene blue), or with serotonin precursors (such as tryptophan supplements), or with antipsychotics or other dopamine antagonists (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Symptoms of serotonin syndrome may include changes in mental status (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, lack of coordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea). In its most severe form, serotonin syndrome may resemble neuroleptic malignant syndrome (NMS), including hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuations in vital signs, and altered mental status.

If concomitant treatment with venlafaxine and other agents affecting serotonergic and/or dopaminergic neurotransmitter systems is clinically justified, careful monitoring of patients, particularly at the beginning of treatment and during dose escalation, is recommended.

Concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended.

Narrow-angle glaucoma

Mydriasis may occur during venlafaxine treatment. Close monitoring is recommended for patients with elevated intraocular pressure or those at increased risk of developing acute narrow-angle glaucoma (closed-angle glaucoma).

Blood pressure

Dose-dependent increases in blood pressure have frequently been reported during venlafaxine treatment. In post-marketing surveillance, cases of severe hypertension requiring immediate treatment have been reported. All patients should be closely monitored by healthcare professionals for the development of high blood pressure. Pre-existing hypertension should be controlled before initiating treatment. Blood pressure should be periodically checked after starting treatment and after dose increases. Caution is advised when treating patients whose underlying conditions may be exacerbated by elevated blood pressure, such as those with impaired cardiac function.

Heart rate

Increased heart rate may occur, particularly at higher doses of the drug. Caution is advised when treating patients whose underlying conditions may be exacerbated by increased heart rate.

Heart disease and risk of arrhythmia

The use of venlafaxine in patients with recent myocardial infarction or unstable heart disease has not been studied. Therefore, this drug should be used with caution in such patients.

In post-marketing surveillance of venlafaxine, cases of QTc prolongation, Torsade de Pointes (TdP), ventricular tachycardia, and fatal cardiac arrhythmias have been reported, particularly in cases of overdose or in patients with other risk factors for QTc/TdP prolongation. The benefit-risk ratio should be carefully considered before prescribing venlafaxine to patients at high risk of serious cardiac arrhythmias or QTc prolongation (see section "Pharmacodynamics").

Seizures

Seizures may occur during treatment with venlafaxine. As with all antidepressants, venlafaxine should be initiated cautiously in patients with a history of seizures, and such patients should be closely monitored. Treatment should be discontinued in any patient who develops seizures.

Hyponatraemia

Hyponatraemia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur during venlafaxine treatment. These events have most commonly been reported in dehydrated or debilitated patients. Elderly patients, patients taking diuretics, and patients with other conditions leading to hypovolaemia are at greater risk of developing these events.

Abnormal bleeding

Medicinal products that inhibit serotonin reuptake may lead to reduced platelet function. Bleeding events associated with SSRIs and SNRIs have ranged from ecchymoses, haematomas, epistaxis, and petechiae to gastrointestinal bleeding and life-threatening haemorrhages. The risk of bleeding may be increased in patients receiving venlafaxine. As with other SSRIs, venlafaxine should be used cautiously in patients predisposed to bleeding, including those receiving anticoagulants or platelet inhibitors. SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see sections "Use during pregnancy or breastfeeding" and "Adverse reactions").

Serum cholesterol levels

Clinically significant increases in serum cholesterol levels were observed in 5.3% of patients receiving venlafaxine and in 0.0% of patients receiving placebo during placebo-controlled clinical trials lasting at least 3 months. Monitoring of serum cholesterol levels should be considered during long-term treatment.

Sexual dysfunction

SNRIs may cause symptoms of sexual dysfunction (see section "Adverse reactions"). In some cases, these symptoms persisted after discontinuation of treatment.

Concomitant use with weight-loss agents

The safety and efficacy of venlafaxine used in combination with weight-loss agents, including phentermine, have not been established. Concomitant use of venlafaxine with weight-loss agents is not recommended. Venlafaxine is not indicated for weight loss, either alone or in combination with other agents.

Mania/hypomania

Mania/hypomania may occur in a small percentage of patients with mood disorders receiving antidepressants, including venlafaxine. As with other antidepressants, venlafaxine should be used cautiously in patients with a personal or family history of bipolar disorder.

Aggression

Aggression may occur in a small number of patients receiving antidepressants, including venlafaxine. This phenomenon has been reported after initiation of treatment, dose adjustment, and after discontinuation of treatment.

