Venlafaxine-zn

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VENLAFAXIN-ZN (VENLAFAXIN-ZN)

Composition:

Active substance: venlafaxine;

One tablet contains venlafaxine hydrochloride equivalent to 37.5 mg or 75 mg of venlafaxine;

Excipients: Celactose 80 (a mixture of monohydrate lactose and powdered cellulose (75:25)), sodium starch glycolate (type A), microcrystalline cellulose, magnesium stearate, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white or almost white, round cylindrical tablets with flat surfaces, bevelled edges, 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 associated with the potentiation of neurotransmitter activity in the central nervous system (CNS). Venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV) are potent, selective inhibitors of serotonin (SSRI) and norepinephrine reuptake, and weak inhibitors of dopamine reuptake. After single or repeated administration, venlafaxine and its active metabolite reduce β-adrenergic responses. They have similar effects on neurotransmitter reuptake and receptor binding.

Venlafaxine has virtually no affinity for muscarinic, cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Pharmacological activity at these receptors may be related to various adverse reactions observed with other antidepressants, namely anticholinergic, sedative, and cardiovascular side effects.

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 mean 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 reached within 3 days of repeated administration. Venlafaxine and ODV exhibit linear kinetics over the dose range of 75–450 mg/day.

Absorption

After administration of a single dose of immediate-release venlafaxine, approximately 92% of the drug is absorbed. Absolute bioavailability is 40–45% due to presystemic metabolism. Following 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.

Metabolism

Venlafaxine undergoes extensive hepatic metabolism. In vitro and in vivo studies have shown that venlafaxine is biotransformed into its active metabolite ODV by the CYP2D6 enzyme system. In vitro and in vivo studies have also shown that venlafaxine is metabolized by CYP3A4 into the less active metabolite N-desmethylvenlafaxine. In vitro and in vivo studies indicate 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 administered 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 different dosing regimens are 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 is reduced by approximately 56%. Dose adjustment is required for patients with severe renal impairment and for those 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 excipients of the medicinal product.

Concomitant use with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of developing serotonin syndrome, which is characterized by symptoms such as agitation, tremor, and hyperthermia. Treatment with venlafaxine should not be initiated within at least 14 days following discontinuation of irreversible MAOIs.

After discontinuation of venlafaxine, therapy with irreversible MAOIs should not be started earlier than 7 days later.

Severe arterial hypertension (blood pressure ≥180/115 mmHg prior to initiation of therapy).

Closed-angle glaucoma.

Urinary retention due to obstructed urinary outflow (e.g., prostate gland disorders).

Severe hepatic or renal insufficiency.

Interaction with other medicinal products and other forms of interaction

Monoamine oxidase inhibitors (MAOIs)

Irreversible non-selective MAOIs

Venlafaxine must not be used in combination with irreversible non-selective MAOIs. Venlafaxine treatment may be initiated no sooner than 14 days after discontinuation of irreversible non-selective MAOIs. After stopping venlafaxine, at least 7 days should elapse before starting therapy with irreversible non-selective MAOIs.

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 not recommended. Venlafaxine treatment may be initiated no sooner than 14 days after discontinuation of reversible MAOIs. After stopping venlafaxine, at least 7 days should elapse before starting therapy with reversible MAOIs.

Reversible non-selective MAOIs (linezolid)

The antibiotic linezolid is a weak, reversible, non-selective MAO inhibitor and should not be administered to patients receiving venlafaxine.

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

Serotonin syndrome, a potentially life-threatening condition, may occur during treatment with venlafaxine, particularly when used concomitantly with medicinal products that affect the serotonergic neurotransmitter system (including triptans, SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), lithium, sibutramine, tramadol, St. John’s wort (Hypericum perforatum)), with medicinal products that interfere with serotonin metabolism (including MAO inhibitors), or with serotonin precursors (e.g., tryptophan supplements).

If concomitant use of venlafaxine with SSRIs, SNRIs, or serotonin receptor agonists (e.g., tryptophan) is clinically warranted, careful patient monitoring is recommended, especially during initiation of treatment and dose escalation. Concomitant use of venlafaxine with serotonin precursors (such as 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 is advised when using venlafaxine concomitantly with other CNS-acting agents.

Alcohol

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

Effects of other medicinal products on venlafaxine

Ketoconazole (CYP3A4 inhibitor)

Pharmacokinetic studies of ketoconazole in both poor (PM) and extensive metabolizers (EM) of CYP2D6 showed increased AUC of venlafaxine (by 70% and 21% in PM and EM CYP2D6, respectively) and O-desmethylvenlafaxine (ODV) (by 33% and 23% in PM and EM CYP2D6, respectively) following ketoconazole administration. Concomitant use of CYP3A4 inhibitors (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.

