Velaxin

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

Composition:

Active substance: venlafaxine;

1 capsule contains 37.5 mg or 75 mg or 150 mg of venlafaxine (equivalent to 42.42 mg or 84.84 mg or 169.68 mg of venlafaxine hydrochloride);

Excipients: microcrystalline cellulose, sodium chloride, anhydrous colloidal silicon dioxide, ethylcellulose, talc, dimethicone, potassium chloride, copovidone, xanthan gum, iron oxide yellow (E 172);

Composition of gelatin capsule (37.5 mg): erythrosine (E 127), indigo carmine (E 132), titanium dioxide (E 171), iron oxide yellow (E 172), gelatin;

Composition of gelatin capsule (75 mg and 150 mg): iron oxide red (E 172), titanium dioxide (E 171), iron oxide yellow (E 172), gelatin.

Medicinal form: Prolonged-release capsules.

Main physicochemical characteristics:

37.5 mg capsules – hard gelatin capsules, size 3, self-sealing, with a light orange cap and a colorless, transparent body; no marking on the capsule; capsule surface is undamaged; mixture of ochre-yellow and white pellets; odorless or nearly odorless;

75 mg capsules – hard gelatin capsules, size 2, self-sealing, with an orange-brown cap and a colorless, transparent body; no marking on the capsule; capsule surface is undamaged; mixture of ochre-yellow and white pellets; odorless or nearly odorless;

150 mg capsules – hard gelatin capsules, size 0EL, self-sealing, with an orange-brown cap and a colorless, transparent body; no marking on the capsule; capsule surface is undamaged; mixture of ochre-yellow and white pellets; odorless or nearly odorless.

Pharmacotherapeutic group: Antidepressants. ATC code: N06AX16.

Pharmacological properties.

Pharmacodynamics.

The antidepressant effect of venlafaxine is associated with enhanced neurotransmitter activity in the central nervous system.

Venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV), are potent dual inhibitors of serotonin and norepinephrine reuptake; they also inhibit dopamine reuptake by neurons.

Venlafaxine and ODV reduce beta-adrenergic responses following single or multiple doses. They have similar effects on neurotransmitter reuptake. Venlafaxine does not inhibit monoamine oxidase (MAO) activity.

Venlafaxine has no affinity for opioid, benzodiazepine, phencyclidine, or N-methyl-D-aspartate (NMDA) receptors, and it does not affect norepinephrine release from brain tissues.

Pharmacokinetics.

Absorption

At least 92% of a single oral dose of venlafaxine is absorbed. Following administration of venlafaxine extended-release capsules, peak plasma concentrations of venlafaxine and ODV are reached at approximately 6.0 ± 1.5 and 8.8 ± 2.2 hours, respectively.

The absorption rate of venlafaxine from venlafaxine extended-release capsules is slower than its elimination rate. Thus, the apparent elimination half-life after administration of venlafaxine extended-release capsules (15 ± 6 hours) actually represents a half-absorption time, rather than the true elimination half-life (5 ± 2 hours) observed after immediate-release tablets.

Following administration of equivalent daily doses of venlafaxine as immediate-release tablets or extended-release capsules, the exposure to both venlafaxine and ODV is similar for the two formulations, while plasma concentration fluctuations are slightly lower after treatment with extended-release capsules. Therefore, venlafaxine extended-release capsules provide a slower absorption rate but a similar extent of absorption compared to immediate-release tablets.

Metabolism

Venlafaxine and its metabolites are primarily eliminated by the kidneys.

Approximately 87% of a venlafaxine dose is excreted in urine within 48 hours as unchanged venlafaxine, unconjugated ODV, conjugated ODV, or other minor metabolites. The elimination half-lives of venlafaxine and its active metabolite, O-desmethylvenlafaxine, are prolonged in patients with renal or hepatic impairment.

Administration of extended-release capsules with food does not affect the absorption of venlafaxine or subsequent formation of ODV.

Special patient groups.

Patient age and gender do not influence the pharmacokinetics of the drug.

In patients with hepatic cirrhosis, the elimination half-life of venlafaxine is prolonged by approximately 30%, and clearance is reduced by approximately 50%; the half-life of ODV is prolonged by approximately 60%, and clearance is reduced by approximately 30%.

