Venlaxor

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VENLAXOR® (VENLAXOR)

Composition:

Active substance: venlafaxine;

1 tablet contains 37.5 mg or 75 mg of venlafaxine (as hydrochloride);

Excipients: calcium hydrogen phosphate, anhydrous lactose, sodium starch glycolate (type A), magnesium stearate, colloidal anhydrous silicon dioxide, iron oxide (E 172).

Pharmaceutical form. Tablets.

Main physicochemical characteristics: light pink, flat cylindrical tablets with dark pink specks, beveled edge and a score line on one side.

Pharmacotherapeutic group.

Antidepressants. ATC code N06A X16.

Pharmacological Properties

Pharmacodynamics

The mechanism of the antidepressant action of venlafaxine in humans is related to the potentiation of neurotransmitter activity in the central nervous system (CNS). Venlafаксine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent, selective inhibitors of serotonin (SSRI) and norepinephrine reuptake, and weak inhibitors of dopamine reuptake. Venlafaxine and its active metabolite reduce beta-adrenergic responses after single or multiple dosing. They have similar effects on neurotransmitter reuptake inhibition and receptor binding.

Venlafaxine has virtually no affinity for muscarinic, cholinergic, H1-histaminergic, or alpha1-adrenergic receptors in vitro. Pharmacological activity at these receptors may be associated with various adverse reactions observed also with other antidepressants, namely anticholinergic, sedative, and cardiovascular adverse reactions.

Venlafaxine does not inhibit monoamine oxidase (MAO) activity.

In vitro studies have shown that venlafaxine has no affinity for opioid or benzodiazepine receptors.

Pharmacokinetics

Venlafaxine is extensively metabolized during first-pass metabolism in the liver, forming the active metabolite ODV. The elimination half-life of venlafaxine is 5±2 hours, and that of ODV is 11±2 hours. Steady-state concentrations of venlafaxine and ODV are achieved within 3 days of multiple dosing. Venlafaxine and ODV exhibit linear kinetics over the dose range of 75–450 mg/day.

Absorption

After a single dose of immediate-release venlafaxine, approximately 92% of the drug is absorbed. 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. Food intake does not affect the bioavailability of venlafaxine or ODV.

Distribution

Plasma protein binding of venlafaxine and ODV is 27% and 30%, respectively. The volume of distribution of venlafaxine at steady state is 4.4±1.6 L/kg following intravenous administration.

Metabolism

Venlafaxine undergoes extensive hepatic metabolism. In vitro and in vivo studies have shown that venlafaxine is metabolized to its active metabolite ODV by the CYP2D6 enzyme system. These studies also demonstrated that venlafaxine is metabolized by CYP3A4 to the less active metabolite N-desmethylvenlafaxine, and that venlafaxine 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 dose is recovered in urine within 48 hours, either as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other inactive metabolites (27%). The mean steady-state clearance of venlafaxine and ODV is 1.3±0.6 L/h/kg and 0.4±0.2 L/h/kg, respectively.

Special Patient Populations

Age and Sex

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

Poor and Extensive CYP2D6 Metabolizers

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

Patients with 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 healthy volunteers. Total clearance of venlafaxine and ODV is reduced. There is a high degree of inter-subject variability. Data in patients with severe hepatic impairment are limited.

Patients with 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 healthy volunteers. For ODV, elimination half-life is prolonged by approximately 142% and clearance reduced by 56%. Dose adjustment is required for patients with severe renal impairment and for patients undergoing hemodialysis.

Clinical characteristics.

Indications.

• Treatment of major depressive episodes.
• Prevention of recurrence of major depressive episodes.

Contraindications.

• Hypersensitivity to venlafaxine or to any of the components of the medicinal product;
• concomitant therapy with any monoamine oxidase inhibitors (MAOIs) (reversible, irreversible, selective, or non-selective);
• patients at high risk of severe ventricular arrhythmia (e.g., with significant left ventricular dysfunction, NYHA functional class III–IV);
• severe arterial hypertension (blood pressure ≥180/115 mmHg prior to initiation of therapy);
• closed-angle glaucoma;
• severe hepatic and/or renal impairment;
• urinary retention due to impaired urinary outflow (e.g., prostate disease).

