VENLAFEKTIN caps. 150 mg

VENLAFEKTIN caps. 150 mg
€ 62.00
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Treatment of major depressive episodes.
For the prevention of recurrence of major depressive episodes.
Treatment of generalized anxiety disorder.
Treatment of Social Anxiety Disorder.
Treatment of panic disorder with or without agoraphobia



VENLAFEKTIN caps. 150 mg

 

Venlafektin 150 mg prolonged-release capsules, hard


PHARMACEUTICAL FORM

Prolonged-release capsules, hard.
Venlafektin 75 mg are hard gelatin capsules transparent flesh-colored (size 0), containing two round tablets.
Venlafektin 150 mg are black transparent hard gelatin capsules (size 00) containing two round tablets.

CLINICAL DATA

 Indications
Treatment of major depressive episodes.
For the prevention of recurrence of major depressive episodes.
Treatment of generalized anxiety disorder.
Treatment of Social Anxiety Disorder.
Treatment of panic disorder with or without agoraphobia.

 Posology and method of administration

Major depressive episodes
The recommended starting dose for prolonged-release venlafaxine is 75 mg, given once daily. Patients not responding to the initial dose of 75 mg / day may benefit from dose increases to a maximum dose of 375 mg / day. Dosage increases can be made at intervals of two weeks or more. If clinically warranted due to symptom severity, dose increases can be made at more frequent intervals, but not less than 4 days.
Due to the risk of dose-related adverse effects, dose increments should be made only after clinical assessment. Must be maintained at the lowest effective dose.
Patients should be treated for a sufficient period of time, usually several months or longer. Treatment should be reassessed regularly on a case by case basis. Longer-term treatment may also be appropriate for prevention of recurrence of major depressive disorder (MDD), in most cases, the recommended dose for the prevention of recurrence of MDE is the same as the one used during this episode.
It of antidepressant drugs should be continued for at least six months following remission.

GAD

The recommended starting dose for prolonged-release venlafaxine is 75 mg, given once daily. For patients not responding to the initial dose of 75 mg, may be beneficial dose increases up to a maximum dose of 225 mg / day. Dose increases can be made at intervals of two weeks or more.
Due to the risk of dose-related adverse effects, dose increments should be made only after a clinical evaluation. Must be maintained at the lowest effective dose.
Patients should be treated for a sufficient period of time, usually several months or more. Treatment should be reassessed regularly on a case by case basis.

Social Anxiety Disorder

The recommended starting dose for prolonged-release venlafaxine is 75 mg, given once daily. There is no evidence that higher doses may result in additional benefit.
However, in individual patients not responding to the initial 75 mg, may be given an increased to a maximum dose of 225 mg / day. Dose increases can be made at intervals of two weeks or more.
Due to the risk of dose-related adverse effects, dose increments should be made only after a clinical evaluation. Must be maintained at the lowest effective dose.
Patients should be treated for a sufficient period of time, usually several months or longer. Treatment should be reassessed regularly on a case by case basis.

Panic disorder

A dose of 37,5 mg prolonged-release venlafaxine be used for 7 days. Dosage should then be increased to 75 mg / day. Patients who do not meet the dose of 75 mg / day may benefit from dose increases up to a maximum dose of 225 mg / day. Dosage increases can be made at intervals of two weeks or more.
Due to the risk of dose-related adverse effects, dose increments should be made only after a clinical evaluation. Must be maintained at the lowest effective dose.
Patients should be treated for a sufficient period of time, usually several months or longer. Treatment should be reassessed regularly on a case by case basis. Use in elderly patients
No specific dose adjustments of venlafaxine are considered necessary based solely on age. However, to be cautious in treating
elderly (eg, due to the possibility of renal failure and potential changes in sensitivity and affinity neurotransmitter occurring with aging). You should always use the lowest effective dose and patients should be carefully monitored when an increase in dose.
Use in children and adolescents under 18 years
Venlafaxine is not recommended for use in children and adolescents.
Controlled clinical studies in children and adolescents with major depressive disorder failed to demonstrate efficacy and do not support the use of venlafaxine in these patients.
The efficacy and safety of venlafaxine for other indications in children and adolescents under the age of 18 years.
Use in patients with hepatic impairment
Patients with mild to moderate hepatic impairment should generally be a 50% dose reduction. However, due to variability in clearance between subjects, it may be desirable to individualize dosage.
There are limited data in patients with severe hepatic impairment. Caution is recommended and should be given a dose reduction by more than 50%. You should consider the potential benefits against the risks in treating patients with severe hepatic impairment.
You should avoid sudden braking. When stopping treatment with venlafaxine, the dose should be gradually reduced over a period of at least one to two weeks. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming Given the previously prescribed dose. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.
For oral administration.
It is recommended that venlafaxine prolonged-release capsules should be taken with food at about the same time each day. The capsules should be swallowed whole with fluid and not be divided, crushed, chewed, or dissolved.
Patients treated with venlafaxine immediate release tablets may be switched to venlafaxine prolonged-release capsules at the nearest equivalent daily dosage. For example, venlafaxine immediate release tablets 37,5 mg twice daily may be switched to venlafaxine prolonged-release capsules 75 mg once daily. May require individual dosage adjustments.
Venlafaxine prolonged-release capsules contain microspheres that release the drug slowly into the digestive tract. Insoluble portion of these spheroids is eliminated and can be found in the faeces.

 Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Concomitant treatment with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serotonin syndrome with symptoms such as agitation, tremor and hyperthermia. Venlafaxine must not be initiated for at least 14 days after stopping treatment with an irreversible MAOI.
Venlafaxine must be discontinued for at least 7 days before starting treatment with an irreversible MAOI.

 Special warnings and precautions for use

Suicide / suicidal thoughts or clinical worsening
Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. General clinical experience that the risk of suicide may increase in the early stages of recovery.
Other psychiatric conditions for which venlafaxine is prescribed can also be associated with an increased risk of suicidal events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.
For patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behavior with antidepressants compared to placebo in patients less than 25 years.
Drug therapy should be accompanied by careful monitoring of patients, especially those at high risk, especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behavior or thoughts and unusual changes in behavior, and seek immediate medical advice if these symptoms present.
Use in children and adolescents under the age of 18
Venlafektin should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviors (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behavior and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, regardless of a decision to treat the patient should be carefully monitored for the appearance of suicidal symptoms. Moreover, no data on long term safety in children and adolescents concerning growth, maturation and
cognitive and behavioral development.
Serotonin syndrome
As with other serotonergic agents, treatment with venlafaxine can serotonin syndrome, a potentially life-threatening condition, particularly with concomitant use of other agents, such as MAO inhibitors that may affect the serotonergic neurotransmitter systems.
Serotonin syndrome symptoms may include mental status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular disorders (eg, hyperreflexia, incoordination) and / or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea).

Narrow-angle glaucoma

In connection with venlafaxine Mydriasis may occur. It is recommended that patients with raised intraocular pressure or patients at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored closely.

Blood pressure

Commonly reported dose-related increases in blood pressure with venlafaxine. In some cases reported postmarketing experience severely elevated blood pressure requiring immediate treatment. All patients should be carefully screened for high blood pressure and pre-existing hypertension should be controlled before starting treatment. Blood pressure should be monitored periodically, after initiation of treatment and after dose increases. Should be approached with caution in patients whose underlying conditions might be compromised by increases in blood pressure, eg. those with impaired cardiac function.
Heart rate
Can occur increases heart rate, especially at higher doses. Should be approached with caution in patients whose underlying conditions might be compromised by increases in heart rate.
Cardiovascular disease and risk of arrhythmia
Venlafaxine has not been evaluated in patients with a history of myocardial infarction or unstable heart disease. Therefore, it should be used with caution in these patients.
In postmarketing experience, fatal cardiac arrhythmias with the use of venlafaxine, especially in overdose. Before prescribing venlafaxine to patients at high risk of serious cardiac arrhythmia should take into account the balance of risks and benefits.
Seizures
With venlafaxine therapy seizures may occur. As with all antidepressants, venlafaxine should be used cautiously in patients with a history of convulsions, and concerned patients should be carefully monitored. Treatment should be discontinued in any patient who develops seizures.
Hyponatraemia
With venlafaxine may occur cases of hyponatremia and / or syndrome of inadequate secretion of antidiuretic hormone (SIADH). This is most commonly reported in volume-depleted or dehydrated patients. Elderly patients, patients taking diuretics, and patients who are otherwise volume-depleted may be at greater risk for this event.
Abnormal bleeding
Medicinal products that inhibit serotonin uptake may lead to reduced platelet function. Risk of skin and mucous membrane bleeding, including bleeding from the gastrointestinal tract may be increased in patients receiving venlafaxine. Like other inhibitors of serotonin reuptake, venlafaxine should be used cautiously in patients predisposed to bleeding, including patients on anticoagulants and platelet aggregation inhibitors.
Serum cholesterol
Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients for at least 3 months in placebo-controlled clinical trials. Determination of serum cholesterol levels should be considered during long-term treatment.
Co-administration with tools for weight loss
The safety and efficacy of venlafaxine therapy in combination with means for weight loss, including phentermine. Not recommended for co-administration of venlafaxine and tools for weight loss. Venlafaxine is not indicated for weight loss alone or in combination with other products.