As with other antidepressants, venlafaxine should be used cautiously in patients with a history of aggression.

Discontinuation of treatment

It is known that antidepressant use may be associated with discontinuation effects, which may sometimes be prolonged and serious. Suicidal behaviour/suicidal thoughts and aggression have been observed in patients during changes in venlafaxine dosing, including during discontinuation. Therefore, careful monitoring is required during dose reduction or discontinuation (see above in section "Special precautions for use" – "Suicide/suicidal thoughts or clinical worsening" and "Aggression", and section "Adverse reactions"). In clinical trials, adverse events upon discontinuation (during and after gradual dose reduction) were observed in approximately 31% of patients receiving venlafaxine and in 17% of those receiving placebo.

The risk of withdrawal symptoms may depend on several factors, including duration of treatment, dose, and rate of dose reduction. Most commonly reported reactions include dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and vivid dreams), agitation or anxiety, nausea and/or vomiting, tremor, headache, visual disturbances, and hypertension. These symptoms are usually mild to moderate in severity, but may be severe in some patients. These symptoms typically occur within the first few days after discontinuation, although isolated reports have described such symptoms in patients who missed a dose due to oversight.

Generally, these symptoms resolve spontaneously, usually within 2 weeks, although in some patients they may persist longer (2–3 months or more). Therefore, venlafaxine dosage should be gradually reduced over several weeks or months, depending on patient needs (see section "Dosage and administration"). In some patients, discontinuation may take months or longer.

Akathisia/psychomotor agitation

Venlafaxine use has been associated with akathisia, characterized by subjectively unpleasant or distressing restlessness and a need to move frequently, accompanied by an inability to sit or stand still. This phenomenon is more likely to occur during the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be harmful.

Dry mouth

Dry mouth has been reported in 10% of patients receiving venlafaxine. This condition may increase the risk of dental caries; therefore, patients should be advised about the importance of maintaining good oral hygiene.

Diabetes mellitus

In patients with diabetes mellitus, treatment with SSRIs or venlafaxine may affect glycaemic control. Doses of insulin and/or oral antidiabetic agents may need to be adjusted.

Interaction with laboratory tests

False-positive results in immunological urine screening tests for phencyclidine (PCP) and amphetamines have been reported in patients taking venlafaxine. This occurs due to the insufficient specificity of screening tests. False-positive results may be expected for several days after discontinuation of venlafaxine therapy. Confirmatory tests such as gas chromatography/mass spectrometry can differentiate venlafaxine from PCP and amphetamines.

Use during pregnancy or breastfeeding.

Pregnancy

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

Animal studies have shown reproductive toxicity. The potential risk to humans is unknown. Venlafaxine should be prescribed to pregnant women only if the expected benefit outweighs the potential risk.

As with other SSRIs/SNRIs, newborns exposed to venlafaxine shortly before or during delivery may experience withdrawal symptoms. In some newborns exposed to venlafaxine in late third trimester, complications have occurred requiring parenteral feeding, assisted ventilation, or prolonged hospitalization. Such complications may occur immediately after delivery.

Newborns whose mothers used SSRIs/SNRIs late in pregnancy may exhibit symptoms such as irritability, tremor, hypotension, persistent crying, feeding difficulties, or sleep disturbances. These symptoms may arise due to serotonergic effects or drug withdrawal. In most cases, these complications occur immediately or within 24 hours after delivery.

Epidemiological data suggest that the use of SSRIs during pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although studies specifically investigating the link between PPHN and SNRI use have not been conducted, this potential risk cannot be excluded with venlafaxine, given its mechanism of action (SSRI component).

Observational data indicate an increased risk (less than 2-fold) of postpartum haemorrhage following SSRI/SNRI exposure within one month before delivery (see sections "Special precautions for use" and "Adverse reactions").

Breastfeeding period

Venlafaxine and its active metabolite ODV are excreted in breast milk. In the post-marketing period, irritability, fussiness, and sleep disturbances have been observed in infants who were breastfed. Symptoms consistent with venlafaxine discontinuation were also reported after cessation of breastfeeding. A risk to the breastfed infant cannot be excluded. Therefore, the decision to discontinue/continue breastfeeding or to discontinue/continue venlafaxine treatment should be made by weighing the benefits of breastfeeding for the child against the benefits of treatment with venlafaxine for the mother.