Interaction with other medicinal products and other types of interactions.

MAO inhibitors

Irreversible non-selective MAO inhibitors

Concomitant use of venlafaxine with irreversible non-selective MAO inhibitors is contraindicated. Venlafaxine therapy may be initiated no earlier than 14 days after discontinuation of irreversible non-selective MAO inhibitors. After discontinuation of venlafaxine, at least 7 days should elapse before starting therapy with irreversible non-selective MAO inhibitors.

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 earlier 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.

Reversible non-selective MAO inhibitors (linezolid)

Concomitant use of the antibiotic linezolid (a weak reversible non-selective MAO inhibitor) with venlafaxine is contraindicated.

Severe adverse reactions have been reported in patients who recently discontinued MAO inhibitor therapy and started treatment with venlafaxine, or who discontinued venlafaxine shortly before starting MAO inhibitors. These reactions included tremor, myoclonus, excessive sweating, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome (NMS), seizures, and fatal outcomes.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome may occur during treatment with venlafaxine, particularly when used concomitantly with medicinal products affecting the serotonergic neurotransmitter system (including triptans, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), amphetamines, lithium, sibutramine, St. John’s wort (Hypericum perforatum), fentanyl and its analogs, tramadol, dextromethorphan, tapentadol, meperidine, methadone, pentazocine), with medicinal products impairing serotonin metabolism (including MAO inhibitors, e.g., methylene blue), with serotonin precursors (e.g., tryptophan), or with antipsychotics or other dopamine antagonists.

Symptoms of serotonin syndrome include mental status changes, autonomic instability, neuromuscular disturbances, and/or gastrointestinal symptoms.

If concomitant use of venlafaxine with SSRIs, SNRIs, or serotonergic receptor agonists (e.g., tryptophan) is clinically warranted, close monitoring of patients is recommended, especially at the beginning of treatment and during dose increases. Concomitant use of venlafaxine with serotonin precursors (e.g., tryptophan) is not recommended.

CNS-acting agents

The risk of using venlafaxine in combination with other CNS-acting medicinal products has not been systematically studied. Therefore, caution should be exercised when using venlafaxine concomitantly with other CNS-acting medicinal products.

Alcohol

Patients should be advised not to consume alcohol due to its CNS effects and potential for worsening psychiatric conditions, as well as the possibility of adverse interactions with venlafaxine, including CNS depression.

Medicinal products that prolong the QT interval

When venlafaxine is used concomitantly with other medicinal products that prolong the QTc interval, the risk of QTc prolongation and/or ventricular arrhythmias (e.g., torsades de pointes) increases. Concomitant use of such medicinal products should be avoided.

These include:

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

This list is not exhaustive; therefore, concomitant use of medicinal products that significantly prolong the QT interval should be avoided.

Effect of other medicinal products on venlafaxine

Ketoconazole (CYP3A4 inhibitor)

A pharmacokinetic study of ketoconazole in poor (PM) and extensive (EM) metabolizers of CYP2D6 showed increased AUC of venlafaxine (70% and 21% in PM and EM CYP2D6, respectively) and O-desmethylvenlafaxine (ODV) (33% and 23% in PM and EM 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 ODV. Therefore, caution is advised when combining a CYP3A4 inhibitor with venlafaxine.

Effect of venlafaxine on other medicinal products

Lithium

Serotonin syndrome may occur during concomitant use of venlafaxine and lithium.

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 ODV. It is unknown whether there is a pharmacokinetic and/or pharmacodynamic interaction with other benzodiazepines.

Imipramine

Imipramine does not affect the pharmacokinetics of venlafaxine or ODV. Venlafaxine does 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 when venlafaxine was administered at doses of 75–150 mg/day. The clinical significance of this interaction is unknown. Caution is advised when using venlafaxine concomitantly with imipramine.