Mania / hypomania

In a small proportion of patients with mood disorders who received antidepressants, including venlafaxine, may occur mania / hypomania. As with other antidepressants, venlafaxine should be used cautiously in patients with a history or family history of bipolar disorder.

Aggression

In a small proportion of patients who received antidepressants, including venlafaxine Aggression may occur. This has been reported under initiation, dose changes and discontinuation.
As with other antidepressants, venlafaxine should be used cautiously in patients with a history of aggression.
Discontinuation of treatment
Are common withdrawal symptoms when stopping treatment, particularly if discontinuation is abrupt. In clinical trials, adverse events seen on treatment discontinuation (tapering and post-tapering) occurred in approximately 31% of patients treated with venlafaxine and 17% of patients receiving placebo.
The risk of withdrawal symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. The most frequently reported adverse reactions were dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and / or vomiting, tremor and headache. Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be more prolonged (2-3 months or more). It is therefore advised that venlafaxine should be gradually tapered when discontinuing treatment over a period of several weeks or months, depending on the patient's needs.
Akathisia / psychomotor restlessness
Venlafaxine is associated with the development of akathisia, characterized by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This occurs most often within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
Dry mouth
Dry mouth is reported in 10% of patients treated with venlafaxine. This may increase the risk of caries, and patients should be informed about the importance of dental hygiene.

 Interaction with other medicinal products and other forms of interaction

Monoamine oxidase inhibitors (MARI) Irreversible, selective MAOIs
Venlafaxine should not be used in combination with irreversible non-selective MAOIs. Venlafaxine must not be initiated for at least 14 days after stopping treatment with an irreversible non-selective MAOIs. Venlafaxine must be discontinued at least 7 days before starting treatment with an irreversible non-selective MAOIs.
Reversible selective inhibitor of MAO-A (moclobemide)
Due to the risk of serotonin syndrome, the combination of venlafaxine with a reversible and selective MAOI, such as moclobemide, is not recommended. After treatment with a reversible MAO inhibitor can be used withdrawal period of at least 14 days before starting treatment with venlafaxine. It is recommended that venlafaxine should be discontinued at least 7 days before starting treatment with a reversible MAOI.
Reversible nonselective MAOI (linezolid)
The antibiotic linezolid is a weak reversible and selective MAOI and should not be given to patients treated with venlafaxine.
Severe adverse reactions in patients who have recently been discontinued from an MAOI and started on venlafaxine, or have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death.
Serotonin syndrome
As with other serotonergic agents, during treatment with venlafaxine can serotonin syndrome, particularly with concomitant use of other agents that can,
affect the serotonergic neurotransmitter system (including triptans, SSRI agents, SNRI agents, lithium, sibutramine, tramadol, or St. John's Wort [Hypericum perforatum]), with drugs which impair metabolism of serotonin (including MAOIs), or with serotonin precursors (such as tryptophan supplements).
If concomitant treatment of venlafaxine with an SSRI, SNRI vehicle or serotonin receptor agonists (triptans), careful patient monitoring, particularly during treatment initiation and dose increases. The concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements).
CNS-active substances
The risk of using venlafaxine in combination with other CNS-active substances has not been systematically evaluated. Therefore, caution is advised when venlafaxine is taken in combination with other CNS-active substances.
Ethanol
Venlafaxine has been shown not to increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS-active substances, patients should be advised to avoid alcohol.
Effects of other medicinal products on venlafaxine
Ketoconazole (inhibitor of CYP3A4)
A pharmacokinetic study with ketoconazole in CYP2D6 extensive (EM) and poor metabolizers (JIM) showed that administration of ketoconazole resulted in higher AUC of venlafaxine (70% and 21% in persons and CYP2D6 JIM EM) and O-desmethylvenlafaxine (33% and 23% in CYP2D6 JIM individuals and EM). Concomitant use of CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, voriconazole, posaconazole, ketoconazole, nelfinavir, ritonavir, saquinavir, telithromycin) and venlafaxine may increase levels of venlafaxine and O-desmethylvenlafaxine. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly.
Effect of venlafaxine on other medicinal products
Lithium
Concomitant use of venlafaxine and lithium can serotonin syndrome (see "Serotonin syndrome").
Diazepam
Venlafaxine has no effects on the pharmacokinetics and pharmacodynamics of diazepam and its active metabolite desmethyldiazepam. Diazepam does not appear to affect the pharmacokinetics of either venlafaxine or O-desmethylvenlafaxine. It is unknown whether a pharmacokinetic and / or pharmacodynamic interaction with other benzodiazepines.
Imipramine
Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. A dose-dependent increase in AUC of 2-OH-desipramine by 2.5 to 4.5 times, when applied 75 to 150 mg venlafaxine daily rag. Imipramine did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. There is no known clinical significance of this interaction. Should be approached with caution co-administration of venlafaxine and imipramine.
Haloperidol
A pharmacokinetic study with haloperidol has shown a 42% decrease in total oral clearance, 70% increase in AUC, 88% increase in Cmax, but no change in half-life of haloperidol. This should be considered in patients treated with haloperidol and venlafaxine concomitantly. There is no known clinical significance of this interaction.
Risperidone
Venlafaxine risperidone AUC increased by 50% but did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). There is no known clinical significance of this interaction.

