Lafaxin® xr asino: detailed information

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

Composition:

Active substance: venlafaxine hydrochloride;

One tablet contains 169.70 mg of venlafaxine hydrochloride, equivalent to 150 mg of venlafaxine base;

Excipients: calcium hydrogen phosphate dihydrate; hypromellose K-100; polyacrylate dispersion 30%; colloidal anhydrous silicon dioxide; magnesium stearate;

coating: polyvinyl acetate dispersion 30%, triethyl citrate, grafted copolymer of polyethylene glycol and polyvinyl alcohol, talc, carnauba wax.

Pharmaceutical form. Extended-release tablets.

Main physicochemical characteristics: round, coated, speckled tablets, white to almost white in color.

Pharmacotherapeutic group.
Antidepressants. ATC code N06A X16.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

The antidepressant mechanism of action of venlafaxine in humans is believed to be related to the enhancement of neurotransmitter activity in the central nervous system. Preclinical studies have shown that venlafaxine and its major metabolite O-desmethylvenlafaxine (ODV) are inhibitors of neuronal reuptake of serotonin and norepinephrine. In addition, venlafaxine weakly inhibits the reuptake of dopamine. Venlafaxine and ODV reduce β-adrenergic responses following single-dose administration and with chronic administration. Venlafaxine and ODV are very similar in their overall effects on neurotransmitter reuptake and receptor binding.

In rodent brain, venlafaxine shows virtually no affinity for muscarinic, cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Pharmacological activity at these receptors may contribute to various adverse effects observed with other antidepressants, such as anticholinergic, sedative, and cardiovascular side effects.

Venlafaxine does not inhibit monoamine oxidase (MAO).

In vitro studies have shown that venlafaxine has virtually no affinity for opioid or benzodiazepine 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 of 4 to 6 weeks' duration using a dose of 375 mg per day. The efficacy of venlafaxine extended-release for the treatment of major depressive episodes was demonstrated in two short-term, placebo-controlled studies of 8 and 12 weeks' duration using doses ranging from 75 to 225 mg per day.

In a long-term study, adult outpatients who had received venlafaxine extended-release (75, 150, or 225 mg) during an 8-week open-label study were randomly assigned to continue the same dose of venlafaxine extended-release or to receive placebo and were observed for relapse over 26 weeks.

In a second long-term study, the efficacy of venlafaxine in preventing relapse of depressive episodes was confirmed over 12 months in a placebo-controlled, double-blind clinical trial in adult outpatients with recurrent major depressive episodes who had responded to venlafaxine (100 to 200 mg per day, divided into two daily doses) during a previous depressive episode.

Generalized anxiety disorder. The efficacy of venlafaxine extended-release in the treatment of generalized anxiety disorder was demonstrated in two 8-week, fixed-dose, placebo-controlled studies (75 to 225 mg per day), a 6-month, fixed-dose, placebo-controlled study (75 to 225 mg per day), and a 6-month, flexible-dose, placebo-controlled study (37.5 mg, 75 mg, and 150 mg per day) in adult outpatients.

While evidence of benefit over placebo was observed even at the 37.5 mg per day dose, this dose was not as consistently effective as higher doses.

Social anxiety disorder. The efficacy of venlafaxine extended-release in the treatment of social anxiety disorder was demonstrated in four double-blind, 12-week, multicenter, placebo-controlled studies with parallel-group comparison using flexible dosing and in a double-blind, 6-month, placebo-controlled study with parallel-group comparison using fixed/flexible dosing in adult outpatients. Patients received doses ranging from 75 to 225 mg per day. In the 6-month study, there was no evidence of greater efficacy in the group receiving 150–225 mg per day compared to the group receiving 75 mg per day.

Panic disorder. The efficacy of venlafaxine extended-release in the treatment of panic disorder was demonstrated in two double-blind, 12-week, multicenter, placebo-controlled studies in adult outpatients with panic disorder with or without agoraphobia. The initial dose in the panic disorder studies was 37.5 mg per day for 7 days. Patients then received fixed doses of 75 or 150 mg per day in one study and 75 or 225 mg per day in the other study.

