Velaxin, 75 mg 28 pcs.

Depressed mood, Depression

• Depression (with or without symptoms of anxiety) in both outpatient and inpatient settings.
• Prevention of relapse of depression (with a positive therapeutic effect).

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Indications

treatment of depression, prevention of relapse;
treatment of generalized anxiety disorders;
treatment of social anxiety disorders;
treatment of panic disorders, accompanied or not by agoraphobia.

Pharmacological effect

Pharmacodynamic properties

Pharmacotherapeutic group: psychoanaleptics, antidepressants, other antidepressants.

ATX code: N06AX16

Mechanism of action, pharmacodynamic effects

Venlafaxine is an antidepressant. Based on its chemical structure, it cannot be classified into any known class of antidepressants (tricyclic, tetracyclic or others). It has two active enantiomeric racemic forms.

The antidepressant effect of venlafaxine is associated with increased neurotransmitter activity in the central nervous system. Venlafaxine and its main metabolite EDV are potent SNRIs and weakly inhibit neuronal dopamine reuptake. Venlafaxine and EDV are equally effective in inhibiting the reuptake of neurotransmitters. Venlafaxine and EDV reduce beta-adrenergic reactions.

Venlafaxine has no affinity for muscarinic, cholinergic, histamine (H1) and α1-adrenergic receptors in the brain. Venlafaxine does not inhibit MAO activity. Has no affinity for opiate, benzodiazepine, phencyclidine or M-methyl-d-aspartate (NMDA) receptors.

Pharmacokinetic properties

Absorption

With a single oral dose, at least 92% of the dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine ranges from 40% to 45%. After oral administration, Cmax of venlafaxine and TDV in blood plasma are reached after 2 and 3 hours, respectively. After administration of venlafaxine in the form of extended-release capsules, venlafaxine Cmax and TDV in blood plasma were achieved after 5.5 and 9 hours, respectively. When venlafaxine is taken in equal daily doses in the form of immediate-release tablets or extended-release capsules, extended-release capsules provide a slower rate of absorption, but the same extent of absorption as when taken in the form of immediate-release tablets.

Steady-state concentrations of venlafaxine and EDV are achieved within 3 days after initiation of multiple-dose oral therapy.
Food intake does not affect the bioavailability of venlafaxine and EDV.

Distribution

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

Biotransformation

Venlafaxine is extensively metabolized, primarily to the active metabolite EDV.
Venlafaxine is predominantly metabolized in the liver with the participation of the CYP2D6 isoenzyme to the formation of the main active metabolite EDV and with the participation of the CYP3A4 isoenzyme to a minor, less active metabolite, N-desmethylvenlafaxine. Results from in vivo studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6 and did not inhibit CYP1A2, CYP2C9 or CYP3A4.

Elimination

Venlafaxine and its metabolites are excreted primarily by the kidneys. Approximately 87% of an oral dose of venlafaxine is found in urine within 48 hours unchanged, as unconjugated ODV, conjugated ODV and other minor inactive metabolites. The mean ± standard deviation of plasma clearance of venlafaxine and EDV at steady state was 1.3 ± 0.6 L/h/kg and 0.4 ± 0.2 L/h/kg, respectively.
The average T1/2 of venlafaxine and EDV from blood plasma is 5 ± 2 and 11 ± 2 hours, respectively

Linearity/nonlinearity

Venlafaxine and ODV show linear kinetics over the dose range from 75 to 450 mg. per day.
Characteristics of individual patient groups

Age and gender

The gender and age of patients do not have a significant effect on the pharmacokinetics of venlafaxine and EDV.
Patients with fast/slow metabolism of the CYP2D6 isoenzyme
Plasma concentrations of venlafaxine are higher in slow metabolizers of the CYP2D6 isoenzyme than in rapid metabolizers. Because the total exposure (AUC) of venlafaxine and EFA is similar in poor and extensive metabolizers, there is no need for different venlafaxine dosing regimens in the two groups.

Liver failure

In patients classified as Class A (mild hepatic impairment) and Class B (moderate hepatic impairment) according to the Child-Pugh classification, T1/2 of venlafaxine and EDV were longer than those in healthy individuals. The clearance of venlafaxine and EDV after oral administration was reduced. A significant degree of interindividual variability was noted. Limited data are available in patients with severe hepatic impairment.

Kidney failure

In patients on dialysis, the T½ of venlafaxine was prolonged by approximately 180% and its clearance was reduced by approximately 57%, compared with healthy subjects, while the T½ of ODV was prolonged by approximately 142% and its clearance was reduced by approximately 56%. Dose adjustment is necessary in patients with severe renal impairment and in patients requiring hemodialysis (see section 4.2).