Metoprolol

Co-administration of venlafaxine and metoprolol to healthy volunteers in a pharmacokinetic interaction study for both medicinal products resulted in increased plasma concentrations of metoprolol by approximately 30-40% without altering the plasma concentrations of its active metabolite a-hydroxymetoprolol. There is no known clinical significance of this finding in patients with hypertension. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite O-desmethylvenlafaxine. Should be treated with caution during concomitant use of venlafaxine and metoprolol.

Indinavir

A pharmacokinetic study with indinavir has shown a 28% decrease in AUC and a 36% decrease in Cmax for indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. There is no known clinical significance of this interaction.

 Pregnancy and lactation

Pregnancy
There are no adequate data from the use of venlafaxine in pregnant women.
Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Venlafaxine must only be administered to pregnant women if the expected benefits outweigh any possible risks.
As with other inhibitors of serotonin reuptake (PHI / BIM) can occur discontinuation symptoms in newborns if venlafaxine is used until or shortly before birth. Some newborns exposed to venlafaxine late in the third trimester have developed complications requiring tube-feeding, respiratory support or prolonged hospitalization. Such complications can arise immediately upon delivery. Can be observed in infants following symptoms: irritability, tremor, hypotonia, persistent crying, and difficulty in sucking or in sleeping. These symptoms may be due to either serotonergic effects or exposure. In most cases, these complications are observed immediately or within 24 hours after birth.
Breastfeeding
Venlafaxine and its active metabolite O-desmethylvenlafaxine are excreted in human milk. It can not be excluded infant. Therefore, we must decide whether to continue / discontinue breast-feeding or to continue / discontinue therapy with Venlafektin, having predvyaytgolzatd of breastfeeding for the child and the benefit of therapy for the woman with Venlafektin.

 Effects on ability to drive and use machines

Any psychoactive medicinal product may impair judgment, thinking, and motor skills. Therefore, any patient receiving venlafaxine should be cautioned about their ability to drive or operate hazardous machinery.

 Undesirable effects

The most common (> 1/10) reported adverse reactions in clinical studies were nausea, dry mouth, headache and sweating (including night sweats).
Adverse reactions are listed below by system organ class and frequency.
Discontinuation of venlafaxine (particularly when abrupt) commonly leads to withdrawal symptoms. The most frequently reported adverse reactions were dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and / or vomiting, tremor, headache and flu syndrome. Generally these events are mild to moderate and self-limiting, but in some patients they may be severe and / or prolonged. It is therefore advised when venlafaxine treatment is no longer necessary to make gradual discontinuation by dose.

Paediatrics

In general, the adverse reaction profile of venlafaxine (in placebo-controlled clinical trials) in children and adolescents (aged 6 to 17) was similar to that seen in adults. As with adults, decreased appetite, weight loss, high blood pressure and elevated serum cholesterol.
In clinical trials with children observed adverse reaction suicidal ideation. There are also increased reports of hostility and, especially in major depressive disorder, self-harm.
In particular, when children experience the following side effects: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia.