Additionally, efficacy was demonstrated in a double-blind, placebo-controlled, long-term study assessing long-term safety, efficacy, and relapse prevention with parallel-group comparison among adult outpatients who underwent open-label treatment. Patients continued to receive the same dose of venlafaxine extended-release (75, 150, or 225 mg) that they had been receiving at the end of the open-label phase.

Cardiac electrophysiology. In a large QT study in healthy volunteers using a dose of 450 mg per day (225 mg twice daily), higher than the therapeutic dose, venlafaxine did not prolong the QT interval to a clinically significant extent. However, post-marketing reports have described cases of QT interval prolongation, torsades de pointes, and ventricular arrhythmias, particularly in cases of overdose or in patients with other risk factors (see sections "Special precautions", "Overdose", and "Adverse reactions").

Pharmacokinetics.

Venlafaxine is extensively metabolized, primarily to the active metabolite O-desmethylvenlafaxine (ODV). Mean values ± SD (standard deviation) for the elimination half-life of venlafaxine and ODV from 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 mg to 450 mg per day.

Absorption. After oral administration of a single dose of immediate-release venlafaxine, approximately 92% of venlafaxine is absorbed. Absolute bioavailability is 40–45%, due to presystemic metabolism. After administration of immediate-release venlafaxine, peak plasma concentrations of venlafaxine and ODV are reached within 2 and 3 hours, respectively. After administration of venlafaxine extended-release, peak plasma concentrations of venlafaxine and ODV are reached within 5.5 and 9 hours, respectively. When equivalent doses of venlafaxine are administered either as an immediate-release tablet or as an extended-release tablet, the extended-release formulation provides a slower rate but the same extent of absorption as the immediate-release tablet. Food has no effect on the bioavailability of venlafaxine and ODV.

Distribution. Venlafaxine and ODV are minimally bound to human plasma proteins (27% and 30%, respectively) at therapeutic concentrations. The volume of distribution of venlafaxine at steady state is 4.4 ± 1.6 L/kg after intravenous administration.

Biological transformation. Venlafaxine is extensively metabolized in the liver. 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 also show that venlafaxine is metabolized by the CYP3A4 enzyme to form its minor, less active metabolite, N-desmethylvenlafaxine. In vitro and in vivo studies have shown that venlafaxine itself is a weak inhibitor of CYP2D6. Venlafaxine does not inhibit CYP1A2, CYP2C9, or CYP3A4.

Elimination. Venlafaxine and its metabolites are primarily excreted by the kidneys. Approximately 87% of the administered dose of venlafaxine is excreted in the 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 the 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 patient groups

Age and gender. Age and gender have no significant effect on the pharmacokinetics of venlafaxine and ODV.

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

Hepatic impairment. In patients with Child-Pugh class A hepatic impairment (mild hepatic dysfunction) and Child-Pugh class B (moderate hepatic dysfunction), the elimination half-life of venlafaxine and ODV is prolonged compared to patients with normal hepatic function. Oral clearance of venlafaxine and ODV is reduced. There is a high degree of variability in these parameters among patients. Data on the use of the drug in patients with severe hepatic impairment are limited (see section "Dosage and administration").

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 the active substance or to any of the excipients.

Concomitant use with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of developing serotonin syndrome, with symptoms such as agitation, tremor, and hyperthermia. Venlafaxine must not be initiated within at least 14 days of discontinuation of irreversible MAOIs. Venlafaxine treatment must be discontinued at least 7 days prior to starting irreversible MAOI therapy (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Monoamine oxidase inhibitors (MAOIs)

Irreversible non-selective MAOIs

Venlafaxine should not be used in combination with irreversible non-selective MAOIs. Venlafaxine therapy may be initiated no sooner than 14 days after discontinuation of irreversible non-selective MAOI therapy. Venlafaxine treatment should be discontinued at least 7 days prior to starting irreversible non-selective MAOI therapy (see sections "Contraindications" and "Special warnings and precautions for use").

Reversible selective MAO-A inhibitors (moclobemide)

Due to the risk of serotonin syndrome, combination of venlafaxine with reversible selective MAO inhibitors such as moclobemide is contraindicated. Venlafaxine therapy may be initiated no sooner than 14 days after discontinuation of reversible MAO inhibitors. After discontinuation of venlafaxine, at least 7 days should elapse before starting therapy with reversible MAO inhibitors (see section "Special warnings and precautions for use").