Special instructions

With caution

Recent myocardial infarction (MI), unstable angina, heart failure (HF), coronary artery disease, changes in the electrocardiogram (ECG), including prolongation of the QT interval, electrolyte imbalance, arterial hypertension (HTN), tachycardia, history of seizures, increased intraocular pressure, angle-closure glaucoma, history of manic states, predisposition to bleeding from the skin and mucous membranes, initially reduced body weight.

Special instructions

Suicide/suicidal ideation or clinical worsening

The risk of suicide attempts should be kept in mind when treating patients with depression.

Depression is associated with an increased risk of suicidal ideation, self-harm, and suicide (suicidal acts). This risk persists until complete remission. There may be no improvement in the first few weeks after starting treatment, and patients should be closely monitored until such improvement occurs. Clinical experience shows that in the early stages of recovery the risk of suicide often increases.
Other mental disorders for which the use of venlafaxine is indicated may also be associated with an increased risk of suicidal behavior and manifestations. In addition, these conditions can occur against the background of major depressive disorder. Therefore, the same precautions should be taken when treating patients with other mental disorders as when treating major depressive disorder.

Patients with a history of suicide-related events or patients with severe suicidal tendencies before treatment are at higher risk of developing suicidal thoughts or suicide attempts and therefore require careful monitoring during treatment with venlafaxine. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with mental disorders found an increased risk of suicidal behavior with antidepressants compared with placebo in patients younger than 25 years.

Patients receiving treatment with venlafaxine, especially those at high risk, should be closely monitored, preferably at the start of treatment or after a dosage change. Patients (and their caregivers) should be cautioned to monitor for signs of clinical worsening, suicidal behavior, and unusual behavioral changes and to seek medical attention promptly upon the onset of such symptoms.

To reduce the risk of overdose of Velaxin, treatment should be started with the lowest possible dose.

Children

Velaxin should not be used in children and adolescents under 18 years of age. Suicidal behavior (suicide attempts and suicidal ideation) and hostility (mainly aggression, oppositional behavior and irritation) were observed most frequently in clinical studies in children and adolescents receiving antidepressants compared with those receiving placebo. If a decision is made to prescribe the drug based on clinical indications, the patient should be closely monitored for the occurrence of suicidal symptoms. In addition, long-term safety data in children and adolescents regarding growth, maturation, cognitive and behavioral development are lacking.

Serotonin syndrome

As with other serotonergic drugs, the potentially life-threatening condition serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions may develop during treatment with venlafaxine, especially when other serotonergic drugs are used concomitantly (including selective serotonin reuptake inhibitors (SSRIs), selective serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, amphetamines, lithium preparations, sibutramine, St. John’s wort preparations, fentanyl and its analogues, buprenorphine, tramadol, dextromethorphan, tapentadol, pethidine, methadone and pentazocine) together with drugs that interfere with serotonin metabolism, for example, MAO inhibitors (including methylene blue), serotonin precursors (such as dietary supplements tryptophan) or antipsychotics and other dopamine antagonists.

Symptoms of serotonin syndrome include changes in mental status (agitation, hallucinations, coma), disorders of the autonomic nervous system (tachycardia, unstable blood pressure (BP), hyperthermia), neuromuscular disorders (hyperreflexia, incoordination) and/or gastrointestinal symptoms (nausea, vomiting, diarrhea).

If serotonin syndrome is suspected, dose reduction or discontinuation of treatment should be considered, depending on the severity of symptoms.

Serotonin syndrome in its most severe form may be similar to NMS, including pyrexia, muscle rigidity, and autonomic nervous system disturbances with potential for rapid changes in vital signs and changes in mental status.
If there are clinical indications for the simultaneous use of venlafaxine and other drugs that affect the serotonergic and/or dopaminergic neurotransmitter systems, the patient’s condition should be carefully monitored, especially at the beginning of treatment and when increasing the dose.

Concomitant use of venlafaxine with serotonin precursors (eg, tryptophan dietary supplements) is not recommended.
In a small number of patients with emotional lability, cases of mania/hypomania have been reported when using venlafaxine. Like other antidepressants, Velaxin should be used with caution in patients with a history of mania.

Seizures develop very rarely. Particular attention should be paid to patients with epilepsy or organic brain lesion syndrome. If necessary, supervision by a neurologist is required. Caution is also necessary when prescribing Velaxin and electroconvulsive therapy simultaneously.
In patients with liver cirrhosis and moderate to severe renal impairment, the renal clearance of venlafaxine and its active metabolites is reduced and the T1/2 of the drug from the blood plasma is prolonged. In such patients, Velaxin is used with caution in smaller doses or with extended intervals between doses.