In patients with renal impairment, the elimination half-life of venlafaxine after oral administration is prolonged by approximately 50%, and clearance is reduced by approximately 24% (in patients with impaired renal function and glomerular filtration rate of 10–70 mL/min). In patients undergoing dialysis, the elimination half-life of venlafaxine is prolonged by approximately 180%, and clearance is reduced by approximately 57%.

Similarly, the elimination half-life of ODV is prolonged by approximately 40%, despite unchanged clearance in patients with renal impairment (GFR 10–70 mL/min). In dialysis patients, the elimination half-life of ODV is prolonged by approximately 142%, and clearance is reduced by approximately 56%. Dose adjustment is required in these patients.

Clinical characteristics.

Indications.

• Treatment of major depressive episodes.
• Prevention of major depressive episodes.
• Generalized anxiety disorders (GAD).
• Social anxiety disorders (social phobia).

Contraindications.

Hypersensitivity to any component of the medicinal product.

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

Angle-closure glaucoma.

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

Severe hepatic or renal impairment.

Concomitant use with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serotonin syndrome, which may present with symptoms such as agitation, tremor, and hyperthermia.

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 treatment may be initiated no earlier 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 contraindicated. Venlafaxine treatment may be initiated no earlier than 14 days after discontinuation of reversible MAO inhibitors. After stopping 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 MAOI therapy and started treatment with venlafaxine, or who discontinued venlafaxine shortly before starting MAOI therapy. These reactions included tremor, myoclonus, excessive sweating, nausea, vomiting, flushing, dizziness, hyperthermia with symptoms resembling neuroleptic malignant syndrome (NMS), seizures, and fatal outcomes.

Serotonin syndrome

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), 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). Symptoms of serotonin syndrome include changes in mental status, autonomic lability, neuromuscular abnormalities, and/or gastrointestinal symptoms.

If concomitant use of venlafaxine with SSRIs, SNRIs, or serotonin receptor antagonists (tryptophan) is clinically warranted, close monitoring of patients is recommended, especially at the beginning of treatment and when increasing the dose. Concomitant use of venlafaxine with serotonin precursors (such as tryptophan) is not recommended.

Medicinal products affecting the nervous system

Given the known mechanism of action of venlafaxine and the risk of serotonin syndrome, caution is advised when using venlafaxine concomitantly with medicinal products that may affect serotonergic neurotransmission (e.g., tricyclics, selective serotonin reuptake inhibitors, or lithium preparations).

The risk of concomitant use of venlafaxine with other medicinal products affecting the central nervous system (including those mentioned above) has not been systematically evaluated. Therefore, caution is recommended when co-prescribing venlafaxine with other similar agents.

Indinavir

When venlafaxine was administered concomitantly with indinavir, a reduction in AUC and Cmax of indinavir by 28% and 36%, respectively, was observed. However, indinavir did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine.

Warfarin

In patients receiving warfarin, initiation of venlafaxine treatment may potentiate the anticoagulant effect, resulting in prolonged prothrombin time.

Diazepam

Venlafaxine did not affect the pharmacokinetic and pharmacodynamic profile of diazepam and its metabolite desmethyldiazepam. The use of venlafaxine did not influence the psychomotor and psychometric effects of diazepam.

Haloperidol

In a pharmacokinetic study of haloperidol, a 42% reduction 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.

Imipramine

Imipramine does not affect the pharmacokinetics of venlafaxine and ODV. Venlafaxine does not affect the pharmacokinetics of imipramine and 2-OH-imipramine. A dose-dependent increase in AUC of 2-OH-desimipramine 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.

Cimetidine

At steady state, cimetidine inhibited the "first-pass" metabolism of venlafaxine but did not significantly affect the formation and elimination of O-desmethylvenlafaxine, which was present in systemic circulation in much higher amounts. Thus, dose adjustment does not appear necessary when cimetidine and venlafaxine are administered concomitantly in healthy adults. However, the drug interaction in elderly patients or those with impaired hepatic function receiving concomitant treatment with venlafaxine and cimetidine is unknown. Such patients require clinical monitoring.

Ethanol

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

Risperidone

When these agents are used concomitantly (despite an increase in risperidone AUC), the pharmacokinetics of the sum of active moieties (risperidone and its active metabolite) are not significantly altered.

Lithium preparations

Venlafaxine did not affect the pharmacokinetic characteristics of lithium preparations.

Medicinal products inhibiting CYP2D6

The isoenzyme CYP2D6, which exhibits genetic polymorphism, is involved in the metabolism of many antidepressants and transforms venlafaxine into its main active metabolite ODV. Therefore, a potential drug interaction exists between venlafaxine and CYP2D6 inhibitor drugs.