Reversible non-selective MAO inhibitors (linezolid)

Concomitant use of the antibiotic linezolid (a weak reversible non-selective MAO inhibitor) with venlafaxine is contraindicated (see section "Special warnings and precautions for use").

Severe adverse reactions have been reported in patients who recently discontinued MAOI therapy and started treatment with venlafaxine, or who discontinued venlafaxine shortly before starting MAOIs. These reactions included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, 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 medicinal products affecting the serotonergic neurotransmitter system (including triptans, SSRIs [selective serotonin reuptake inhibitors], SNRIs [serotonin-norepinephrine reuptake inhibitors], 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]), with medicinal products that interfere with serotonin metabolism (e.g., MAO inhibitors such as methylene blue), or with serotonin precursors (e.g., tryptophan supplements), or with antipsychotics or other dopamine antagonists (see sections "Contraindications" and "Special warnings and precautions for use").

If concomitant treatment with venlafaxine and SSRIs, SNRIs, or serotonin receptor antagonists (triptans) is clinically necessary, careful patient monitoring is recommended, especially at the beginning of treatment and when increasing the dose. Concomitant use of venlafaxine and serotonin precursors (e.g., tryptophan supplements) is not recommended (see section "Special warnings and precautions for use").

Central nervous system (CNS)-acting agents

The risk of using venlafaxine in combination with other medicinal products acting on the central nervous system (CNS) has not been systematically studied. Therefore, caution should be exercised when using venlafaxine in combination with other CNS-acting medicinal products.

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 adverse interactions with venlafaxine, including CNS depression.

Agents that prolong the QT interval

The risk of QTc prolongation and/or ventricular arrhythmia (e.g., torsades de pointes) increases with concomitant use of other medicinal products that prolong the QTc interval. Therefore, concomitant use of such medicinal products should be avoided (see section "Special warnings and precautions for use").

These include the following classes of medicinal products:

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

This list is not exhaustive. Combinations with other individual agents capable of significantly prolonging the QT interval should also be avoided.

Effect of other medicinal products on venlafaxine

Ketoconazole (CYP3A4 inhibitor)

Pharmacokinetic studies with ketoconazole in both extensive metabolizers (EM) and poor metabolizers (PM) of CYP2D6 showed increased AUC of venlafaxine (70% and 21% in PM and EM of CYP2D6, respectively) and O-desmethylvenlafaxine (33% and 23% in PM and EM of CYP2D6, respectively) after ketoconazole administration. Concomitant use of CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, voriconazole, posaconazole, ketoconazole, nelfinavir, ritonavir, saquinavir, telithromycin) with venlafaxine may increase plasma levels of venlafaxine and O-desmethylvenlafaxine. Therefore, caution should be exercised when combining a CYP3A4 inhibitor with venlafaxine.

Effect of venlafaxine on other medicinal products

Lithium

Concomitant use of venlafaxine and lithium may result in serotonin syndrome (see "Serotonin syndrome" above).

Diazepam

Venlafaxine does not affect the pharmacokinetics or pharmacodynamics of diazepam or its active metabolite desmethyldiazepam. Diazepam does not affect the pharmacokinetics of venlafaxine or O-desmethylvenlafaxine. It is unknown whether there is a pharmacokinetic or pharmacodynamic interaction with other benzodiazepines.

Imipramine

Venlafaxine does not affect the pharmacokinetics of imipramine or 2-hydroxyimipramine. A dose-dependent increase in AUC of 2-hydroxydesipramine by 2.5–4.5 times was observed when venlafaxine was administered at doses of 75–150 mg per day. Imipramine did not affect the pharmacokinetics of venlafaxine or O-desmethylvenlafaxine. The clinical significance of this interaction is unknown. Caution should be exercised when venlafaxine and imipramine are used concomitantly.

Haloperidol

Results from a pharmacokinetic study of venlafaxine with haloperidol showed a 42% decrease in total oral clearance, a 70% increase in AUC, and an 88% increase in Cmax, but the elimination half-life of haloperidol remained unchanged. This should be taken into account if a patient is receiving concomitant treatment with haloperidol and venlafaxine. 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 + 9-hydroxyrisperidone). The clinical significance of this interaction is unknown.

