Venlafaxine, tablets 75 mg 30 pcs

Venlafaxine is an antidepressant that is not chemically related to any class of antidepressants (tricyclic, tetracyclic or other) and is a racemate of two active enantiomers.

Venlafaxine and its main metabolite, O-desmethylvenlafaxine (ODV), are potent serotonin and noradrenaline reuptake inhibitors (abbreviated: SSRIs or SSRIs) and weak dopamine reuptake inhibitors.

The mechanism of antidepressant action is associated with the ability of the drug to increase the activity of neurotransmitters in the transmission of nerve impulses in the central nervous system (CNS).

. Venlafaxine and EFAs are equally effective in affecting the reuptake of the above neurotransmitters, with no affinity (studied in vitro) for cholinergic (muscarinic), histamine (H1), alpha1-adrenergic, opioid and benzodiazepine receptors and no inhibition of monoamine oxidase (MAO) activity. Venlafaxine is inferior to selective serotonin reuptake inhibitors (SSRIs) in serotonin reuptake inhibition.

Indications

Depression. Prevention and treatment.

Active ingredient

Composition

One tablet contains:

the active ingredient:

Venlafaxine hydrochloride – 84.84 mg, which corresponds to 75 mg of venlafaxine;

auxiliary substances:

Microcrystalline cellulose – 134.62 mg,

Pregelatinized starch – 99.00 mg,

colloidal silica (aerosil) – 1.64 mg,

talcum powder – 6.60 mg,

magnesium stearate – 3.30 mg.

How to take, the dosage

Ingestion.

The drug Venlafaxine is taken with food, preferably at the same time, without chewing and with liquids. The recommended starting dose is 75 mg in two doses daily (37.5 mg twice daily). Depending on tolerability and effectiveness, the dose may be gradually increased to 150 mg/day. If necessary, the dose is increased to 225 mg/day. Dose increases of 75 mg/day can be made at intervals of 2 weeks or more, in case of clinical necessity, due to severity of symptoms it is possible to increase the dose in shorter terms, but not less than 4 days. Higher doses (up to a maximum daily dose of 375 mg/day in 2-3 doses) require inpatient monitoring of patients. After achieving the desired therapeutic effect, the daily dose can be gradually reduced to the minimum effective level.

Supportive therapy and relapse prevention:supportive treatment may continue for 6 months or longer. Minimal effective doses used in the treatment of the depressive episode are prescribed.

Renal failure:In mild renal failure (glomerular filtration rate (GFR) greater than 30 ml/min) dosing regimen adjustment is not required. In moderate renal failure (GFR 10-30 ml/min) the dose should be reduced by 25-50%. Due to the prolonged elimination half-life of venlafaxine and its active metabolite (AML), such patients should take the entire dose once daily. It is not recommended to use venlafaxine in severe renal insufficiency (GFR less than 10 ml/min), as there are no reliable data on such therapy. In hemodialysis the daily dose should be reduced by 50%, the drug should be taken after the end of hemodialysis session.

Hepatic failure:In mild hepatic failure (prothrombin time (PV) less than 14 sec) no dosage adjustment is required. In moderate hepatic insufficiency (PV of 14 to 18 sec), the daily dose should be reduced by 50% or more. It is not recommended to use venlafaxine in severe hepatic impairment, since there are no reliable data on such therapy.

Elderly patients:Elderly patients in the absence of any acute and chronic conditions do not require a change in dose, but (as with other medications) caution is required when treating elderly patients. Elderly patients should use the lowest effective dose. Patients should be under close medical supervision if the dose is increased.

Stopping the drug

Stopping the drug should be done gradually to minimize the risks associated with withdrawal. For a treatment course of 6 weeks or more, the period of gradual withdrawal should be at least 2 weeks, depending on the dose, length of therapy, and individual patient characteristics.

Interaction

Venlafaxine itself does not have increased binding to plasma proteins, practically does not increase the concentration of concomitantly taken drugs, which are characterized by high binding to plasma proteins. No clinically significant interaction with antihypertensive drugs (of many pharmacological groups, including beta-blockers, angiotensin-converting enzyme inhibitors and diuretics) and antidiabetic drugs was found. Caution should be exercised when concomitant administration with other drugs affecting the central nervous system (CNS), because combinations of venlafaxine with all such drugs have not been studied.