Haloperidol

In a pharmacokinetic study, haloperidol showed a 42% decrease in renal clearance, an 88% increase in maximum plasma concentration, and a 70% increase in AUC, without change in its elimination half-life. This should be considered when using haloperidol concomitantly with venlafaxine.

Risperidone

Venlafaxine increases the AUC of risperidone by 50%, but does not significantly alter the pharmacokinetics of active components (risperidone and 9-hydroxyrisperidone). The clinical significance of this interaction is unknown.

Metoprolol

Concomitant administration of venlafaxine and metoprolol in healthy volunteers in a pharmacokinetic study resulted in approximately a 30–40% increase in plasma concentration of metoprolol, without affecting plasma levels of its active metabolite, alpha-hydroxymetoprolol. The clinical significance of this effect in patients with hypertension is unknown. Metoprolol does not alter the pharmacokinetics of venlafaxine or its active metabolite ODV. Caution is advised when using venlafaxine concomitantly with metoprolol.

Indinavir

Concomitant use of venlafaxine with indinavir reduces the AUC of indinavir by 28% and Cmax by 36%. The pharmacokinetic parameters of venlafaxine and its metabolite ODV are not altered. The clinical significance of this interaction is unknown.

Warfarin

Venlafaxine may potentiate the anticoagulant effect of warfarin.

Cimetidine

At steady state, cimetidine inhibits the "first-pass" metabolism of venlafaxine but does not significantly affect the formation or elimination of ODV. However, drug interaction may be more pronounced in elderly patients and in patients with impaired liver function.

Medicinal products that inhibit CYP2D6

In vitro and in vivo studies have shown that venlafaxine is metabolized to the active metabolite ODV via CYP2D6. This isoenzyme, responsible for genetic polymorphism, is the main pathway for the metabolism of many antidepressants. Therefore, a potential drug interaction exists between venlafaxine and CYP2D6-inhibiting medicinal products. Drug interactions that reduce the conversion of venlafaxine to ODV may potentially increase serum concentrations of venlafaxine and reduce concentrations of its active metabolite. The pharmacokinetic profile of venlafaxine in patients receiving one CYP2D6 inhibitor at a time may not differ significantly from that in patients who are poor metabolizers of CYP2D6; therefore, dose adjustment is not required.

Medicinal products metabolized by cytochrome P450 isoenzymes

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 taking oral contraceptives concomitantly with venlafaxine. There is insufficient evidence that these pregnancies were due to a drug interaction with venlafaxine. Studies on interaction with hormonal agents have not been conducted.

Antihypertensive and antidiabetic agents

No clinically significant interactions between venlafaxine and antihypertensive or antidiabetic agents have been observed.

The potential benefit of combined therapy with venlafaxine and other antidepressants has not been evaluated.

The benefit of combining electroconvulsive therapy with venlafaxine treatment has not been assessed.

After discontinuation of venlafaxine treatment, increased clozapine levels were temporally associated with adverse effects, including seizures.

Venlafaxine is 27% protein-bound, while ODV is 30% protein-bound. Therefore, drug interactions due to protein binding of venlafaxine and its main metabolite are unlikely. Venlafaxine does not inhibit tolbutamide—a CYP1A2 substrate—in vitro, does not inhibit caffeine metabolism, does not inhibit CYP2C19 in vitro, does not inhibit CYP3A4 in vitro, and is a weak inhibitor of CYP2D6. Since venlafaxine elimination occurs via CYP2D6 and CYP3A4, concomitant use with strong inhibitors of these enzymes is not recommended.

Special precautions for use.

Overdose.

Patients should be advised not to consume alcohol due to its effects on the CNS and the potential for clinical worsening of psychiatric conditions, 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 primarily been observed in cases involving concomitant use with alcohol and/or other medicinal products, including cases with fatal outcomes (see section "Overdose").

Venlafaxine should be prescribed at the lowest effective dose with appropriate monitoring of the patient to minimize the risk of overdose (see section "Overdose").

Risk of suicide / suicidal thoughts or clinical worsening.

Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide attempts (suicidal behaviour). This risk persists until significant remission occurs. Since improvement may not occur during the first few weeks or for a prolonged period after initiation of treatment, patients require close monitoring until their condition improves. Clinical experience with antidepressant treatment indicates that the risk of suicide may increase in the early stages of recovery.

Other psychiatric disorders for which venlafaxine is prescribed may also be associated with an increased risk of suicidal behaviour. In addition, these disorders may be accompanied by major depressive disorder; therefore, the same safety precautions should be followed when treating patients with other psychiatric disorders as when treating patients with major depressive disorder.

Patients with a history of suicidal behaviour, as well as those exhibiting pronounced suicidal ideation prior to treatment initiation, are at higher risk of developing suicidal thoughts or attempts and should be closely monitored during treatment. In placebo-controlled clinical trials, a meta-analysis of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients under the age of 25.

Close monitoring of patients, particularly those at risk, is necessary during treatment with venlafaxine, especially in the early stages of treatment and after dose adjustments.

Patients (and caregivers) should be warned to monitor for clinical worsening, emergence of suicidal thoughts or behaviours, or unusual changes in behaviour, and to seek immediate medical attention if such symptoms occur.

Children.

Venlafaxine should not be used in the treatment of children and adolescents under 18 years of age. Signs of behaviour indicating suicidal tendencies (suicide attempts and suicidal thoughts), as well as aggression (primarily aggression, hostile behaviour, anger), were observed more frequently in clinical trials among children and adolescents receiving antidepressant therapy compared to those treated with placebo. If, due to clinical necessity, a decision is made to initiate this treatment, careful monitoring is required to detect early signs of suicidal behaviour. Furthermore, data on the long-term safety of the drug in children and adolescents, including its effects on growth, puberty, cognitive development, and behavioural development, are insufficient.

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 patients receiving antidepressants, including venlafaxine. Reports have occurred at the beginning of treatment, after dose adjustments, and upon discontinuation of treatment. As with other antidepressants, venlafaxine should be prescribed with caution in patients with a history of aggression.

Akathisia/psychomotor agitation

Treatment with venlafaxine may be associated with the development of akathisia, which is subjectively characterized by unpleasant or distressing restlessness and a compelling need to move frequently, accompanied by an inability to sit or stand still. This most commonly occurs during the first few weeks of treatment. For patients who develop such symptoms, dose escalation may be detrimental.

Serotonin syndrome

There is a risk of serotonin syndrome, a potentially life-threatening condition, during treatment with venlafaxine, particularly when used concomitantly with other drugs affecting the serotonergic neurotransmitter system (including triptans, SSRIs, SNRIs, amphetamines, lithium, sibutramine, St John’s wort (Hypericum perforatum), fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, pethidine, methadone, and pentazocine), with medicinal products that impair serotonin metabolism (such as MAO inhibitors, e.g., methylene blue), with serotonin precursors (e.g., tryptophan supplements), or with antipsychotics or other dopamine antagonists. Symptoms of serotonin syndrome may include changes in mental status (e.g., anxious agitation, hallucinations, coma), autonomic nervous system disturbances (e.g., tachycardia, unstable blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination), and/or gastrointestinal disturbances (e.g., nausea, vomiting, diarrhoea). Severe 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 use of venlafaxine with other agents that may affect serotonergic and/or dopaminergic neurotransmission is clinically justified, close monitoring of patients is recommended, particularly at the beginning of treatment and during dose escalation.

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

Neuroleptic malignant syndrome

Use with caution in patients taking neuroleptic agents due to the risk of developing neuroleptic malignant syndrome.

Angle-closure glaucoma

Cases of mydriasis have been reported with the use of venlafaxine. Therefore, careful monitoring is recommended for patients with elevated intraocular pressure or at risk of developing acute angle-closure glaucoma.

Arterial pressure

Venlafaxine may increase arterial pressure in a dose-dependent manner. In some cases during post-marketing use, marked increases in blood pressure have been observed, requiring emergency treatment. Blood pressure should be checked before initiating venlafaxine, and existing hypertension should be carefully controlled. Blood pressure should be measured periodically—initially at the start of treatment and after dose increases. Caution is advised in patients whose underlying condition could be exacerbated by increased arterial pressure, such as patients with cardiac impairment.