Effects of venlafaxine on other medicinal products

Lithium

Serotonin syndrome may develop when venlafaxine is used concomitantly with 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

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 to 4.5 times was observed when venlafaxine was administered at doses of 75–150 mg/day. Imipramine does not affect the pharmacokinetics of venlafaxine or ODV. The clinical significance of this interaction is unknown. Caution is advised when using venlafaxine concomitantly with imipramine.

Haloperidol

In a pharmacokinetic study of haloperidol, a 42% decrease in renal clearance, an 88% increase in maximum plasma concentration, and a 70% increase in AUC of haloperidol were observed, without changes in its elimination half-life. This should be taken into account when using haloperidol concomitantly with venlafaxine. The clinical significance of this interaction is unknown.

Risperidone

Venlafaxine increases the AUC of risperidone by 50%, but does not significantly alter the pharmacokinetics of the 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 an approximately 30–40% increase in plasma concentration of metoprolol, without affecting plasma levels of its active metabolite α-hydroxymetoprolol. The clinical significance of this effect in patients with arterial 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

When venlafaxine is administered concomitantly with indinavir, the AUC of indinavir decreases by 28% and Cmax by 36%. The pharmacokinetic parameters of venlafaxine and its metabolite ODV are not affected. The clinical significance of this interaction is unknown.

Special precautions for use.

Overdose

Patients should be advised to avoid 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 been reported primarily in combination with alcohol and/or other medicinal products, including cases with fatal outcome (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").

Suicidal risk / 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 lack of improvement may occur during the first few weeks or for a longer period after initiation of treatment, patients require close monitoring until their condition improves. Clinical experience with antidepressant therapy indicates that the risk of suicide may increase during 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 with those suffering from major depressive disorder.

Patients with a history of suicidal behaviour, as well as patients with pronounced suicidal ideation prior to treatment initiation, are at higher risk of developing suicidal thoughts or suicide attempts and should be closely monitored during treatment.

Careful monitoring of patients, especially those belonging to high-risk groups, should accompany pharmacological treatment, particularly in the early stages of therapy and after dose adjustments. Patients and caregivers should be alerted to the need to detect any clinical worsening, emergence of suicidal thoughts or behaviours, or unusual changes in behaviour, and to seek immediate medical attention if such symptoms occur.

Mania / hypomania

Patients with mood disorders receiving antidepressants, including venlafaxine, may develop mania or hypomania. As with other antidepressants, venlafaxine should be prescribed cautiously to patients with a family history of bipolar disorder.

Aggression

Aggression may develop in patients receiving antidepressants, including venlafaxine. Cases have been reported at the beginning of treatment, after dose changes, and upon discontinuation of treatment. As with other antidepressants, venlafaxine should be prescribed cautiously to 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. Dose increases may be harmful to patients who develop such symptoms.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome—a potentially life-threatening condition—may occur during treatment with venlafaxine, as well as reactions resembling neuroleptic malignant syndrome (NMS), particularly when used concomitantly with other serotonergic agents (including SSRIs, SNRIs, and triptans) and drugs that interfere with serotonin metabolism, such as MAO inhibitors, or with neuroleptics or other dopamine antagonists.

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

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

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

Narrow-angle glaucoma

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

Blood pressure

Venlafaxine may increase blood pressure in a dose-dependent manner. Cases of severe hypertension requiring immediate treatment have been reported.

Blood pressure parameters should be carefully monitored in all patients. Pre-existing hypertension should be controlled before initiating venlafaxine therapy. Blood pressure should be measured periodically—at the beginning of treatment and after dose increases. Caution is advised in patients whose underlying condition may be exacerbated by increased blood pressure, such as patients with cardiac dysfunction.

Heart rate

Heart rate may increase, particularly with high-dose administration. 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. Cases of fatal cardiac arrhythmia have been reported.

The benefit-risk ratio should be carefully considered before prescribing venlafaxine to patients at high risk of severe cardiac arrhythmia.

Seizures

Seizures may occur during treatment with venlafaxine. Venlafaxine should be used cautiously in patients with a history of seizures. Such patients should be closely monitored. Treatment with the drug should be discontinued if seizures occur.

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 otherwise prone to hypovolaemia are at increased risk of developing hyponatraemia.

Abnormal bleeding

Medicinal products that inhibit serotonin reuptake may impair platelet function. The risk of skin bleeding and mucosal bleeding, including gastrointestinal bleeding, may be increased in patients taking venlafaxine. As with other serotonin reuptake inhibitors, venlafaxine should be used cautiously in patients with a predisposition to bleeding, including those taking anticoagulants or platelet function inhibitors.