Cimetidine

The concomitant administration of cimetidine and venlafaxine has been shown to delay the metabolism of “first pass” venlafaxine. The clearance of venlafaxine during oral administration decreased by 43%, and the area under the pharmacokinetic curve (AUC) and maximum concentration (Cmax) of this drug increased by 60%. However, a similar effect was not seen with EFA. Since the overall activity of venlafaxine and EFA is expected to increase only marginally, no dose adjustment will be required for most normal patients. However, patients with existing (identified) hypertension, elderly patients, and those with impaired hepatic or renal function may require dose adjustments for venlafaxine.

Haloperidol

In a study where venlafaxine was administered at equilibrium concentration stage at a dose of 150 mg/day, there was a 42% reduction in overall clearance of oral haloperidol after an oral dose of 2 mg; while the area under the pharmacokinetic curve (AUC) increased by 70% and Cmax increased by 88%, with no change in the haloperidol half-life (T 1/2). This should be considered for proper dose selection of haloperidol.

Imipramine

Venlafaxine does not impair the pharmacokinetics of imipramine and 2-hydroxyimipramine. However, the AUC, Cmax, and Cmin of imipramine (the active metabolite of imipramine) were increased by approximately 35% when venlafaxine was taken concomitantly. There is also a 2.5 to 4.5-fold increase (depending on the dose of venlafaxine: 37.5 mg for 12 hours or 75 mg for 12 hours) in the concentration of 2-hydroxydesipramine, but the clinical significance of this fact is not known.

Metoprolol

. Caution should be exercised when using metoprolol and venlafaxine concomitantly because due to the pharmacokinetic interaction, the plasma concentration of metoprolol increases by approximately 30-40%, without changing the concentration of its active metabolite α-hydroxymethoprolol. The clinical significance of this interaction has not been investigated. Metoprolol has no effect on the AUC of venlafaxine and EFA.

Risperidone

The pharmacokinetics of the pair of active molecules (risperidone and 9-hydroxirisperidone) are not significantly altered when combined with venlafaxine (despite increased AUC of risperidone).

Clozapine

A postmarketing study of venlafaxine found that its plasma concentrations increased with clozapine. This was manifested by an increase in the side effects of clozapine, especially with regard to the incidence of seizures.

Indinavir

The pharmacokinetics of indinavir are altered with concomitant use (AUC decreased by 28% and Cmax decreased by 36%). No changes in pharmacokinetics are observed with venlafaxine. The clinical significance of this fact is unknown.

Ketoconazole

. A pharmacokinetics study in combination with ketoconazole showed increased plasma concentrations of venlafaxine and EFA in subjects whose initial metabolism involving the CYP2D6 isoenzyme is both good (X-Met) and poor (P-Met). Specifically, the Cmax of venlafaxine was increased by 26% in X-Met and by 48% in P-Met. Cmax EFA values increased by 14% and 29% in X-Met and P-Met subjects, respectively. The AUC of venlafaxine increased 21% in X-Met and 70% in P-Met. EFA AUC values increased 23% and 33% in X-Met and P-Met subjects, respectively.

Monoamine oxidase inhibitors (MAOIs)

The simultaneous use of venlafaxine with MAOI inhibitors is contraindicated, as well as within 14 days after their withdrawal (risk of severe side effects up to death is likely). Therapy with MAO inhibitors can be administered at least 7 days after withdrawal of the drug Venlafaxine. Venlafaxine should be discontinued at least 7 days before starting reversible selective MAO inhibitors (moclobemide). The mildly reversible and non-selective MAOI inhibitor linensolid (antimicrobial drug) and methylene blue (intravenous dosage form) are also not recommended for concomitant use with venlafaxine.

Serotonergic agents

We should be cautious about the concomitant use of drugs that affect the serotonin mediator system, such as triptans (sumatriptan, zolmitriptan, etc.), selective serotonin reuptake inhibitors (SSRIs) and SSRIs (prolonged seizures have been reported), tricyclic antidepressants, lithium, sibutramine or fentanyl (and its analogues dextromethorphan, tramadol, etc), and an excess of tryptophan sources due to an increased potential risk of serotonin syndrome.