Metoprolol

Concomitant administration of venlafaxine and metoprolol in a pharmacokinetic interaction study in healthy volunteers resulted in approximately 30–40% higher plasma concentrations of metoprolol, without changes in plasma concentrations of its active metabolite alpha-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 O-desmethylvenlafaxine. Caution should be exercised 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 Cmax of indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine or O-desmethylvenlafaxine. The clinical significance of this interaction is unknown.

Medicinal products metabolized by cytochrome P450 isoenzymes

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

Oral contraceptives

During the post-marketing period, unintended pregnancies have been reported in women using oral contraceptives during venlafaxine treatment. There is no clear evidence that these pregnancies were caused by an 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 central nervous system (CNS) effects and potential for clinically worsening psychiatric disorders, as well as the possibility of adverse interactions with venlafaxine, including CNS depression (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 maintain patient monitoring, in order to minimize the risk of overdose (see section "Overdose").

Suicide / suicidal thoughts or worsening of clinical condition

Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide attempts (suicidal behavior). This risk persists until significant remission occurs. Since lack of improvement may persist during the first few weeks or longer after initiation of treatment, patients require close monitoring until their condition improves. Clinical experience with antidepressant treatment shows that the risk of suicide may increase during the early stages of recovery.

Other psychiatric disorders for which venlafaxine is prescribed are also associated with an increased risk of suicidal behavior. Moreover, these conditions may coexist with depressive disorders (major depressive episodes). Therefore, the same precautions should be taken when treating patients with other psychiatric disorders as when treating patients with major depressive disorder.

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

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

Children and adolescents

Laflaxin® XR Asino should not be used in children and adolescents under 18 years of age. Suicidal behaviors (suicide attempts and suicidal thoughts) and hostility (mainly aggression, oppositional defiant behavior, and anger) were observed more frequently in clinical trials among children and adolescents treated with antidepressants compared to those receiving placebo. If treatment is clinically necessary, the patient's condition should be carefully monitored for the emergence of suicidal symptoms. In addition, long-term safety data regarding growth, sexual maturation, and cognitive and behavioral 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 agents affecting serotonergic neurotransmission (including triptans, 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]), with medicinal products affecting serotonin metabolism (e.g., MAOIs such as methylene blue), with serotonin precursors (e.g., tryptophan supplements), or with neuroleptics or other dopamine antagonists (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular disturbances (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). In its most severe form, serotonin syndrome may resemble neuroleptic malignant syndrome (NMS), which includes hyperthermia, muscle rigidity, autonomic instability with 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 the patient is recommended, especially at the beginning of treatment and during dose escalation.

Concomitant use of venlafaxine with serotonin precursors (e.g., tryptophan supplements) is not recommended.

Closed-angle glaucoma

Mydriasis may occur during treatment with venlafaxine. Therefore, careful monitoring is recommended for patients with elevated intraocular pressure or at risk of developing acute closed-angle glaucoma.

Blood pressure

Dose-dependent increases in blood pressure have frequently been reported during treatment with venlafaxine. In several post-marketing cases, severe increases in blood pressure requiring immediate treatment have been reported. Blood pressure parameters should be closely monitored in all patients, and blood pressure should be normalized before initiating venlafaxine therapy. Blood pressure should be measured periodically—at the beginning of treatment and after dose increases. Caution is advised when prescribing the drug to patients whose underlying condition could be exacerbated by elevated blood pressure, such as patients with cardiac dysfunction.

Heart rate

Heart rate may increase, especially with high-dose treatment. Caution is advised in patients whose clinical status may be affected by changes in heart rate.

Cardiac disease and risk of arrhythmia

Venlafaxine has not been evaluated in patients with recent myocardial infarction or unstable cardiac disease. Therefore, the drug should be used with caution in such patients.

During post-marketing use of venlafaxine, cases of QTc interval prolongation, ventricular tachycardia of the "torsades de pointes" type, ventricular tachycardia, and fatal cardiac rhythm disturbances have been reported, particularly in cases of overdose or in patients with other risk factors. Before prescribing venlafaxine to patients at high risk of serious cardiac arrhythmia or QTc prolongation, the benefit-risk ratio should be carefully considered (see section "Pharmacodynamics").