 Overdose

In postmarketing experience, overdose with venlafaxine was reported predominantly in combination with alcohol and / or drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, convulsion, and vomiting. Other reported: include electrocardiographic changes (eg extension of the O-T interval), ventricular tachycardia, bradycardia, vertigo, and death.
Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher suicide risk factors than patients on SSRI. It is unclear to what extent the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristics of patients treated with venlafaxine. Prescriptions for venlafaxine should be written for the smallest quantity of drug consistent with good patient management to reduce the risk of overdose.

Recommended treatment

Recommended General supportive and symptomatic measures should be monitored cardiac rhythm and vital signs. If there is a risk of aspiration is not recommended induce vomiting. Gastric lavage may be indicated if performed soon after ingestion or in symptomatic patients. Administration of activated charcoal may also limit absorption of the active substance. It is unlikely that forced diuresis, dialysis, hemoperfusion and exchange transfusion are useful. There are no known specific antidotes for venlafaxine.

 Pharmacological Properties

 Pharmacodynamic properties
It is believed that the mechanism of antidepressant action of venlafaxine in humans is associated with its potentiation of neurotransmitter activity in the central nervous system. Preclinical studies have shown that venlafaxine and its major metabolite O-desmethylvenlafaxine (ODV), are inhibitors of the reuptake of serotonin and noradrenaline. Venlafaxine also weakly inhibits dopamine reuptake. Venlafaxine and its active metabolite decreased ß-adrenergic responsiveness after both acute (single dose) and chronic administration. Venlafaxine and ODV are very similar with respect to their overall action on neurotransmitter reuptake and receptor binding.
Venlafaxine has virtually no affinity in vitro muscarinic cholinergic, Hi-y-histaminergic or adrenergic receptors in rat brain. Pharmacologic activity at these receptors may be associated with various side effects seen with other antidepressant drugs, such as anticholinergic, sedative and cardiovascular side effects.
Venlafaxine does not possess monoamine oxidase inhibitory activity (MAO).
In vitro studies revealed that venlafaxine has virtually no affinity for opiate receptors.

Major depressive episodes

The efficacy of venlafaxine immediate-release as a treatment for major depressive episodes was demonstrated in five randomized, double-blind, placebo-controlled, short-term studies lasting 4 to 6 weeks at doses up to 375 mg / day. The efficacy of venlafaxine extended release for the treatment of major depressive disorder was established in two placebo-controlled short-term studies for 8 and 12 weeks, which included a dose range of 75 to 225 mg / day.
GAD
The efficacy of venlafaxine prolonged-release capsules as a treatment for generalized anxiety disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose (75 to 225 mg / day), a 6-month, placebo-controlled, fixed-dose study (75 to 225 mg / day) and a 6-month, placebo-controlled dose changes (37.5, 75 and 150 mg / day) in adult outpatients. While there was also evidence for superiority dose of 37,5 mg / day to placebo, it is not as consistently effective as higher doses.

Social Anxiety Disorder

The efficacy of venlafaxine prolonged-release capsules as a treatment for social anxiety disorder was established in four double-blind, parallel-group, 12-week, multicenter, placebo-controlled flexible-dose and one double-blind, parallel-group, 6-month, placebo controlled, fixed / flexible-dose study in adult outpatients. Patients received doses ranging from 75 to 225 mg / day. No evidence of greater effectiveness of the 150 to 225 mg / day group compared to the 75 mg / day at 6-month study.

Panic disorder

The efficacy of venlafaxine prolonged-release capsules as a treatment for panic disorder was established in two double-blind, 12-week, multicenter, placebo-controlled studies in adult outpatients with panic disorder with or without agoraphobia. The starting dose for panic disorder studies was 37,5 mg / day for 7 days. Patients then received fixed doses of 75 or 150 mg / / day in one study and 75 or 225 mg / day in the other study.
Efficacy was also established in a long-term, double-blind, placebo-controlled, parallel study of long-term safety, efficacy and prevention of relapse in adult outpatients who responded to open-label treatment. Patients continued to receive the same dose of venlafaxine extended release, which are taken at the end of the open phase (75.150 or 225 mg / day).

 Pharmacokinetic properties

Venlafaxine is extensively metabolised, primarily to the active metabolite O-desmethylvenlafaxine (ODV). Mean ± SD plasma half-life of venlafaxine and ODV are 5 ± 2 hours and 11 ± 2 hours. Steady-state concentrations of venlafaxine and ODV are attained within 3 days of oral multiple-dose therapy. Venlafaxine and ODV exhibit linear kinetics over the dose range of 75 mg to 450 mg / day.