SSRIs/SNRIs increase the risk of postpartum haemorrhage (see sections "Use in pregnancy or lactation" and "Side effects").

Serum cholesterol

Serum cholesterol levels should be monitored during long-term treatment with venlafaxine.

Concomitant use with weight-reduction agents

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

Discontinuation of treatment

Withdrawal symptoms usually occur upon discontinuation of treatment, particularly after abrupt cessation.

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, and headache are the most commonly reported withdrawal reactions. These symptoms are generally mild or moderate; however, in some patients, they may be severe. Symptoms usually appear within the first few days after discontinuation, although several cases have been reported in patients who accidentally missed a dose. These symptoms usually resolve without treatment within 2 weeks, although in some individuals 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.

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

Sexual dysfunction

SSRIs may cause symptoms of sexual dysfunction (see section "Side effects"). Cases of persistent sexual dysfunction, in which symptoms persisted despite discontinuation of SSRIs, have been reported.

Lactose

Venlafaxine-ZN 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 compounds

This medicinal product contains sodium starch glycolate (type A). Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or lactation.

Pregnancy

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

The use of this drug during pregnancy is contraindicated.

As with other serotonin reuptake inhibitors (SSRIs/SNRIs), newborns may experience withdrawal symptoms if venlafaxine was used shortly before delivery. In some newborns exposed to venlafaxine in late third trimester, complications occurred that required parenteral nutrition, assisted mechanical ventilation, and prolonged hospitalization. Such complications may occur immediately after birth.

Newborns may experience the following symptoms if the mother used SSRIs/SNRIs during late pregnancy: irritability, tremor, hypotonia, persistent crying, and difficulty breastfeeding or difficulty sleeping. These symptoms may occur due to serotonergic effects or drug exposure. In most cases, these complications occur immediately or within 24 hours after delivery.

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

Observational data indicate an increased (approximately twofold) risk of postpartum haemorrhage with the use of SSRIs/SNRIs during the last month of pregnancy (see sections "Special precautions for use" and "Side effects").

Lactation

Venlafaxine and its active metabolite ODV are excreted into breast milk. In the post-marketing period, irritability, crying, and sleep disturbances have been observed in infants who were breastfed. 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 venlafaxine should be made after weighing the benefits of breastfeeding for the child against the benefits of venlafaxine treatment for the mother.

Ability to affect reaction speed when driving vehicles or operating machinery.

Any therapy with psychotropic agents may impair cognitive or motor performance. Therefore, patients taking venlafaxine should exercise caution when driving vehicles or operating potentially hazardous machinery.

Dosage and Administration

The medication should be administered orally.

Venlafaxine immediate-release tablets should be taken with food, preferably at the same time each day.

Major Depressive Episodes

The recommended initial dose of venlafaxine (immediate-release tablets) is 75 mg/day, administered in two or three divided doses. Tablets should be taken with food. For patients in whom the initial dose of 75 mg/day is not effective, the dose may be increased up to a maximum of 375 mg/day. Dose increases should be made at intervals of at least 2 weeks. In more severe cases, dose increases may be made at shorter intervals, but not more frequently than every 4 days.

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

Treatment usually requires a prolonged duration, often several months or longer. Treatment efficacy should be regularly reassessed on an individual basis. Long-term treatment may also be appropriate for the prevention of relapse of major depressive episodes (MDE). In most cases, the recommended dose for relapse prevention is the same as that used during treatment of the acute depressive episode.

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

Use in Elderly Patients

Age alone does not necessitate dose adjustment. However, caution should be exercised when treating elderly patients (e.g., due to possible renal impairment and age-related changes in neurotransmitter sensitivity and receptor affinity). The lowest effective dose should be used, and patients should be closely monitored medically when dose increases are made.

Use in Patients with Hepatic Impairment

In patients with mild to moderate hepatic impairment, it is recommended to reduce the daily dose by 50%. However, due to inter-individual variability in clearance, dose adjustment should be individualized.

Data on the use of venlafaxine in patients with severe hepatic impairment are limited. Therefore, caution is advised, and the daily dose should be reduced by more than 50%. The potential benefits and risks should be carefully weighed before prescribing venlafaxine 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 (GFR) of 30–70 mL/min, caution is still advised. For patients on 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, individualized dose adjustment 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. If symptoms of intolerance 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.

Children

The efficacy and safety of venlafaxine in children (under 18 years of age) have not been established; therefore, the drug should not be used in this patient population.