Seizures

Seizures may occur during treatment with venlafaxine. As with all antidepressants, venlafaxine should be used with caution in patients with a history of seizures, and such patients should be closely monitored. If seizures occur, the drug should be discontinued.

Hyponatremia

Hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) may develop during treatment with venlafaxine. These events have most commonly been observed in patients with hypovolemia or dehydration. Elderly patients, patients taking diuretics, and patients with dehydration from other causes have an increased risk of developing hyponatremia.

Abnormal bleeding

Medicinal products that inhibit serotonin reuptake may impair platelet function. Bleeding associated with SSRIs and SNRIs has ranged from ecchymoses, hematomas, epistaxis, and petechiae to gastrointestinal and life-threatening hemorrhages. SSRIs/SNRIs, including venlafaxine, increase the risk of postpartum hemorrhage (see sections "Use in pregnancy or lactation" and "Adverse reactions").

The risk of bleeding is increased in patients taking venlafaxine. Therefore, venlafaxine should be used with caution in patients predisposed to bleeding, including those taking anticoagulants or platelet function inhibitors, as with other serotonin reuptake inhibitors.

Serum cholesterol

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

Concomitant use with weight-loss medicinal products

The safety and efficacy of venlafaxine used in combination with weight-loss medicinal products, including phentermine, have not been established. Concomitant use of venlafaxine with weight-loss medicinal products is not recommended. Venlafaxine is not indicated for weight reduction, including when used in combination with other medicinal products.

Mania/hypomania

Mania or hypomania may develop in patients with mood disorders receiving antidepressants, including venlafaxine. As with other antidepressants, venlafaxine should be prescribed with caution in patients with a family history of bipolar disorder.

Aggression

Aggression may develop in some patients receiving antidepressants, including venlafaxine. This has been reported at the beginning of treatment, after dose changes, and during discontinuation of treatment.

As with other antidepressants, venlafaxine should be prescribed with caution in patients with a history of aggression.

Withdrawal symptoms following discontinuation of treatment

Withdrawal symptoms are known to occur with antidepressant use; sometimes these symptoms may be prolonged and severe. Suicidal behavior/suicidal thoughts and aggression have been observed in patients when changing or discontinuing venlafaxine treatment. Therefore, patients should be closely monitored when tapering or discontinuing treatment (see above in this section "Suicide / suicidal thoughts or worsening of clinical condition" and "Aggression"). Withdrawal symptoms frequently occur after treatment discontinuation, especially if treatment is stopped abruptly (see section "Adverse reactions"). In clinical trials, adverse effects following discontinuation (during and after dose reduction) were observed in approximately 31% of patients receiving venlafaxine and in 17% of patients receiving placebo.

The risk of withdrawal symptoms may depend on several factors, including duration of treatment, dose, and rate of dose reduction. Dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), agitation or anxiety, nausea and/or vomiting, tremor, headache, blurred vision, and increased blood pressure are the most commonly reported withdrawal reactions. These symptoms are generally mild or moderate, but in some patients they may be severe. They usually occur within the first few days after discontinuation of treatment, although in rare cases such symptoms have been observed in patients who accidentally missed a dose. These symptoms are usually self-limiting and resolve within 2 weeks. In some individuals, they may persist longer (2–3 months or more). Therefore, it is recommended to gradually reduce the dose of venlafaxine over several weeks or months, depending on the patient's needs, when discontinuing treatment (see section "Dosage and administration"). In some patients, discontinuation may take at least several months.

Sexual dysfunction

Selective serotonin and norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section "Adverse reactions"). Reports of persistent sexual dysfunction, where symptoms persist despite discontinuation of SNRIs, have been documented.

Akathisia / psychomotor agitation

Venlafaxine use has been associated with akathisia, subjectively characterized by unpleasant or anxious restlessness, an urge to move frequently, and inability to sit or stand still. This phenomenon most commonly occurs during the first few weeks of treatment. For patients who develop such symptoms, dose escalation may be detrimental.

Dry mouth

Dry mouth occurred in 10% of patients receiving venlafaxine. Dry mouth increases the risk of dental caries; therefore, patients should be reminded of the importance of dental hygiene.