Absorption

At least 92% of venlafaxine is absorbed following single oral doses of immediate-release venlafaxine. The absolute bioavailability is 40% to 45% due to presystemic metabolism. After administration of immediate-release venlafaxine peak plasma concentrations of venlafaxine and ODV occur in 2 and 3 hours. After administration of venlafaxine extended-release capsules, peak plasma concentrations of venlafaxine and ODV are attained within 5.5 hours and 9 hours. When equal daily doses of venlafaxine, either as immediate-release tablet or prolonged-release capsule, extended release capsule provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet. Food does not affect bioavailability of venlafaxine and ODV.

Distribution

Venlafaxine and ODV at therapeutic concentrations bind minimally to human plasma proteins (27% and 30%). The volume of distribution for venlafaxine at steady state is 4,4 ± 1,6 L / kg following intravenous administration.

Metabolism

Venlafaxine undergoes extensive metabolism in the liver. In vitro and in vivo studies indicate that venlafaxine is biotransformed to its major active metabolite, ODV, by CYP2D6. In vitro and in vivo studies indicate that venlafaxine is metabolized to a minor, less active metabolite, N-desmethylvenlafaxine by CYP3A4. In vitro and in vivo studies indicate that venlafaxine is a weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP1A2, CYP2C9 or CYP3A4.
Elimination
Venlafaxine and its metabolites are excreted primarily through the kidneys. Approximately 87% of a venlafaxine dose is excreted in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (%), or other minor inactive metabolites (27%). Mean ± SD plasma steady-state clearances of venlafaxine and ODV 1,3 ± 0,6 L / h / kg and 0,4 ± 0,2 L / h / kg.
Special populations
Age and sex
Age and gender do not significantly affect the pharmacokinetics of venlafaxine and ODV. CYP2D6 extensive / poor metabolisers
Plasma concentrations of venlafaxine were higher in CYP2D6 poor metabolizers than in extensive metabolizers. Because the total exposure (AUC) of venlafaxine and ODV was similar in poor and extensive metabolizers, there is no need for different venlafaxine dosing regimens for these two groups.
Patients with hepatic impairment
In patients with Child-Pugh class A (mildly hepatically impaired) and Child-Pugh B (moderately hepatically impaired) half-life of venlafaxine and ODV is prolonged compared to normal subjects. Clearance of both venlafaxine and ODV was reduced. A large degree of variability between individuals. There are limited data in patients with severe hepatic impairment.
Patients with renal impairment
In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects, while ODV elimination half-life was prolonged by about 142% and clearance - reduced by about 56%. Adjustment is necessary for patients with severe renal impairment and in patients who require hemodialysis.
 Preclinical safety data
Studies with venlafaxine in rats and mice showed no evidence of carcinogenicity. Venlafaxine was not mutagenic in a wide range of in vitro and in vivo.
Reproductive toxicity studies in animals showed decreased pup weight in rats, an increase in stillborn pups, and increased pup deaths during the first 5 days of lactation. The reason for these deaths is not known. These effects occurred at 30 mg / kg / day, which is four times the daily human dose of 375 mg of venlafaxine (on an mg / kg). No-effect dose for these findings was 1.3 times higher than the human dose. The potential risk for humans is unknown.
Reduced fertility was observed in a study in which both male and female rats were exposed to ODV. This exposure was approximately 1 to 2 times higher than the dose of venlafaxine in humans of 375 mg / day. The significance of this finding is unknown.

 PHARMACEUTICAL PARTICULARS

 List of excipients Venlafaktin 75 mg capsules
Core mg
Hypromellose
Ammonium methacrylate, copolymer (type B) Powder (Eudragit RS = 100) Sodium Magnesium Stearate laurisulfat
Coating mg
Ammonium methacrylate, copolymer
(Eudragit E 12.5)
Gelatin
Titanium dioxide (E171) iron oxide red erythrosine (127) Indigotine I (E 132)
Venlafaktin 150 mg capsules
Core mg
Hypromellose
Ammonium methacrylate, copolymer (type B) Powder (Eudragit RS = 100) Sodium laurisulfat
Magnesium stearate mg
Ammonium methacrylate, copolymer
(Eudragit E 12.5)
Gelatin
Titanium dioxide (E171) erythrosine (127) Indigo carmine I (E 132)
 Incompatibilities
None known.

Shelf Life

Three years.
€ 62.00
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