Reproductive function

In rat studies, reduced fertility was observed, with both male and female rats exposed to O-desmethylvenlafaxine. The relevance of these findings to human use is unknown.

Ability to affect reaction speed when driving or operating machinery.

Any psychoactive medicinal product may impair judgment, thinking, and motor skills. Therefore, patients receiving venlafaxine should be warned about the potential effects of the drug on driving and operating machinery.

Method of Administration and Dosage

Doses

Major depressive episodes: the recommended starting dose of venlafaxine prolonged release is 75 mg once daily. In patients who do not respond to the initial dose of 75 mg/day, dose escalation up to the maximum of 375 mg/day may be considered. Doses may be increased at intervals of 2 weeks or longer. If clinically necessary due to severity of symptoms, dose increases may be performed more frequently, but not more often than every 4 days. Because of the risk of dose-dependent adverse effects, the dose should be increased only after clinical assessment (see section "Special instructions"). The lowest effective dose should be maintained.

Patients should receive treatment for a sufficient duration, usually several months or longer. Treatment should be regularly reviewed in each individual case. Longer-term treatment may also be appropriate for prevention of relapse of major depressive episodes (MDE). In most cases, the recommended dose for prevention of MDE relapse is the same as the dose used during treatment of the current episode.

Antidepressants should be continued for at least 6 months after remission is achieved.

Generalized anxiety disorder: the recommended starting dose of venlafaxine prolonged release is 75 mg once daily. In patients who do not respond to the initial dose of 75 mg/day, dose escalation up to the maximum of 225 mg/day may be considered. Doses may be increased at intervals of 2 weeks or longer.

Because of the risk of dose-dependent adverse effects, the dose should be increased only after clinical assessment (see section "Special instructions"). The lowest effective dose should be maintained.

Patients should receive treatment for a sufficient duration, usually several months or longer. Treatment should be regularly reviewed in each individual case.

Social anxiety disorder: the recommended dose of venlafaxine prolonged release is 75 mg once daily. There is no evidence of additional benefit with higher doses. However, for individual patients who do not respond to the initial dose of 75 mg/day, dose escalation up to the maximum of 225 mg/day may be considered. Doses may be increased at intervals of 2 weeks or longer.

Patients should receive treatment for a sufficient duration, usually several months or longer. Treatment should be regularly reviewed in each individual case.

Panic disorder: recommended initial dose is 37.5* mg/day of venlafaxine prolonged release for 7 days. After this period, the dose should be increased to 75 mg/day. In patients who do not respond to the dose of 75 mg/day, dose escalation up to the maximum of 225 mg/day may be considered. Doses may be increased at intervals of 2 weeks or longer.

Patients should receive treatment for a sufficient duration, usually several months or longer. Treatment should be regularly reviewed in each individual case.

*Use venlafaxine formulations at the appropriate dosage strength.

Elderly patients: there is no need for specific dose adjustment based solely on patient age. However, caution should be exercised when treating elderly patients (e.g., due to possible impairment of renal function, possible changes in sensitivity to neurotransmitters, and increased susceptibility to these effects with age). The lowest effective dose should always be used, and if dose escalation is necessary, patients should be closely monitored.

Patients with hepatic impairment: in patients with mild to moderate hepatic impairment, a 50% reduction in dose should generally be considered. However, due to variability in clearance among patients, individualized dose titration is advisable.

Data are limited in patients with severe hepatic impairment. Caution is recommended when administering the drug to this patient population, and consideration should be given to reducing the dose by more than 50%. The potential benefits and risks of treatment should be carefully evaluated in patients with severe hepatic impairment.

Patients with renal impairment: although dosage adjustment is not necessary for patients with glomerular filtration rate (GFR) of 30–70 mL/min, caution is recommended when prescribing the drug. For patients requiring hemodialysis and for those with severe renal impairment (GFR < 30 mL/min), the dose should be reduced by 50%. Due to inter-individual variability in clearance in these patients, individualized dose titration is advisable.

Withdrawal symptoms of venlafaxine: abrupt discontinuation of the drug should be avoided. When stopping treatment with venlafaxine, the dose should be gradually reduced over at least 1–2 weeks to minimize the risk of withdrawal reactions (see sections "Special instructions" and "Adverse reactions").

However, the time required for tapering and the degree of dose reduction may depend on the dose, duration of therapy, and individual patient characteristics. In some patients, discontinuation may require a very gradual reduction over months or longer.