Diabetes mellitus

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

Effect on laboratory tests

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

Sodium

One of the excipients — 30% polyvinyl acetate dispersion — contains sodium. The medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of venlafaxine in pregnant women are insufficient.

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

As with other SSRIs/SNRIs, withdrawal syndrome may occur in newborns if venlafaxine was used before or shortly before delivery. In some newborns exposed to venlafaxine late in the third trimester, complications occurred that required tube feeding, respiratory support, or prolonged hospitalization. Such complications may occur immediately after birth.

Observational data indicate an increased risk (approximately twice) of postpartum hemorrhage associated with SSRI/SNRI use within one month before delivery (see sections "Special precautions for use" and "Adverse reactions").

Epidemiological data suggest that use of SSRIs during pregnancy, particularly in late pregnancy, increases the risk of primary pulmonary hypertension in the newborn (PPHN, also known as persistent pulmonary hypertension of the newborn). Although studies specifically investigating the link between PPHN and SNRI use have not been conducted, this risk cannot be excluded with venlafaxine due to its similar mechanism of action (inhibition of serotonin reuptake).

If a woman has used SSRIs/SNRIs in late pregnancy, the newborn may exhibit symptoms such as irritability, tremor, muscle hypotonia, uncontrolled crying, and difficulty breastfeeding or difficulty falling asleep. These symptoms may arise from serotonergic effects or drug withdrawal symptoms. These complications are usually observed immediately after birth or within 24 hours.

Lactation. Venlafaxine and its active metabolite O-desmethylvenlafaxine are excreted in breast milk. During post-marketing use, irritability, crying, and sleep disturbances have been observed in infants breastfed by mothers taking the drug. Symptoms consistent with venlafaxine discontinuation were also reported after cessation of breastfeeding. The risk to the breastfed infant cannot be excluded. Therefore, the decision to discontinue/continue breastfeeding or to discontinue/continue treatment with Laflaxin® XR Asino should be made by weighing the benefits of breastfeeding for the child against the benefits of treatment with Laflaxin® XR Asino for the mother.

Fertility. Reduced fertility was observed in a study where both male and female rats were exposed to O-desmethylvenlafaxine. The relevance of these findings to humans is unknown.

Ability to influence reaction speed when driving or operating machinery.

Any psychoactive medicinal product may impair the ability to make decisions, think, or perform motor functions. Therefore, patients receiving venlafaxine should be warned about their reduced ability to drive or operate dangerous machinery.

Dosage and Administration

Dosing

Major Depressive Episodes

The recommended initial dose of extended-release venlafaxine is 75 mg once daily. For patients who do not respond adequately to the initial dose of 75 mg per day, dose escalation up to the maximum of 375 mg per day may be beneficial. Dose increases should be made at intervals of 2 weeks or longer. In more severe cases, if clinically indicated, the dose may be increased at shorter intervals, but not more frequently than every 4 days.

Due to the risk of dose-dependent adverse reactions, dose escalation should only be performed after careful clinical evaluation (see section "Special Precautions"). The lowest effective dose should be used.

Treatment of patients requires a relatively long duration, typically several months or longer. The effectiveness of treatment should be regularly re-evaluated on a case-by-case basis. Long-term treatment may also be appropriate for the prevention of relapse in major depressive episodes (MDE). In most cases, the recommended dose for relapse prevention is the same as that used for treatment of an acute depressive episode.

After remission, antidepressant therapy should be continued for at least 6 months.

Generalized Anxiety Disorder

Treatment of patients requires a relatively long duration, typically several months or longer. The effectiveness of treatment should be regularly re-evaluated on a case-by-case basis.

Social Anxiety Disorder

The recommended initial dose of extended-release venlafaxine is 75 mg once daily. There is no evidence that higher doses provide additional benefit.

For patients who do not respond adequately to the initial dose of 75 mg per day, dose escalation up to the maximum of 225 mg per day may be beneficial. Dose increases should be made at intervals of 2 weeks or longer.

Treatment of patients requires a relatively long duration, typically several months or longer. The effectiveness of treatment should be regularly re-evaluated on a case-by-case basis.