During treatment with antidepressants, including SSRIs, hyponatremia may occasionally develop. Increased attention should be paid to elderly patients, patients taking diuretics, or those with signs of dehydration. Rare cases of hyponatremia have been reported when taking venlafaxine, especially in elderly patients; The patients’ condition improved after discontinuation of the drug.

In the following cases, regular monitoring of the patient’s condition is necessary:

• for urinary disorders (for example, prostate hypertrophy);
• for angle-closure glaucoma;
• with high or low blood pressure;
• for cardiovascular diseases, such as conduction disorders, angina pectoris and recent MI.

Angle-closure glaucoma

Mydriasis may occur during the use of venlafaxine. Close monitoring of patients with elevated intraocular pressure or patients at risk for developing angle-closure glaucoma is recommended.

Caution should be exercised when using multiple medications at the same time.

In some patients, venlafaxine therapy is accompanied by an increase in blood pressure, which may persist with long-term use of the drug. In patients with recent myocardial infarction or stroke who have diabetes mellitus, strict blood pressure monitoring is required during treatment with venlafaxine. Blood pressure monitoring is recommended in every patient taking venlafaxine. When diastolic blood pressure increases above 100 mm Hg. Art. You must stop taking venlafaxine.
Cases of QTc prolongation, torsade de pointes (TdP), torsade de pointes (TdP), and fatal cardiac arrhythmias have been reported during postmarketing experience with venlafaxine, particularly in overdose or in patients with other risk factors for QTc prolongation/TdP. The benefit-risk ratio should be assessed before prescribing venlafaxine to patients at high risk of severe cardiac arrhythmia or QTc prolongation.

When using venlafaxine, especially in high doses, the heart rate (HR) may increase. Caution should be exercised when using venlafaxine in patients with tachyarrhythmias.

If long-term therapy with venlafaxine is necessary, it is necessary to regularly monitor the concentration of cholesterol in the blood plasma. If hypercholesterolemia develops, the question of whether to continue therapy with Velaxin or to replace it with another antidepressant should be decided.
When treating the depressive phase of manic-depressive psychosis, a transition to a manic state may develop, which requires a rapid assessment of the patient’s condition and therapy.

Venlafaxine should be prescribed with caution to patients who have recently had a myocardial infarction and/or with unstable angina and hypertension.
The effectiveness and safety of venlafaxine when used concomitantly with drugs for weight loss, including phentermine, have not been studied. The simultaneous use of venlafaxine with such drugs is not recommended. Venlafaxine is not indicated for weight loss, either alone or in combination with other drugs.

Pathological bleeding

Drugs that inhibit serotonin uptake may lead to decreased platelet function. Bleeding events associated with SSRIs and SNRIs ranged from ecchymoses, hematomas, epistaxis, petechiae, gastrointestinal bleeding and life-threatening bleeding. The risk of bleeding may be increased in patients receiving venlafaxine. As with other serotonin reuptake inhibitors, venlafaxine should be used with caution in patients predisposed to bleeding, including patients receiving anticoagulants and platelet aggregation inhibitors.

SSRIs/SNRIs may increase the risk of postpartum hemorrhage.

Aggressive behavior

Aggressive behavior is possible in a small number of patients using antidepressants, including venlafaxine. This symptom was observed after the start of treatment, when changing the dosage and after stopping treatment.
Like other antidepressants, venlafaxine should be used with caution in patients with a history of aggressive behavior.

Withdrawal syndrome

It is well known that withdrawal symptoms occur when you stop taking antidepressants, and sometimes these symptoms can be long-lasting and severe. Suicidal behavior/suicidal ideation and aggression were observed in patients when the dosage regimen of venlafaxine was changed, as well as when it was discontinued. In this regard, patients should be under close medical supervision during dose reduction or during drug withdrawal (see subsections Suicide/suicidal ideation or clinical worsening and Aggressive behavior).

Withdrawal syndrome upon cessation of therapy occurs quite often, especially if treatment was interrupted suddenly. In clinical studies, adverse events observed after discontinuation of treatment (dose reduction and post-dose reduction) were observed in approximately 31% of patients receiving venlafaxine and in 17% of patients receiving placebo.

The risk of withdrawal symptoms may depend on several factors, including the duration of treatment and dosage of the drug, as well as the rate of dose reduction. Dizziness, sensory disturbances (including paresthesia), sleep disturbance (including insomnia and intense dreams), agitation or restlessness, nausea and/or vomiting, tremor, headache, blurred vision and hypertension are the most common adverse reactions. In general, these symptoms are mild to moderate, but in some patients they can be severe.