Heart rate

An increase in heart rate may occur, particularly with high doses of venlafaxine. Caution is advised in patients whose clinical status may be affected by changes in heart rate.

Cardiac disease and risk of arrhythmia

The use of venlafaxine has not been studied in patients who have recently experienced myocardial infarction or who have decompensated heart failure. Therefore, venlafaxine should be used with caution in such patients.

During post-marketing use, cases of QT interval prolongation, ventricular tachycardia of the torsades de pointes type, ventricular tachycardia, and fatal arrhythmias have been reported, particularly in cases of overdose or in patients with other risk factors for QT prolongation/ventricular tachycardia of the torsades de pointes type. The benefit-risk ratio should be carefully considered before initiating venlafaxine treatment in patients at high risk of serious cardiac arrhythmias or QT interval prolongation.

Seizures

Seizures may occur during venlafaxine therapy. Venlafaxine should be used with caution in patients with a history of seizures. Such patients should be closely monitored. If seizures occur, treatment should be discontinued.

Hyponatraemia

Hyponatraemia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) may develop during treatment with venlafaxine. This has most commonly been observed in patients with dehydration or reduced blood volume. Elderly patients, patients taking diuretics, and patients with reduced blood volume for other reasons are at higher risk of developing this complication.

Abnormal bleeding

Medicinal products that inhibit serotonin reuptake may lead to impaired platelet function. Bleeding associated with SSRIs and SNRIs ranges from ecchymoses, haematomas, epistaxis, and petechiae to gastrointestinal and life-threatening haemorrhages. The risk of bleeding may be increased in patients taking venlafaxine. As with other SSRIs, venlafaxine should be used cautiously in patients predisposed to bleeding, including those taking anticoagulants or platelet function inhibitors.

SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see sections "Use during pregnancy or breastfeeding" and "Undesirable effects").

Serum cholesterol

Clinically significant increases in serum cholesterol levels were observed in 5.3% of patients taking venlafaxine and in 0.0% of patients taking placebo during 3 months of placebo-controlled clinical trials. Serum cholesterol levels should be monitored during long-term treatment with venlafaxine.

Concomitant use with weight-loss agents

The safety and efficacy of using venlafaxine 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 reduction, either as monotherapy or in combination with other agents.

Sexual dysfunction

Serotonin and norepinephrine reuptake inhibitors (SNRIs) may cause sexual dysfunction. Reports of persistent sexual dysfunction despite discontinuation of SNRIs have been documented.

Discontinuation of treatment

It is well known that discontinuation effects occur with the use of antidepressants, and these effects may sometimes be prolonged and severe. Suicide/suicidal thoughts and aggression have been observed in patients during changes in the dosing regimen of venlafaxine, including during discontinuation. Therefore, patients should be carefully monitored during dose reduction or discontinuation.

Withdrawal symptoms usually occur upon discontinuation, particularly with abrupt cessation. In clinical trials, adverse reactions after discontinuation (during and after tapering) occurred in approximately 31% of patients receiving venlafaxine and in 17% of those receiving placebo.

The risk of developing withdrawal symptoms may depend on several factors, including duration of treatment, dose, and speed of dose reduction. 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 are the most commonly reported withdrawal reactions. These symptoms are generally mild or moderate; however, in some patients, they may be severe. Symptoms typically occur within the first few days after discontinuation, although several cases have been reported in patients who inadvertently missed a dose. These symptoms usually resolve without treatment within 2 weeks, although in some patients they may persist longer (2–3 months or more). Therefore, when discontinuing treatment, it is recommended to gradually reduce the dose of venlafaxine over several weeks or months, depending on the patient's needs. In some patients, discontinuation may take several months or longer.

Dry mouth

Dry mouth may occur during treatment with venlafaxine. This may increase the risk of dental caries, and patients should be reminded of the importance of dental hygiene.

Diabetes

In patients with diabetes mellitus, the use of SSRIs or venlafaxine may alter glycaemic control. Adjustment of insulin and/or oral antidiabetic agent doses may be necessary.