Alcohol

Alcohol should be completely avoided during treatment with venlafaxine. Alcohol increases the psychomotor dysfunction that venlafaxine can cause.

Lithium

Lithium preparations have no significant effect on the pharmacokinetics of venlafaxine.

Diazepam

There was no effect of orally administered diazepam on the pharmacokinetics of venlafaxine and EFA, and conversely, venlafaxine did not alter the pharmacokinetics of diazepam and its metabolite desmethyldiazepam. In addition, administration of both of these drugs did not impair diazepam-induced psychomotor and psychometric effects.

Medications affecting blood clotting and platelet function (NSAIDs, acetylsalicylic acid drugs and other anticoagulants)

The serotonin released by platelets plays an important role in hemostasis (stopping bleeding). Epidemiological studies demonstrate a relationship between the intake of psychotropic drugs that interfere with serotonin reuptake and the incidence of bleeding in the upper gastrointestinal tract. This relationship is increased if nonsteroidal anti-inflammatory drugs (NSAIDs), drugs containing acetylsalicylic acid, or other anticoagulants are used simultaneously. The risk of bleeding has been shown to increase when SSRIs and SSRIs (including venlafaxine) are prescribed concomitantly with warfarin. Patients who are prescribed warfarin should be closely monitored for prothrombin time and/or partial thromboplastin time, especially when co-administration with venlafaxine begins or ends.

Interaction with other drugs at the level of studied metabolism with cytochrome P450 isoenzymes

The main pathways of venlafaxine metabolism include the CYP2D6 and CYP3A4 isoenzymes: The former converts venlafaxine to its active metabolite EFA, and the latter is less important in venlafaxine metabolism than CYP2D6 and forms the product N-desmethylvenlafaxine with little pharmacological activity. Preclinical studies have shown, and then confirmed clinically, that venlafaxine is a relatively weak inhibitor of CYP2D6. Therefore, even when administered with drugs that moderately inhibit the activity of this enzyme (see the imipramine example above), or in patients with genetically determined decreased CYP2D6 function, no dose adjustment of venlafaxine is required, because the total concentration of the active substance and the active metabolite (venlafaxine and EFA) does not change significantly. This characterizes venlafaxine positively in comparison with other antidepressants. Caution should be exercised when concomitant administration with CYP2D6 inhibitors such as quinidine, paroxetine, fluoxetine, haloperidol, perphenazine, levomepromazine, because in this case venlafaxine may potentially increase the plasma concentration of these CYP2D6 substrates. In combination with drugs that inhibit both enzymes (CYP2D6 and CYP3A4), special caution is required. These drug interactions have not been well studied, and in this case such combination of drugs is not recommended.

In addition, venlafaxine does not inhibit the activity of CYP3A4, CYP1A2 and CYP2C9 enzymes, so there are no significant interactions with such drugs as alprozolam, caffeine, carbamazepine, diazepam, tolbutamide, terfenadine.

The interaction with ketoconazole is described above. CYP3A3/4 inhibitors such as itraconazole, ritonavir may have a similar effect.

Other interactions with various concomitant therapeutic factors and food

Particular caution should be exercised with venlafaxine during electroconvulsive therapy, as there is no experience with venlafaxine in these conditions.

There are no significant effects of different types of food on the absorption of venlafaxine and its subsequent conversion to EFAs. Foods (typically high in protein, e.g., hard cheeses, fish roe, turkey) and supplements and fitness diets that are increased sources of tryptophan potentially contribute to greater serotonin production in the body, which may enhance the serotonergic side effects of venlafaxine.

An undesirable pharmacodynamic interaction can occur when venlafaxine is taken simultaneously with the herb St. John’s wort (an herb or various preparations of it), this combination is not recommended.

There have been reports of false-positive urine immunochromatographic rapid test results (test strips) for phencyclidine and amphetamines in patients taking venlafaxine, even several days after withdrawal of venlafaxine. This may be explained by the lack of specificity of this test. Only a confirmatory test in a specialized anti-doping lab can differentiate venlafaxine from phencyclidine and amphetamines.

To date, venlafaxine has not shown itself to be a drug of abuse or addiction (both in preclinical studies of receptor affinity and in clinical practice).