Drug interactions that reduce the conversion of venlafaxine to ODV (see section above on imipramine) may potentially increase plasma concentrations of venlafaxine and decrease concentrations of its active metabolite.

The pharmacokinetic profile of venlafaxine in subjects receiving one CYP2D6 inhibitor at the same time may not differ significantly from that in individuals with poor CYP2D6 metabolizer status (see section on metabolism). Therefore, dose adjustment is not required.

Medicinal products metabolized by cytochrome P450 isoenzymes

Venlafaxine does not inhibit the metabolism of diazepam, which is partially metabolized by CYP2C19.

Venlafaxine is a relatively weak inhibitor of CYP2D6.

Venlafaxine is protein-bound by 27%, while ODV is protein-bound by 30%. Therefore, drug interactions due to protein binding of venlafaxine and its main metabolite are unlikely.

Ketoconazole (CYP3A4 inhibitor)

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

Antihypertensive and antidiabetic agents

No clinically significant interactions between venlafaxine and antihypertensive agents (including β-blockers, angiotensin-converting enzyme (ACE) inhibitors, and diuretics) or antidiabetic agents have been identified.

The potential benefit of combination therapy with venlafaxine and another antidepressant has not yet been evaluated.

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

In such cases, an increase in clozapine levels, temporally associated with adverse effects including seizures, has been reported after discontinuation of venlafaxine treatment.

Medicinal products that prolong the QT interval

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

These include:

• Class 1a and III antiarrhythmic agents (e.g., quinidine, amiodarone, sotalol, dofetilide)
• Certain antipsychotic agents (e.g., thioridazine)
• Certain macrolides (e.g., erythromycin)
• Certain antihistamines
• Certain quinolone antibiotics (e.g., moxifloxacin).

The list above is not exhaustive. Concomitant use of other medicinal products that significantly prolong the QT interval should be avoided.

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 concentrations of its active metabolite α-hydroxymetoprolol. The clinical significance of this finding in patients with arterial hypertension is unknown. Metoprolol does not alter the pharmacokinetics of venlafaxine and its active metabolite ODV. Caution is advised when using venlafaxine and metoprolol concomitantly.

Special precautions for use.

In some cases, particularly in elderly patients, arterial hypotension may develop at the beginning of treatment. Blood pressure should be corrected before initiating venlafaxine therapy. Cases of increased heart rate have been reported, especially when high doses of venlafaxine are prescribed.

Venlafaxine may cause mydriasis. Therefore, close monitoring of patients with elevated intraocular pressure or closed-angle glaucoma is recommended.

In some patients with depression receiving antidepressants (including venlafaxine), activation of mania or hypomania may occur. Venlafaxine should be prescribed with caution to patients with a history of mania.

Treatment with venlafaxine may cause seizures; therefore, it should be used cautiously in patients with a history of seizures. If a seizure occurs in any patient, venlafaxine therapy should be discontinued.

Exanthema developed in 3% of patients receiving venlafaxine. Patients should be informed about the necessity to report to the physician any occurrence of exanthema, urticaria, or any other allergic reaction.

During clinical studies, no evidence of tolerance to the drug, drug-seeking behavior, dependence, or dose escalation over time was observed in patients receiving venlafaxine. Physicians should closely monitor patients for signs of drug abuse, particularly in those with a history of such symptoms.

In patients with moderate to severe renal impairment or hepatic cirrhosis, clearance of venlafaxine and its active metabolite is reduced, and elimination half-life is prolonged. Therefore, dose reduction may be required in such patients. As with other antidepressants, venlafaxine should be prescribed with caution in these patients. Renal and hepatic function should be assessed before initiating treatment.

Hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been observed during venlafaxine treatment, usually in patients with reduced circulating blood volume or in dehydrated patients, including elderly patients and those receiving diuretics. Precautionary measures should be taken in such patients.

Abnormal bleeding.

Medicinal products that inhibit serotonin reuptake may impair platelet function. The risk of bleeding at skin or mucous membrane sites, including gastrointestinal bleeding, may be increased in patients taking venlafaxine. Venlafaxine should be used with caution in patients predisposed to bleeding, including those taking anticoagulants or platelet function inhibitors. SSRIs/SNRIs increase the risk of postpartum hemorrhage (see sections "Use in pregnancy or lactation" and "Adverse reactions").