These symptoms usually develop within the first few days after stopping treatment, but in rare cases the development of similar symptoms has been reported in patients who accidentally missed a dose. In general, these symptoms go away on their own within 2 weeks, although in some patients they may persist for a longer period (2-3 months or longer). Therefore, if discontinuation of treatment is necessary, a gradual reduction in the dose of venlafaxine over several weeks or months is recommended, depending on the patient’s condition. In some patients, drug withdrawal may take several months or longer.

Akathisia/psychomotor agitation

The use of venlafaxine has been associated with the development of akathisia, characterized by subjectively unpleasant or distressing motor restlessness and the need to move while being unable to sit or stand quietly. This phenomenon most often develops during the first few weeks from the start of treatment. In patients with such symptoms, increasing the dose of Velaxin may lead to adverse effects.

Sexual dysfunction

SSRIs/SNRIs may cause symptoms of sexual dysfunction. Long-term sexual dysfunction has been reported, with symptoms persisting after discontinuation of SSRIs/SNRIs.

Dryness of the oral mucosa

Dry oral mucosa was observed in 10% of patients receiving venlafaxine. This may increase the risk of tooth decay, so patients should pay special attention to oral hygiene.

Diabetes mellitus

In patients with diabetes mellitus, the use of SSRIs or venlafaxine may lead to changes in glycemic control. Dosage adjustments of insulin and/or oral hypoglycemic medications may be required.

Effect of venlafaxine on laboratory test results

False-positive urine enzyme-linked immunosorbent assay results for phencyclidine and amphetamines have been reported in patients treated with venlafaxine. This effect is explained by the lack of specificity of laboratory data. False negative results may occur for several days after stopping use of venlafaxine. Control laboratory tests, such as gas chromatography or mass spectrometry, can distinguish venlafaxine from phencyclidine and amphetamine.

If skin rash, urticaria or other allergic reactions occur, you must stop treatment with Velaxin.
During treatment with Velaxin, it is recommended to refrain from drinking alcohol.

Sodium content

Each capsule of Velaxin 75 mg contains less than 1 mmol (23 mg) sodium, that is, practically no sodium.
Each capsule of Velaxin 150 mg contains 36 mg sodium, which corresponds to 1.8% of the WHO recommended daily sodium intake for adults (2 g).

Impact on the ability to drive vehicles and operate machinery

The drug affects psychophysical abilities. It may also reduce reactions in some patients. This should be taken into account when operating vehicles, operating machinery and performing tasks that require increased attention.

Active ingredient

Venlafaxine

Composition

Active ingredient: venlafaxine.

Pregnancy

Pregnancy

The safety of venlafaxine during pregnancy has not been proven, so use during pregnancy (or intended pregnancy) is only possible if the potential benefit to the mother outweighs the possible risk to the fetus. Women of childbearing age should be warned about this before starting treatment and should immediately consult a doctor if they become pregnant or plan to become pregnant during treatment with the drug.
Observational data indicate an increased risk (less than 2-fold) of postpartum hemorrhage after taking an SSRI/SNRI in the month before delivery.

Lactation

Venlafaxine and its metabolite (EFV) are excreted into breast milk. The safety of these substances for newborns has not been proven, so taking venlafaxine during breastfeeding is not recommended. If it is necessary to take the drug during lactation, the issue of stopping breastfeeding should be decided. If the mother’s treatment was completed shortly before delivery, the newborn may experience drug withdrawal symptoms.

Fertility

No data available.

Contraindications

• Hypersensitivity to venlafaxine or any of the excipients listed in section 6.1;
• Concomitant use of monoamine oxidase inhibitors (MAO) (see section 4.5.);
• Severe renal and/or liver dysfunction (GFR 18 seconds);
• Age under 18 years (safety and effectiveness for this age group have not been proven);
• Pregnancy or suspected pregnancy;
• Lactation period (insufficient data from controlled studies).

Side Effects

Security Profile Summary

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

Most of the adverse reactions listed below depend on the dose taken. With long-term treatment, the severity and frequency of most adverse reactions decreases, and there is no need to discontinue therapy.

Summary of Adverse Reactions

Adverse reactions are presented below as a distribution by system-organ class, indicating the frequency of their occurrence and in decreasing order of severity within each category.

The frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency unknown (cannot be estimated by available data).Blood and lymphatic system disorders:
rarely – thrombocytopenia;
very rarely – agranulocytosis, aplastic anemia, neutropenia, pancytopenia.
Endocrine disorders:
infrequently – syndrome of inappropriate secretion of antidiuretic hormone (SNA ADH);
very rarely – increased concentration of prolactin in the blood plasma.
Metabolic and nutritional disorders:
often – loss of appetite;
infrequently – hyponatremia.
Mental disorders:
very often – insomnia, agitation;
often – a confused state of consciousness, unusual dreams, anxiety, anorgasmia; infrequently – apathy, hallucinations, decreased libido, bruxism (involuntary grinding of teeth);
rarely – mania, hypomania;
very rarely – nonsense.
Nervous system disorders:
very often – headache, dizziness, drowsiness;
often – increased muscle tone, paresthesia, tremor;
infrequently – fainting, myoclonus, disturbance of taste;
rarely – ataxia, speech disorders, including dysarthria, manifestations resembling NMS, seizures, serotonin syndrome;
very rarely – extrapyramidal disorders, including dyskinesia, dystonia, tardive dyskinesia, psychomotor agitation/akathisia.
Visual disorders:
often – disturbance of accommodation, mydriasis, visual impairment.
Disorders of the hearing organ and labyrinth:
often – tinnitus.
Cardiac disorders:
often – rapid heartbeat;
infrequently – tachycardia;
very rarely – polymorphic ventricular tachycardia of the “pirouette” type, prolongation of the QT interval on the ECG, ventricular tachycardia, ventricular fibrillation.
Vascular disorders:
often – hypertension, dilation of blood vessels (“flushes” of blood);
infrequently – orthostatic hypotension.
Gastrointestinal disorders:
often – nausea, vomiting, dry mouth, constipation;
rarely – gastrointestinal bleeding;
very rarely – pancreatitis.
Disorders of the liver and biliary tract:
infrequently – a reversible increase in the activity of liver enzymes;
rarely – hepatitis.
Skin and subcutaneous tissue disorders:
often – sweating, skin rash, itching;
infrequently – hemorrhages into the skin (ecchymosis), photosensitivity reactions, angioedema, maculopapular rashes, urticaria;
rarely – alopecia, erythema multiforme, Stevens-Johnson syndrome.
Muscle, skeletal and connective tissue disorders:
often – arthralgia, myalgia;
infrequently – muscle spasm;
rarely – rhabdomyolysis.
Renal and urinary tract disorders:
infrequently – urinary retention.
Disorders of the reproductive system and mammary glands:
often – disorders of ejaculation, erection;
uncommon – menstrual irregularities, menorrhagia;
rarely – galactorrhea;
frequency unknown – postpartum hemorrhage*.
General disorders and reactions at the injection site:
often – weakness, fatigue, abdominal pain, fever, chills;
infrequently – hemorrhages in the mucous membranes.
Laboratory and instrumental data:
often – loss of body weight, increased concentration of cholesterol in the blood serum;
infrequently – disturbance of laboratory tests of liver function;
rarely – prolongation of bleeding time.
* This adverse reaction has been reported for drugs belonging to the SSRI/SNRI group.

Withdrawal syndrome

After abrupt withdrawal of venlafaxine or a reduction in its dose, the following may be observed: fatigue, drowsiness, headache, nausea, vomiting, anorexia, dry oral mucosa, dizziness, diarrhea, insomnia, restlessness, anxiety, disorientation, hypomania, paresthesia, sweating.

These withdrawal symptoms are usually mild and go away without treatment. Because these symptoms are likely to occur, it is very important to gradually reduce the dose of the drug (as with any antidepressant), especially after taking high doses. The duration of the period required to reduce the dose of Velaxin depends on the dose size, duration of therapy, as well as the individual sensitivity of the patient.

Children

The following side effects have been observed in children: abdominal pain, chest pain, tachycardia, food refusal, weight loss, constipation, nausea, ecchymosis, epistaxis, mydriasis, myalgia, dizziness, emotional lability, tremor, hostility and suicidal ideation.

Overdose

Symptoms

ECG changes (prolongation of the QT interval, bundle branch block, widening of the QRS complex), sinus or ventricular tachycardia, bradycardia, arterial hypotension, convulsive states, depression of consciousness (decreased level of wakefulness). Death has been reported in cases of overdose of venlafaxine when taken concomitantly with alcohol and/or other psychotropic drugs.

Treatment

Symptomatic. Specific antidotes are unknown. Continuous monitoring of vital functions (respiration and circulation) is recommended. Prescribing activated carbon to reduce drug absorption. Inducing vomiting is not recommended due to the risk of aspiration. Venlafaxine and EDV are not eliminated by dialysis.

Storage conditions

Store at a temperature not exceeding 30 °C.

Shelf life

5 years

Manufacturer

EGIS, Hungary