Special Instructions

Suicide and suicidal behavior

Depression is associated with an increased risk of suicidal ideation, self-harm and suicide (suicidal behavior). This risk persists until the onset of a pronounced remission. Since there may be no improvement during the first few weeks of therapy or even longer, close monitoring of patients is necessary until such improvement occurs. Clinical experience has shown that suicide risk may increase in the early stages of recovery.

Patients with a history of suicide attempts or high levels of suicidal ideation prior to treatment are at greater risk for suicidal thoughts or suicide attempts, and these patients should be closely monitored. A meta-analysis of placebo-controlled clinical trials of antidepressants involving adult patients with psychiatric disorders found that taking antidepressants compared to placebo increased the risk of suicidal behavior in patients under 25 years of age. Medication treatment of these patients, and in particular those at high risk for suicide, should be accompanied by close monitoring, especially in the early phase of therapy and during dose adjustments. Patients (and caregivers of such patients) should be warned to monitor for any signs of clinical deterioration, suicidal behavior or thoughts, and unusual behavioral changes, and to seek medical attention immediately if these symptoms appear.

A small number of patients taking antidepressants, including venlafaxine, may experience aggression during treatment initiation, dose changes, or discontinuation.

The clinical studies conducted to date have not shown venlafaxine tolerance or dependence. However, as with other central nervous system medications, clinicians should monitor patients closely for signs of abuse, as well as those with a history of such symptoms.

Special patient groups

Venlafaxine is not approved for use in children.

In patients with a history of aggression, venlafaxine should be used with caution. Hypomanic and manic states may occur in patients with mood disorders, bipolar disorder when treated with antidepressants, including venlafaxine. Like other antidepressants, venlafaxine should be prescribed with caution in patients with a history of mania. Such patients need to be medically monitored.

Convulsive disorders may occur with venlafaxine therapy. Like all antidepressants, venlafaxine should be used with caution in patients with a history of seizure disorders, and these patients should be closely monitored. Treatment should be discontinued if seizures develop.

Akathisia

The use of venlafaxine has been associated with the development of akathisia, which is characterized by an unpleasant feeling of internal motor restlessness for the patient and manifested in the patient’s inability to sit quietly in one posture for long periods or remain motionless for long periods. This condition may be observed at the beginning of treatment and during the first weeks of treatment. Increasing the dose is not recommended in patients who develop these symptoms.

Bipolar disorder

Before starting treatment, those patients who are at risk for bipolar disorder should be identified. Such screening should include a detailed review of medical history, including family history, to identify cases of suicide, bipolar disorder. It should be noted that venlafaxine is not recommended for use in the treatment of bipolar depression.

Application in patients with comorbidities

The clinical experience with venlafaxine in patients with comorbidities is limited.

The use should be used with caution in patients with conditions in which the effects of venlafaxine on hemodynamic parameters and/or metabolism may be significant.

Patients should be warned to seek immediate medical attention if a rash, uretic elements or other allergic reactions occur.

In some patients, a dose-dependent increase in blood pressure and/or increased heart rate has been noted while taking venlafaxine, so regular monitoring of blood pressure and ECG is recommended, especially during refining or increasing doses of venlafaxine. Fatal cardiac arrhythmias have been reported in post-marketing experience with venlafaxine (in overdose). Before prescribing venlafaxine to patients at high risk of developing serious cardiac arrhythmias, the ratio of probable benefit to possible risk during use should be assessed.

Patients, especially the elderly, should be warned about the possibility of dizziness and impaired sense of balance in order to prevent injury.

Hyponatremia and/or insufficient antidiuretic hormone secretion syndrome may occur during administration of venlafaxine, especially in conditions of dehydration or decreased circulating blood volume (including elderly patients and patients taking diuretics).

Venlafaxine has not been studied in patients with recent myocardial infarction and decompensated heart failure. The drug should be prescribed with caution in these patients.

The administration of SSRIs or venlafaxine in patients with diabetes mellitus may cause changes in plasma glucose levels. Adjustment of the dose of insulin and/or antidiabetic medications may be required.

During treatment it is recommended to refrain from taking any alcohol-containing beverages.