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

The efficacy and safety of venlafaxine in combination with weight-reducing agents have not been established. Concomitant administration of venlafaxine with weight-loss agents is not recommended. Monotherapy with venlafaxine or its combination with other weight-reducing agents is not indicated.

In a small number of patients treated with antidepressants, including venlafaxine, aggression may develop, requiring dose reduction or discontinuation of treatment. As with other antidepressants, venlafaxine should be prescribed with caution in patients with a history of aggression.

Overdose

Patients should be advised to avoid alcohol consumption due to its effects on the CNS and potential for worsening psychiatric status, as well as the risk of adverse interactions with venlafaxine, including CNS depression (see section "Interaction with other medicinal products and other types of interactions"). Cases of venlafaxine overdose, including fatal outcomes, have been reported, primarily when combined with alcohol and/or other medicinal products (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 worsening 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 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 behavior. Moreover, 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 behavior, as well as those with pronounced suicidal ideation before treatment initiation, are at higher risk of developing suicidal thoughts or attempts and should be closely monitored during treatment.

Close monitoring of patients, especially those at risk, is necessary during venlafaxine treatment, particularly in the early stages of therapy and after dose adjustments. Patients (and caregivers) should be warned to monitor for worsening clinical condition, emergence of suicidal thoughts or behaviors, and unusual changes in behavior, and to seek immediate medical attention if such symptoms occur.

Serotonin syndrome.

Treatment with venlafaxine, especially in combination with other agents affecting the serotonergic neurotransmitter system such as MAO inhibitors, may lead to serotonin syndrome—a potentially life-threatening condition.

Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination), and/or gastrointestinal disturbances (e.g., nausea, vomiting, diarrhea).

Akathisia/Psychomotor agitation.

Use of venlafaxine may be associated with akathisia, subjectively characterized by unpleasant or anxious restlessness and an urge to move frequently, accompanied by inability to sit or stand still. This most commonly occurs during the first few weeks of treatment. In patients developing such symptoms, dose escalation may be detrimental.

Dry mouth.

Dry mouth was observed in 10% of patients treated with venlafaxine. This may increase the risk of dental caries, and patients should be reminded of the importance of dental hygiene.

Angle-closure glaucoma

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

Blood pressure

Venlafaxine may increase blood pressure in a dose-dependent manner. Blood pressure parameters should be carefully monitored in all patients. Blood pressure should be normalized before initiating venlafaxine therapy and measured periodically—initially at treatment onset and after dose increases. Caution is advised in patients whose underlying conditions could be exacerbated by elevated blood pressure, such as those with cardiac dysfunction. Postural hypotension may occur; therefore, patients, especially elderly ones, should be warned about possible dizziness and impaired motor coordination.

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

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.

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

Venlafaxine should be used cautiously in patients with cardiovascular disorders due to the risk of ventricular arrhythmia. PR and QTc interval changes may be observed on ECG.

Seizures

Seizures may occur during venlafaxine therapy. Venlafaxine should be used cautiously in patients with a history of seizures. Close monitoring is required in such patients. If seizures occur, treatment with the drug should be discontinued.

Serum cholesterol

Serum cholesterol levels should be measured during long-term venlafaxine therapy.

Mania/hypomania

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

Clinical studies have not demonstrated drug dependence, tolerance, or need for dose escalation in patients taking venlafaxine.

Aggression

Aggression may develop in patients receiving antidepressants, including venlafaxine. This has been reported at the beginning of treatment, after dose changes, and upon discontinuation. As with other antidepressants, venlafaxine should be prescribed cautiously in patients with a history of aggression.

Discontinuation of treatment

Withdrawal symptoms commonly occur upon discontinuation, particularly with abrupt cessation.

The risk of withdrawal symptoms may depend on several factors, including duration of treatment, dose, and speed of dose reduction. Dizziness, sensory disturbances (including paresthesia), 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 stopping treatment, although several cases have been reported in patients who missed a dose. These symptoms usually resolve spontaneously 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 taper the dose of venlafaxine over several weeks or months, depending on the patient's needs.

Diabetes

Venlafaxine may alter glycemic control, which may necessitate adjustments in the dosage of antidiabetic agents and/or insulin.