If intolerable symptoms develop after dose reduction or upon discontinuation of treatment, reinitiation of the previously prescribed dose may be considered. Subsequently, the physician may continue tapering the dose, but more gradually.

Method of Administration

For oral use.

Venlafaxine prolonged release should be taken with food at approximately the same time each day. Tablets should be swallowed whole with liquid. They must not be divided, crushed, chewed, or dissolved.

Patients previously treated with immediate-release venlafaxine tablets may switch to venlafaxine prolonged-release tablets at the nearest equivalent daily dose. For example, taking immediate-release venlafaxine tablets at 37.5 mg twice daily may be replaced with prolonged-release venlafaxine tablets at 75 mg once daily. Individual dose adjustment may be required.

Children

Lafaxin® XR Asino should not be used to treat children and adolescents under 18 years of age.

Controlled clinical trials in children and adolescents with major depressive disorder have not demonstrated efficacy and do not support the use of venlafaxine in these patients (see sections "Special instructions" and "Adverse reactions").

Overdose

In post-marketing experience, cases of venlafaxine overdose have been reported, primarily in combination with alcohol and/or other medicinal products, including fatal cases. The most frequently reported overdose effects include tachycardia, altered level of consciousness (from drowsiness to coma), mydriasis, seizures, and vomiting. Other reported effects include changes in electrocardiogram parameters (e.g., QT interval prolongation, bundle branch block, QRS prolongation on ECG (see section "Pharmacological properties")), ventricular tachycardia, bradycardia, hypotension, hypoglycemia, and vertigo, as well as fatal outcomes. Severe poisoning symptoms may occur in adults after ingestion of approximately 3 grams of venlafaxine.

Published retrospective studies have reported that venlafaxine overdose may be associated with an increased risk of fatality compared to selective serotonin reuptake inhibitors (SSRIs), but this risk is lower than with tricyclic antidepressants.

Epidemiological study data have shown that patients receiving venlafaxine treatment have a more severe suicide risk profile compared to patients receiving SSRIs. The extent to which the observed increased risk of fatal outcomes is attributable to venlafaxine toxicity in overdose, as opposed to certain characteristics of patients prescribed venlafaxine, remains unclear.

Recommended Treatment

Severe poisoning may require comprehensive emergency treatment and monitoring. Therefore, in case of suspected venlafaxine overdose, immediate medical attention is recommended.

General supportive and symptomatic measures are recommended; cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended if there is a risk of aspiration. Gastric lavage may be performed shortly after drug ingestion or in patients exhibiting symptoms. Administration of activated charcoal may also limit absorption of the active substance. Forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. There are no specific antidotes for venlafaxine.

Adverse Reactions

Summary of Safety Profile

The most commonly observed adverse reactions (>1/10) were: nausea, dry mouth, headache, and excessive sweating (including night sweats).

List of Adverse Reactions

Adverse reactions are listed below by system organ class, frequency of occurrence, and in descending order of severity within each frequency category.

Frequency is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders:
Rare – agranulocytosis*, aplastic anemia*, pancytopenia*, neutropenia*; very rare – thrombocytopenia*.

Immune system disorders:
Rare – anaphylactic reaction*.

Endocrine disorders:
Rare – syndrome of inappropriate antidiuretic hormone secretion (SIADH)*; very rare – increased blood prolactin levels*.

Metabolism and nutrition disorders:
Common – decreased appetite; rare – hyponatremia*.

Psychiatric disorders:
Very common – insomnia; common – confusion*, depersonalization*, unusual dreams, restlessness, decreased libido, agitation*; uncommon – mania, hypomania, hallucinations, derealization, abnormal orgasm, bruxism*, apathy; rare – delirium*; frequency not known – suicidal ideation and suicidal behaviora, aggressionb.

Nervous system disorders:
Very common – headache*c, dizziness, sedation; common – akathisia*, tremor, paresthesia, dysgeusia; uncommon – syncope, myoclonus, impaired balance*, coordination disorder*, dyskinesia*; rare – CNS*, serotonin syndrome*, seizures, dystonia*; very rare – tardive dyskinesia*.

Eye disorders:
Common – visual disturbance, accommodation disorder, including blurred vision, mydriasis; rare – angle-closure glaucoma*.

Ear and labyrinth disorders:
Common – tinnitus*; frequency not known – vertigo.