Overdose

Symptoms: Tachycardia, altered level of consciousness (ranging from somnolence to coma), mydriasis, seizures, vomiting, electrocardiographic changes (QT interval prolongation, bundle branch block, QRS widening), ventricular tachycardia and bradycardia, hypotension, hypoglycemia, vertigo. There is a risk of fatal outcome. Reports of venlafaxine overdose have primarily involved concomitant use with alcohol and/or other medications, including cases with fatal outcomes. Severe poisoning may occur in adults after ingestion of approximately 3 grams of venlafaxine.

Treatment: Severe poisoning may require complex emergency management and monitoring. Therefore, in case of suspected venlafaxine overdose, immediate contact with a poison control specialist (e.g., toxicology unit) is recommended. General supportive and symptomatic therapy is advised, including cardiac rhythm and vital signs monitoring. If aspiration risk is present, induction of emesis is not recommended. If ingestion was recent and the patient is conscious, gastric lavage should be considered. Administration of activated charcoal may also reduce absorption of the active substance. The effectiveness of measures such as forced diuresis, dialysis, hemoperfusion, and exchange transfusion is unlikely. There is no specific antidote for venlafaxine.

Adverse Reactions

Blood and lymphatic system disorders: ecchymosis, gastrointestinal hemorrhage, mucosal bleeding, prolonged bleeding time, thrombocytopenia, persistent pathological changes in blood cell composition (including agranulocytosis, aplastic anemia, neutropenia, pancytopenia).

Immune system disorders: anaphylactic reactions, angioedema.

Endocrine system disorders: increased blood prolactin levels.

Metabolism and nutrition disorders: increased serum cholesterol levels, weight loss, weight gain, hyponatremia, syndrome of inappropriate antidiuretic hormone secretion (SIADH), elevated prolactin levels.

Psychiatric disorders: unusual dreams, decreased libido, insomnia, nervousness, sedation, confusion, depersonalization, apathy, hallucinations, anxiety agitation, manic reactions, delirium, suicidal thoughts and suicidal behavior*.

Nervous system disorders: headache, dizziness, muscle hypertonia, tremor, paresthesia, stupor, yawning, myoclonus, impaired balance and coordination, akathisia, seizures, neuroleptic malignant syndrome (NMS), serotonin syndrome, extrapyramidal reactions (including dystonia and dyskinesia), tardive dyskinesia, aggression, loss of consciousness.

Eye disorders: accommodation disorders, mydriasis, visual disturbances, closed-angle glaucoma.

Ear and labyrinth disorders: tinnitus, vertigo.

Cardiac disorders: palpitations, tachycardia, QT interval prolongation, ventricular flutter, ventricular tachycardia (including torsades de pointes), hypertension, vasodilation (mainly hot flushes), orthostatic hypotension, syncope, hypotension, palpitations, postural hypotension, ventricular fibrillation.

Respiratory system disorders: yawning, pulmonary eosinophilia.

Gastrointestinal disorders: nausea, dry mouth, decreased appetite (anorexia), constipation, vomiting, taste disturbances, bruxism, diarrhea, pancreatitis.

Hepatobiliary disorders: hepatitis, abnormal liver function tests.

Skin and subcutaneous tissue disorders: excessive sweating (including night sweats), rash, alopecia, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, pruritus, urticaria, photosensitivity reactions.

Musculoskeletal and connective tissue disorders: rhabdomyolysis.

Renal and urinary disorders: micturition disorders (mainly difficulty), polyuria, urinary retention, urinary incontinence.

Reproductive system and breast disorders: pathological ejaculation/orgasm in males, anorgasmia, erectile dysfunction (impotence), menstrual cycle disturbances associated with increased irregular bleeding (e.g., menorrhagia, metrorrhagia), pathological orgasm in females; postpartum hemorrhage**.

General disorders: asthenia (fatigue), malaise, chills.

* Cases of suicidal thoughts and suicidal behavior have been reported during venlafaxine therapy or immediately after discontinuation of therapy.

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

Discontinuation of venlafaxine treatment (especially abrupt) commonly leads to withdrawal syndrome. The most frequently observed adverse reactions following abrupt discontinuation of venlafaxine include dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), anxiety agitation or anxiety, nausea and/or vomiting, tremor, headache, and flu-like symptoms. These reactions are usually mild or moderate and resolve spontaneously, but in some patients they may be severe and/or prolonged. Therefore, it is recommended to discontinue venlafaxine treatment gradually by tapering the dose.

Shelf life. 2 years.

Storage conditions.

Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 10 tablets per blister. 3 or 5 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

Limited liability company "Kharkiv Pharmaceutical Enterprise "Zdorovya Narodu".

Manufacturer's address and place of business.

41 Kuilikivska Street, Kharkiv, Kharkiv Oblast, 61002, Ukraine.