Drug interaction laboratory tests

False-positive results in immunological urine screening for phencyclidine and amphetamines have been reported in patients taking venlafaxine. This may be due to lack of specificity in screening tests. False-positive results may persist for several days after discontinuation of venlafaxine. Confirmatory tests such as gas chromatography/mass spectrometry can differentiate venlafaxine from phencyclidine and amphetamine.

Use during pregnancy or breastfeeding.

Pregnancy

Studies on the use of venlafaxine in pregnant women have not been conducted. Reproductive toxicity studies in animals are insufficient. The potential risk to humans is unknown. 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"). Venlafaxine increases the risk of persistent pulmonary hypertension in newborns. Neonatal withdrawal syndrome may occur if venlafaxine is used by the mother before delivery. Venlafaxine is contraindicated in pregnant women.

Breastfeeding

Venlafaxine and its metabolite ODV pass into breast milk in significant amounts and may cause serious adverse reactions in the infant; therefore, venlafaxine is contraindicated during breastfeeding. If treatment is necessary, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery.

Patients should refrain from driving or operating machinery while taking this medication.

Method of Administration and Dosage

Swallow the capsule whole with water during a meal. Do not open, crush, chew, or place the capsule in water. Take once daily at approximately the same time each day, either in the morning or evening.

Depression.

The usual recommended dose of Velaxin® for the treatment of depression is 75 mg once daily. If necessary, after completing 2 weeks of treatment, the dose may be increased to 150 mg once daily to achieve further clinical improvement. If needed, the dose may be increased up to 225 mg/day in mild depression and up to 375 mg/day in severe depression. Any dose increase should be made in increments of 37.5–75 mg every 2 weeks or longer, but no more frequently than every 4 days.

Antidepressant effect at the 75 mg dose was observed after 2 weeks of treatment.

GAD and Social Phobia.

The usual recommended daily dose for the treatment of specific anxiety disorders, including social phobia, is 75 mg once daily. If necessary, after 2 weeks of treatment, the dose may be increased to 150 mg once daily to achieve clinical improvement. If needed, the dose may be further increased to 225 mg once daily. Dose increases should be made in increments of 75 mg every 2 weeks or longer, but no more frequently than every 4 days.

Anxiolytic effect at the 75 mg dose was observed after 1 week of treatment.

Maintenance Therapy/Relapse Prevention.

According to specialist recommendations, treatment of a depressive episode should last at least 6 months.

For maintenance therapy and prevention of relapses or new depressive episodes, the same doses that were effective during the acute episode should generally be used. The physician should regularly monitor the effectiveness of long-term Velaxin® therapy, at least once every 3 months.

Discontinuation of Venlafaxine.

When discontinuing venlafaxine treatment, gradual dose reduction is recommended: if venlafaxine has been used for more than 6 weeks, dose reduction should be carried out over at least 2 weeks.

The time required for gradual dose reduction depends on the dose, duration of treatment, and individual patient sensitivity.

Renal or Hepatic Impairment.

In renal impairment with glomerular filtration rate (GFR) > 30 mL/min, no dose adjustment is required; if GFR < 30 mL/min, the total daily dose of venlafaxine should be reduced by 50%. For patients undergoing hemodialysis, the total daily dose of venlafaxine should also be reduced by 50%. Administration of the drug should be delayed until after completion of the hemodialysis procedure.

In moderate hepatic impairment, the daily dose of venlafaxine should be reduced by 50%. In individual cases, dose reduction by more than 50% may be necessary.

Geriatric Patients.

Dose reduction in elderly patients should not be based solely on age.

Treatment should be conducted cautiously, as with all other medications. Particular caution should be exercised when increasing the dose.

Maintenance/Continuous/Long-Term Therapy.

According to generally accepted principles, treatment of the acute phase of major depression should be continued for several months or longer. In specific anxiety disorders, including social phobia, patients may suffer for prolonged periods and therefore may require long-term therapy.

Discontinuation of Venlafaxine.

When discontinuing venlafaxine treatment, gradual dose reduction is recommended: if venlafaxine has been used for more than 6 weeks, dose reduction should be carried out over at least 2 weeks.

The time required for gradual dose reduction depends on the dose and duration of treatment.

Children.

The safety and efficacy of the drug in children have not been established; therefore, the drug should not be used in this age group.

Overdose.