Panic Disorder

It is recommended to initiate treatment with a daily dose of 37.5 mg of extended-release venlafaxine for 7 days. After this period, the dose should be increased to 75 mg per day. For patients who do not respond adequately to the initial dose of 75 mg per day, dose escalation up to the maximum of 225 mg per day may be beneficial. Dose increases should be made at intervals of 2 weeks or longer.

Treatment of patients requires a relatively long duration, typically several months or longer. The effectiveness of treatment should be regularly re-evaluated on a case-by-case basis.

Elderly Patients

Dose adjustment based on age is not required. However, treatment of elderly patients should be carried out with caution (e.g., due to possible impairment of renal function, age-related changes in neurotransmitter sensitivity and affinity). The lowest effective dose should be used, and patients should be under close medical supervision when the dose is increased.

Patients with Hepatic Impairment

For patients with mild to moderate hepatic impairment, a 50% dose reduction should generally be considered. However, due to inter-individual variability in clearance, dose selection should be individualized.

Data on the use of venlafaxine in patients with severe hepatic impairment are limited. Therefore, caution is advised when treating such patients, and a daily dose reduction of more than 50% is recommended. The expected benefit should be weighed against the potential risk before prescribing the drug to patients with severe hepatic impairment.

Patients with Renal Impairment

Although dose adjustment is not required for patients with a glomerular filtration rate (GFR) of 30–70 mL/min, caution is advised. For patients undergoing hemodialysis and those with severe renal impairment (GFR < 30 mL/min), a 50% dose reduction is recommended. Due to inter-individual variability in clearance in these patients, dose selection should be individualized.

Discontinuation Syndrome after Stopping Venlafaxine

Abrupt discontinuation of venlafaxine treatment should be avoided. After stopping treatment, a gradual dose reduction over 1–2 weeks is recommended to minimize the risk of discontinuation syndrome (see sections "Special Precautions" and "Adverse Reactions"). However, the duration and extent of dose tapering may depend on the dose, duration of therapy, and individual patient factors. For some patients, an extremely gradual discontinuation over several months may be necessary. If intolerance symptoms occur after dose reduction or discontinuation, consideration should be given to resuming the previously prescribed dose. The physician may then continue tapering the dose, but more slowly.

Administration Instructions

It is recommended to take the extended-release tablets at approximately the same time each day, with food. The extended-release tablets should be swallowed whole with liquid. Tablets must not be divided, crushed, chewed, or dissolved.

Patients receiving immediate-release venlafaxine tablets may be switched to extended-release venlafaxine tablets at the nearest equivalent daily dose. For example, immediate-release venlafaxine 37.5 mg twice daily can be replaced with extended-release venlafaxine 75 mg once daily. Dose adjustments may be required on an individual basis.

Children and Adolescents

Venlafaxine is not recommended for use in children and adolescents.

Controlled clinical trials in children and adolescents with major depressive disorder have not demonstrated efficacy and have not confirmed the appropriateness of venlafaxine use in this age group (see sections "Special Precautions" and "Adverse Reactions").

The safety and efficacy of venlafaxine for other indications in children and adolescents under 18 years of age have not been established.

Overdose. Overdose with venlafaxine has been reported in the post-marketing period, primarily in association with alcohol and/or other drugs, including cases with fatal outcomes. The most commonly reported symptoms in overdose include tachycardia, changes in level of consciousness (from somnolence to coma), mydriasis, seizures, and vomiting. Other reported effects include electrocardiogram (ECG) changes (e.g., QT and QRS interval prolongation, bundle branch block [see section "Pharmacological Properties"]), ventricular tachycardia, bradycardia, hypotension, hypoglycemia, dizziness, and fatal outcomes. Severe poisoning may occur in adults after ingestion of approximately 3 grams of venlafaxine.

Published retrospective studies report that venlafaxine overdose carries a higher risk of fatality compared to SSRIs and a lower risk compared to tricyclic antidepressants. Epidemiological studies have shown that patients treated with venlafaxine are more likely to attempt suicide than those receiving SSRIs. It is unclear to what extent the increased risk of fatal outcome is related to the toxicity of venlafaxine in overdose or to the underlying condition of patients receiving venlafaxine.