Cardiac disorders:
Common – tachycardia, palpitations*; rare – torsade de pointes*, ventricular tachycardia*, ventricular fibrillation, QT interval prolongation on ECG*; frequency not known – stress cardiomyopathy (Takotsubo cardiomyopathy)*.

Vascular disorders:
Common – hypertension, flushing; uncommon – orthostatic hypotension, hypotension*.

Respiratory, thoracic and mediastinal disorders:
Common – dyspnea*, yawning; rare – interstitial lung disease*, pulmonary eosinophilia*.

Gastrointestinal disorders:
Very common – nausea, dry mouth, constipation; common – diarrhea*, vomiting; uncommon – gastrointestinal hemorrhage*; rare – pancreatitis*.

Hepatobiliary disorders:
Uncommon – liver function test abnormalities*; rare – hepatitis*.

Skin and subcutaneous tissue disorders:
Very common – hyperhidrosis* (including night sweats)*; common – rash, pruritus*; uncommon – urticaria*, alopecia*, ecchymosis, angioedema*, photosensitivity reaction; rare – Stevens-Johnson syndrome*, toxic epidermal necrolysis*, erythema multiforme*.

Musculoskeletal and connective tissue disorders:
Common – hypertonia; rare – rhabdomyolysis*.

Renal and urinary disorders:
Common – difficulty in initiating micturition, urinary retention, frequent micturition*; uncommon – urinary incontinence*.

Reproductive system and breast disorders:
Common – menorrhagia*, metrorrhagia*, erectile dysfunctionb, ejaculation disorderb; frequency not known – postpartum hemorrhage*d.

General disorders and administration site conditions:
Common – weakness, asthenia, chills*; very rare – mucosal bleeding*.

Investigations:
Common – weight decreased, weight increased, increased blood cholesterol; very rare – prolonged bleeding time*.

* Adverse reactions identified during post-marketing use of the drug.

a Cases of suicidal ideation and suicidal behavior have been reported during treatment with venlafaxine or shortly after discontinuation (see section "Special Warnings and Precautions for Use").

b See section "Special Warnings and Precautions for Use".

c In pooled results of clinical trials, the incidence of headache during treatment with venlafaxine was similar to that with placebo.

d Applies to the therapeutic group of SSRIs/SNRIs (see sections "Special Warnings and Precautions for Use" and "Use in Pregnancy and Lactation").

Discontinuation of Treatment

Discontinuation of venlafaxine (especially abrupt) frequently leads to withdrawal symptoms. The most commonly reported reactions include: dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), agitation or anxiety, nausea and/or vomiting, tremor, vertigo, headache, flu-like symptoms, visual disturbances, and hypertension. These events are usually mild or moderate in intensity and resolve spontaneously; however, in some patients they may be severe and/or prolonged. Therefore, if continued treatment with venlafaxine is not required, it is recommended to gradually discontinue therapy by slowly reducing the dose. However, in some patients, severe aggression and suicidal thoughts may occur during dose reduction or discontinuation (see sections "Special Warnings and Precautions for Use" and "Dosage and Administration").

Children

Overall, the adverse reaction profile of venlafaxine (in placebo-controlled clinical trials) in children and adolescents (aged 6 to 17 years) was similar to that observed in adults. As in adults, decreased appetite, weight loss, increased blood pressure, and increased serum cholesterol levels were observed (see section "Special Warnings and Precautions for Use").

In clinical studies involving children, suicidal ideation was reported as an adverse reaction. Hostility and self-harm behaviors were also reported more frequently, especially in patients with major depressive disorders.

Specific adverse reactions observed in pediatric patients include: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia.

Reporting of Suspected Adverse Reactions

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

Shelf Life. 3 years.

Storage Conditions. Store out of reach and sight of children at a temperature not exceeding 25 °C.

Packaging. 14 tablets in a blister with calendar strip; 2 blisters per cardboard pack.

Prescription Category. Prescription only.

Manufacturer. Dexcel Ltd./Dexcel Ltd.

Manufacturer's Address and Place of Business.
1 Dexcel St., Or Akiva, 3060000, Israel / 1 Dexcel St., Or Akiva, 3060000, Israel.

Marketing Authorization Holder. Dexcel Pharma Technologies Ltd., Israel / Dexcel Pharma Technologies Ltd., Israel.

In case of adverse reactions or questions regarding safety and efficacy of the medicinal product, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINE" at:
8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine; Tel/Fax: +38 044 281 2333.