Drug–laboratory test interaction

False-positive screening test results for phencyclidine and amphetamines in urine have been reported in patients receiving venlafaxine due to lack of assay specificity. False-positive results are expected for several days after discontinuation of venlafaxine. Venlafaxine can be differentiated from phencyclidine and amphetamines by confirmatory testing, such as gas chromatography/mass spectrometry.

Lactose

Venlaxor® tablets contain lactose. This medicinal product should not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Sodium-containing compounds

This medicinal product contains sodium starch glycolate (type A). Caution should be exercised when administering to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy

The amount of data on the use of venlafaxine in pregnant women is insufficient.

Animal studies have shown reproductive toxicity. The potential risk to humans is unknown. Venlafaxine may be used during pregnancy only if the expected benefit outweighs the potential risks.

As with other serotonin reuptake inhibitors (SSRIs, SNRIs), withdrawal symptoms may occur in newborns if venlafaxine was used by the mother shortly before delivery. In some newborns exposed to venlafaxine during the third trimester, complications occurred that required tube feeding, mechanical ventilation, and prolonged hospitalization. Such complications may appear immediately after delivery.

Observational data indicate an increased risk (less than 2-fold) of postpartum haemorrhage following exposure to SSRIs/SNRIs within one month before delivery (see sections "Special precautions for use" and "Undesirable effects").

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 clinical studies on the association between PPHN and SNRIs have not been conducted, due to the similar mechanism of action (inhibition of serotonin reuptake), this potential risk with venlafaxine cannot be excluded.

When SSRIs/SNRIs are used by the mother in late pregnancy, the newborn may exhibit symptoms such as irritability, tremor, hypotonia, persistent crying, feeding difficulties, or sleep disturbances. These symptoms may be due to serotonergic effects or may represent withdrawal symptoms. In most cases, these complications occur immediately after delivery or develop within 24 hours.

Breastfeeding

Venlafaxine and its metabolite O-desmethylvenlafaxine (ODV) are excreted in breast milk. Post-marketing experience has reported irritability, agitation, and sleep disturbances in infants. Symptoms observed after discontinuation of venlafaxine are also observed after cessation of breastfeeding. A risk to breastfed infants cannot be excluded. Therefore, the decision to breastfeed or discontinue breastfeeding, or to continue or discontinue venlafaxine therapy, should be made by weighing the benefits of breastfeeding for the infant against the benefits of venlafaxine therapy for the mother.

Fertility

Reduced fertility was observed in a study where male and female rats were exposed to ODV. The significance of this finding in the human population is unknown.

Ability to affect reaction speed when driving or operating machinery.

Any psychotropic therapy may impair cognitive or motor performance. Given the CNS-related side effects, patients taking venlafaxine should ensure that their ability to concentrate and coordinate movements is not impaired.

Method of Administration and Dosage.

The drug should be taken orally during meals, preferably at the same time each day.

Major Depressive Episodes

The recommended initial dose of venlafaxine is 75 mg/day, administered in 2 or 3 divided doses. For patients in whom the initial dose of 75 mg/day is not effective, the dose may be increased up to the maximum dose of 375 mg/day. Dose increases should be made at intervals of 2 weeks or longer. In more severe cases, the dose may be increased at shorter intervals, but not less than every 4 days.

Due to the risk of dose-dependent adverse reactions, dose escalation should only be performed after clinical evaluation. The lowest effective dose should be maintained.

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

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

Use in Elderly Patients

Patient age does not require dose adjustment. However, caution should be exercised when treating elderly patients (e.g., due to possible renal impairment, age-related changes in sensitivity and affinity to neurotransmitters). In such cases, the lowest effective dose should be used, and patients should be closely monitored when the dose is increased.

Use in Patients with Hepatic Impairment

In patients with mild or moderate hepatic impairment, it is recommended to reduce the daily dose by 50%. 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 in treating such patients, and the daily dose should be reduced by more than 50%. The expected benefit and potential risk should be carefully weighed before prescribing the drug to patients with severe hepatic impairment.