The safety and effectiveness of venlafaxine in combination with drugs that reduce body weight (including phentermine) have not been established. Concomitant use of venlafaxine and body weight-lowering drugs is not recommended.

Women of childbearing age should use appropriate contraception while taking venlafaxine.

Explanation of special symptoms and conditions that may occur when treated with the drug

Dry mouth has been reported in 10% of patients receiving venlafaxine. This may increase the risk of tooth decay. Patients should be careful with oral hygiene.

The use of venlafaxine may cause akathisia, characterized by subjective discomfort or motor restlessness and the need to move frequently, often accompanied by an inability to sit or stand still. This occurs mostly during the first few weeks of treatment. Increasing the dose in patients who develop these symptoms may cause adverse effects.

In placebo-controlled clinical trials, a clinically significant increase in serum cholesterol was reported in 5.3% of patients. Monitoring of cholesterol levels during long-term treatment is necessary.

Cancellation Syndrome

Cancellation syndrome is common during treatment discontinuation, especially if it is abrupt termination. The risk of withdrawal syndrome can depend on several factors, including the duration of treatment, the size of the therapeutic doses, and the rate at which they are reduced. Very rarely are these symptoms reported in patients who accidentally miss taking the drug.

The withdrawal symptoms usually occur within the first few days of stopping treatment. These symptoms usually go away within 2 weeks, although some people may have them for 2-3 months or more. It is recommended that the dose of venlafaxine be gradually reduced when discontinuing the drug – over a period of weeks or months, depending on the severity of the clinical symptoms.

Serotonin syndrome

. Taking venlafaxine, like other serotonergic drugs, can cause serotonin syndrome, a potentially life-threatening condition, especially with concomitant use of other medications that can affect serotonergic neurotransmitter systems, such as, MAO inhibitors (see See “Interactions with other medicinal products”).

The symptoms of serotonin syndrome may include changes in mental status (agitation, hallucinations, coma), autonomic instability (tachycardia, blood pressure lability, hyperthermia), neuromuscular disorders (hyperreflexia, poor coordination) and/or gastrointestinal symptoms (nausea, vomiting, diarrhea).

Information on possible effect of the drug on the ability to drive vehicles, machinery

When using the drug, caution must be exercised while performing potentially hazardous activities requiring increased concentration and rapid psychomotor reaction (including driving and operating machinery).

Contraindications

Hypersensitivity to venlafaxine or any of the excipients, concomitant use with MAO inhibitors (see also section “Interaction with other medicinal products”), severe renal and/or hepatic impairment (glomerular filtration rate (GFR) less than 10 ml/min).

The drug is contraindicated in patients under 18 years of age, during pregnancy and lactation.

With caution:

Recent myocardial infarction, unstable angina pectoris, arterial hypertension, arrhythmias (especially tachycardia), history of seizures, elevated intraocular pressure, closed-angle glaucoma, history of manic states, suicidal tendencies, predisposition to bleeding from the skin and mucous membranes, initially low body weight, hyponatremia, dehydration, simultaneously with diuretics or medicinal products (drugs) used for treatment of obesity (see also section “Special Indications”). See also section “Special Indications”).

Side effects

Additional effects frequency: very common (≥1/10), common (≥1/100 to <1/10), infrequent (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), frequency not determined (no data on the incidence of adverse reactions are available at this time).

Nervous system disorders:very common – dry mouth, headache; common – unusual dreams, decreased libido, dizziness, insomnia, hyperexcitability, paresthesias, stupor, confusion, depersonalization, increased muscle tone, tremor; infrequent – apathy, agitation, hallucinations, myoclonus, impaired coordination of movement and balance; rare – akathisia, psychomotor agitation, epileptic seizures, manic reactions; infrequent – dizziness, malignant neuroleptic syndrome (MNS), serotonin syndrome, delirium, extrapyramidal reactions (including dystonia and dyskinesia), tardive dyskinesia, suicidal thoughts and behavior, aggression.

Gastrointestinal tract:very frequently, nausea; frequently, decreased appetite (anorexia), constipation, vomiting; infrequently, bruxism, diarrhea; rarely, hepatitis; frequency not determined, pancreatitis.