Signs of venlafaxine overdose (when used as monotherapy or in combination with alcohol and/or other drugs), including fatal cases, include: electrocardiogram changes (QT interval prolongation, bundle branch block, QRS complex widening), sinus and ventricular tachycardia, bradycardia, arterial hypotension, hypoglycemia, altered level of consciousness (from drowsiness to coma), seizures, mydriasis, vomiting, vertigo. These symptoms and abnormalities usually resolve spontaneously. Severe symptoms of poisoning may occur in adults after ingestion of approximately 3 g of venlafaxine.

Treatment of Overdose.

Severe poisoning may require complex emergency treatment and close monitoring of the patient. Therefore, in case of suspected venlafaxine overdose, immediate contact with a specialist experienced in managing poisoning (e.g., a toxicology unit) is recommended.

Treatment includes maintaining airway patency, adequate oxygenation, and appropriate ventilation.

Prolonged monitoring of heart rate and vital signs is recommended, along with general supportive and symptomatic therapy. Administration of activated charcoal may be considered. Induction of vomiting is not recommended due to the risk of aspiration.

Adverse Reactions

Blood and lymphatic system disorders:
ecchymosis (bleeding into the skin or mucous membranes), gastrointestinal hemorrhage, bleeding from mucous membranes, prolonged bleeding time, thrombocytopenia, blood dyscrasias (including agranulocytosis, aplastic anemia, neutropenia, pancytopenia).

Immune system disorders:
anaphylactic reactions.

Endocrine system disorders:
increased blood prolactin levels, syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders:
increased blood cholesterol levels, weight loss, weight gain, hyponatremia, decreased appetite.

Psychiatric disorders:
abnormal dreams, decreased libido, insomnia, nervousness, sedation, confusion, depersonalization, apathy, hallucinations, anxiety, manic reactions, delirium (deliriousness), suicidal thoughts and suicidal behavior (cases of suicidal ideation and suicidal behavior have been reported during treatment with venlafaxine or immediately after discontinuation of treatment), phobias, speech disorders (including dysarthria), mania, hypomania, bruxism, abnormal orgasms (in women), apathy.

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

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

Ear and labyrinth disorders:
tinnitus (ringing in the ears).

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

Respiratory, thoracic and mediastinal disorders:
yawning, pulmonary eosinophilia, dyspnea (shortness of breath).

Gastrointestinal disorders:
nausea, dry mouth, decreased appetite, anorexia, constipation, vomiting, taste disturbances, diarrhea, pancreatitis, dyspepsia, abdominal pain.

Hepatobiliary disorders:
hepatitis, abnormal liver function tests.

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

Musculoskeletal and connective tissue disorders:
rhabdomyolysis, arthralgia, myalgia, muscle spasms.

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

Pregnancy, puerperium and perinatal conditions:
postpartum hemorrhage* (frequency unknown).

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

Reproductive system and breast disorders:
pathological ejaculation/orgasm in men, anorgasmia, erectile dysfunction (impotence), menstrual cycle disturbances associated with increased irregular bleeding (e.g., menorrhagia, metrorrhagia), pathological orgasm in women, galactorrhea, decreased libido.

General disorders:
asthenia (increased fatigue), fever, increased body temperature.

Withdrawal syndrome:
Discontinuation of venlafaxine treatment (especially abrupt) usually leads to a withdrawal syndrome. The most commonly observed adverse reactions following abrupt discontinuation of venlafaxine include dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), anxiety or agitation, nausea and/or vomiting, tremor, headache, flu-like symptoms, diarrhea, palpitations, excessive sweating, emotional instability. The risk of developing withdrawal symptoms depends on several factors, including duration of treatment, dose, and rate of dose reduction. Symptoms typically occur within the first few days after discontinuation, but there have been reports of such symptoms in patients who accidentally missed a dose. These reactions are usually mild or moderate and resolve within 2 weeks, but in some patients they may be severe and/or prolonged (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.

Investigations:
increased blood cholesterol, weight gain, weight loss, electrocardiographic corrected QT prolongation, prolonged bleeding time, increased blood prolactin levels.

Reporting of suspected adverse reactions after marketing authorization is highly important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life:
5 years.

Storage conditions:
Store in the original packaging at a temperature not exceeding 30°C. Keep out of the reach of children.

Packaging:
10 capsules per blister, 3 blisters per cardboard box;
14 capsules per blister, 2 blisters per cardboard box.

Prescription status:
Prescription only.

Manufacturer:
Egis Pharmaceuticals Ltd., Hungary.

Manufacturer’s address:
65 Matyas kiraly Street, Kermend, 9900, Hungary.