Use in Patients with Renal Impairment

Although dose adjustment is not required in patients with a glomerular filtration rate of 30–70 mL/min, caution is still advised. In patients undergoing hemodialysis and in those with severe renal impairment (glomerular filtration rate < 30 mL/min), it is recommended to reduce the dose by 50%. Due to inter-individual variability in clearance in these patients, individualized dose titration is advisable.

Discontinuation Syndrome after Stopping Venlafaxine

Abrupt discontinuation of venlafaxine treatment should be avoided. Therefore, upon discontinuation, a gradual dose reduction over 1–2 weeks is recommended to minimize the risk of discontinuation syndrome. However, the duration and extent of dose tapering may depend on the dose, duration of therapy, and individual patient factors. In some patients, discontinuation may need to be very gradual over months or longer. If intolerance symptoms occur during dose reduction or after stopping treatment, consideration should be given to returning to the previously prescribed dose. The physician may then continue tapering the dose, but more slowly.

Children.

Venlafaxine is not recommended for 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 Warnings and Precautions for Use" and "Adverse Reactions").

Overdose.

In the post-marketing period, venlafaxine overdose has been observed predominantly in cases of concomitant use with alcohol and/or other medicinal products, including cases with fatal outcomes.

Symptoms: tachycardia, altered level of consciousness (ranging from drowsiness to coma), mydriasis, seizures, vomiting, ECG changes (QT interval prolongation, bundle branch block, QRS widening), ventricular tachycardia and bradycardia, hypotension, hypoglycemia, vertigo. A fatal outcome is possible. Severe poisoning symptoms may occur in adults after ingestion of approximately 3 grams of venlafaxine.

Published retrospective studies report that venlafaxine overdose may be associated with an increased risk of fatality compared to patients taking SSRIs, but lower than in those taking tricyclic antidepressants. Epidemiological studies have shown that patients receiving venlafaxine have more risk factors for suicide than those receiving SSRIs. It is not clear whether these findings of increased fatality risk are related to the toxicity of venlafaxine in overdose or to individual patient characteristics of those prescribed venlafaxine.

Treatment. Severe poisoning may require complex emergency management and monitoring. Therefore, in case of suspected venlafaxine overdose, immediate contact with a poisoning specialist (e.g., toxicology unit) is recommended.

General supportive and symptomatic therapy is recommended; cardiac rhythm and vital signs should be monitored. If there is a risk of aspiration, induction of emesis is not recommended. If the drug was recently ingested and the patient is conscious, gastric lavage should be performed. Administration of activated charcoal may also reduce absorption of the active substance. The effectiveness of measures such as forced diuresis, dialysis, hemoperfusion, and blood exchange transfusion is unlikely. There is no specific antidote for venlafaxine.

Adverse reactions.

Summary of safety profile

Adverse reactions reported in clinical trials as very common (> 1/10): nausea, dry mouth, headache, and increased sweating (including night sweats).

Table of adverse reactions

Adverse reactions are categorized by system organ class, frequency, and decreasing order of severity within each frequency category. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); not known (cannot be estimated from available data).

Body system	Very common	Common	Uncommon	Rare	Very rare	Frequency unknown
Blood and lymphatic system disorders				Agranulocytosis*, aplastic anemia*, pancytopenia*, neutropenia*	Thrombocytopenia*
Immune system disorders				Anaphylactic reaction*