Treatment Recommendations

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

Standard 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 indicated in early stages or in patients with signs of intoxication. Absorption of the active substance may also be reduced by administration of activated charcoal. Forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. There are no known specific antidotes for venlafaxine.

Side effects.

Very common (> 1/10) adverse reactions reported in clinical trials were nausea, dry mouth, headache, and sweating (including night sweats).

The following adverse reactions are listed by system organ class, frequency of occurrence, and decreasing severity within each frequency group.

Frequency is defined as: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10,000, < 1/1000), very rare (< 1/10,000), not known (frequency 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 system 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, nervousness, decreased libido, agitation*; uncommon — mania, hypomania, hallucinations, derealization, orgasm dysfunction, bruxism*, apathy; rare — delirium*; not known — suicidal thoughts and suicidal behavioura, aggressionb.

Nervous system disorders: very common — headachec*, dizziness, sedation; common — akathisia*, tremor, paresthesia, dysgeusia; uncommon — syncope, myoclonus, impaired balance*, coordination disorder*, dyskinesia*; rare — neuroleptic malignant syndrome (NMS)*, serotonin syndrome*, seizures, dystonia*; very rare — tardive dyskinesia*.

Eye disorders: common — visual disturbance, accommodation disorder, including blurred vision, mydriasis; rare — closed-angle glaucoma*.

Ear and labyrinth disorders: common — tinnitus*; not known — vertigo.

Cardiac disorders: common — tachycardia, palpitations*; rare — torsades de pointes ventricular tachycardia*, ventricular tachycardia*, ventricular fibrillation, prolonged QT interval*; not known — stress cardiomyopathy (takotsubo cardiomyopathy)*.

Vascular disorders: common — increased blood pressure, hot flushes; uncommon — orthostatic hypotension, arterial 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, angioneurotic edema*, photosensitivity reactions; 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 micturition, urinary retention, polyuria*; uncommon — urinary incontinence*.

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

General disorders and administration site conditions: common — fatigue, asthenia, chills*; very rare — mucosal bleeding*.

Investigations: common — weight decreased, weight increased, increased cholesterol levels; very rare — prolonged bleeding time*.

* Adverse reactions identified during the post-marketing period.

a Suicidal thoughts or behaviour have been reported during therapy with venlafaxine or shortly after discontinuation of treatment (see section "Special precautions").

b See section "Special precautions".

c In pooled clinical trials, the incidence of headache was similar during venlafaxine and placebo treatment.

d This phenomenon relates to the therapeutic class of SSRIs/SNRIs (see sections "Special precautions" and "Use during pregnancy or breastfeeding").

Children.

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

In pediatric clinical trials, suicidal thoughts were observed as an adverse effect. Hostility has been frequently reported, and particularly in cases of major depressive disorders, self-harm.

Specifically, the following adverse reactions were observed in pediatric patients: abdominal pain, agitation, dyspepsia, minor skin bleeding, epistaxis, and myalgia.

Discontinuation of treatment

Discontinuation of venlafaxine treatment (especially abrupt discontinuation) frequently leads to withdrawal symptoms. The most commonly reported reactions include: dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and restless sleep), agitation or anxiety, nausea and/or vomiting, tremor, vertigo, headache, flu-like symptoms, visual disturbances, and increased blood pressure. These symptoms are usually mild to moderate in severity and resolve spontaneously, although in some patients they may be severe and/or prolonged. Therefore, it is advisable to gradually reduce the dose when venlafaxine treatment is no longer required. However, during dose reduction or discontinuation, some patients experienced severe aggression and suicidal thoughts (see sections "Dosage and administration" and "Special precautions").

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

In case of adverse effects or questions regarding the safety of the medicinal product, please contact the pharmacovigilance department of LLC "ASINO UKRAINE" at:

Vatslava Havela Boulevard, 8, Kyiv, 03124, Tel./Fax: +38 044 281 2333.

Shelf life. 3 years.

Storage conditions. Store in a place inaccessible to children, at a temperature not exceeding 25 °C.

Packaging. 14 tablets in a blister; 2 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Dexcel Pharma Technologies Ltd. /
Dexcel Pharma Technologies Ltd.

Manufacturer's address and place of business.

10 HaKidma St., Yokne’am, 2069200, Israel /
10 HaKidma St., Yokne’am, 2069200, Israel