With the hematopoietic system: infrequent – bleeding in the skin (ecchymoses), gastrointestinal bleeding; frequency not established – mucosal hemorrhage, prolonged bleeding time, thrombocytopenia, abnormal blood changes (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia).

In metabolic disorders:frequent – increased serum cholesterol levels, decreased body weight; infrequent – increased body weight; very rare – increased prolactin content; frequency not determined – changes in laboratory liver function tests, hepatitis, hyponatremia, antidiuretic hormone secretion failure syndrome.

Respiratory organs:often – yawning, bronchitis, dyspnea; rarely: interstitial lung disease (ILD) and eosinophilic pneumonia, chest pain.

Cardiovascular system disorders: often – arterial hypertension, skin hyperemia; infrequent – postural hypotension, tachycardia, syncope; frequency not determined – hypotension, QT interval prolongation, ventricular fibrillation, ventricular tachycardia (including bidirectional tachycardia).

Urogenital system disorders: often – ejaculation/orgasm disorders (in men), erectile dysfunction (impotence), anorgasmia, dysuric disorders (mainly – difficulty in beginning urination), pollakiuria, menstrual disorders associated with increased bleeding or increased irregular bleeding (menorrhagia, metrorrhagia); infrequent – disorders of orgasm (in women), urinary retention; rarely – urinary incontinence.

Sensory organs:often – accommodation disorders, mydriasis, visual disturbances; infrequent – taste disturbances, tinnitus or ringing in the ears; frequency not determined – closed-angle glaucoma.

Skin disorders:very common: sweating; infrequent: alopecia, transient rash; frequency not established: erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, pruritus, urticaria.

Musculoskeletal system:frequency is not established – rhabdomyolysis.

General symptoms:often – weakness, increased fatigue, chills; infrequently – Quincke’s edema, photosensitization reactions; frequency not established – anaphylactic reactions.

If venlafaxine is discontinued, abruptly withdrawn, or if the dose is reduced, symptoms that belong to the so-called withdrawal syndrome may be observed: increased fatigue, asthenia, headache, dizziness, sleep disturbances (drowsiness or insomnia, difficulty falling asleep, the appearance of unusual dreams), hypomania, anxiety, agitation (increased nervous excitability and irritability), confusion, paresthesias (spontaneous unpleasant feelings of numbness, tingling, burning, crawling goosebumps, etc.etc.), increased sweating, dry mouth, decreased appetite, nausea, vomiting, diarrhea (most of these reactions are mild and do not require treatment).

Overdose

Symptoms of overdose:consciousness disturbance (from drowsiness to coma), agitation, possible vomiting, diarrhea; tremor, decreased or (mildly) increased blood pressure, dizziness, mydriasis, seizures, sinus or ventricular tachycardia or bradycardia; ECG changes (Q-T interval prolongation, Gis bundle leg block, QRS complex extension).

Postmarketing experience of use indicates that the most frequent overdose of venlafaxine occurred with concomitant ingestion of alcohol and/or with other psychotropic medications. There have been repeated reports of fatal outcomes.

Published literature on retrospective studies of venlafaxine overdoses reports that this increased risk of fatal outcomes may be specific to venlafaxine when comparing it to medically available SSRI antidepressants, but the risk is lower than that of tricyclic antidepressants. Epidemiological studies have shown that those patients treated with venlafaxine have a higher risk of suicide compared to those treated with SSRIs (other than venlafaxine). However, the extent to which these high rates of death (due to venlafaxine overdose) are due to the toxic properties of the drug itself or to the specific characteristics of the patient group treated with venlafaxine remains unclear. According to clinical experience, it is recommended that venlafaxine prescriptions be written with the lowest possible amount of the drug, sufficient only until the patient’s next visit, in order to reduce the risk of intentional overdose (see also the “Special Instructions” section).

Treatment:Symptomatic and supportive therapy is given. Specific antidotes are not known. Continuous monitoring of vital functions (respiration, circulation and heart rhythm) is recommended. In case of overdose, immediate gastric lavage and administration of activated charcoal to reduce absorption of the drug is recommended. It is not recommended to induce vomiting if there is a risk of aspiration of vomit. Forced diuresis, dialysis, blood transfusion are ineffective.

Similarities