Endocrine system disorders				Inappropriate antidiuretic hormone secretion*	Elevated blood prolactin level*
Metabolism and nutrition disorders		Decreased appetite		Hyponatremia*
Psychiatric disorders	Insomnia	Confusional state*, depersonalization*, abnormal dreams, restlessness, decreased libido, agitation*, anorgasmia	Mania, hypomania, hallucinations, derealization, abnormal orgasm, bruxism*, apathy	Delirium*		Suicidal ideation and suicidal behaviour*a, aggression*b
Nervous system disorders	Headache*v, dizziness, somnolence	Akathisia*, tremor, paraesthesia, dysgeusia	Syncope, myoclonus, balance disorder*, coordination disorder*, dyskinesia*	CNS*, serotonin syndrome*, seizures, dystonia*	Tardive dyskinesia*
Eye disorders		Vision disorders, accommodation disorder, including blurred vision, mydriasis		Angle-closure glaucoma*
Ear and labyrinth disorders		Tinnitus				Vertigo
Cardiac disorders		Tachycardia, palpitations*		Ventricular tachycardia of torsades de pointes type*, ventricular tachycardia*, ventricular fibrillation, QT interval prolongation on electrocardiogram*		Takotsubo cardiomyopathy (stress-induced cardiomyopathy)*
Vascular disorders		Arterial hypertension, flushing	Orthostatic hypotension, hypotension*
Respiratory, thoracic and mediastinal disorders		Dyspnoea*, yawning		Interstitial lung disease*, pulmonary eosinophilia*
Gastrointestinal disorders	Nausea, dry mouth, constipation	Diarrhoea*, vomiting	Gastrointestinal haemorrhage*	Pancreatitis*
Hepatobiliary disorders			Abnormal liver function tests*	Hepatitis*
Skin and subcutaneous tissue disorders	Hyperhidrosis* (including night sweats)*	Rash, pruritus*	Urticaria*, alopecia*, ecchymosis, angioneurotic oedema*, photosensitivity reaction	Stevens-Johnson syndrome*, toxic epidermal necrolysis*, erythema multiforme*
Musculoskeletal and connective tissue disorders		Hypertonia		Rhabdomyolysis*
Renal and urinary disorders		Urinary hesitation, urinary retention, pollakiuria*	Urinary incontinence
Reproductive system and breast disorders		Menorrhagia*, metrorrhagia*, erectile dysfunctionb, ejaculation disorderb				Postmenopausal bleedingg
General disorders and administration site conditions		Malaise, asthenia, chills*			Mucosal haemorrhage*
Investigations		Increased body weight, decreased body weight, increased blood cholesterol level			Increased bleeding time*

*Post-marketing experience.

a) Cases of suicidal ideation and suicidal behavior have been reported during treatment with venlafaxine or immediately after discontinuation of therapy.

b) See section "Special precautions"

c) In pooled clinical trials, the incidence of headache with venlafaxine was comparable to that in the placebo group.

d) This event has been reported for the therapeutic class of SSRIs/SNRIs (see sections "Special precautions" and "Use in pregnancy or lactation").

Discontinuation of treatment.

The risk of developing withdrawal symptoms may depend on several factors, including duration of treatment, dose, and rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and vivid dreams), agitation or anxiety, nausea and/or vomiting, tremor, headache, flu-like symptoms, visual disturbances, and hypertension are the most commonly reported withdrawal reactions. These symptoms are generally mild or moderate in severity; however, in some patients they may be severe. Therefore, it is recommended that venlafaxine dosage be gradually reduced over several weeks or months, depending on the individual patient's needs. However, in some patients, severe aggression and suicidal ideation have been reported during dose reduction or upon discontinuation (see sections "Dosage and administration" and "Special precautions").

Pediatric population.

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 in adults. As in adults, decreased appetite, weight loss, increased blood pressure, and increased serum cholesterol levels were observed.

In pediatric clinical trials, adverse reactions associated with suicidal ideation were observed. Increased hostility and, in cases of major depressive disorders, self-injury were reported.

Adverse reactions particularly observed in pediatric patients included abdominal pain, restlessness, dyspepsia, hemorrhage, epistaxis, and myalgia.

Shelf life. 5 years.

Do not use after the expiry date stated on the packaging.

Storage conditions. Store at temperatures not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

10 tablets in a blister; 3 blisters in a cardboard carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "Grindeks".

Manufacturer's address and place of business.

53, Krustpils Street, Riga, LV-1057, Latvia.

Marketing Authorization Holder.

JSC "Grindeks".

Address of the Marketing Authorization Holder and/or its representative.

53, Krustpils Street, Riga, LV-1057, Latvia.

Tel./Fax: +371 67083205 / +371 67083505.

E-mail: [email protected]