Велафакс

General characteristics. Structure:

Active agent: венлафаксин in the form of a hydrochloride of 37,5 mg or 75 mg and excipients; cellulose microcrystallic, corn starch, ferrous oxide yellow (Е 172), sodium carboxymethylstarch (type A), talc, silicon dioxide colloid anhydrous, magnesium stearate.
Description: tablets of 37,5 mg - oblong tablets of light yellow color with dividing risky on both sides; tablets of 75 mg - round tablets of light yellow color with dividing risky on one party and an engraving of "PLIVA" on other party.

Pharmacological properties:

Pharmacodynamics. Venlafaksin - the antidepressant which is chemically not belonging to one class of antidepressants (tricyclic, tetracyclic or others), is a racemate of two active enantomer.
The mechanism of antidepressive influence of drug is connected with its ability to potentsiirovat transfer of nervous impulse in the central nervous system (CNS).
Venlafaksin and his main metabolite O-desmetilvenlafaksin (ODV) are strong inhibitors of the return serotonin reuptake and noradrenaline (SNRI) and weak inhibitors of the return capture of a dopamine. Besides, венлафаксин and O-desmetilvenlafaksin reduce beta and adrenergic reactivity both after single introduction, and at constant reception. Venlafaksin and ODV equally effectively influence the return capture of neurotransmitters.
Venlafaksin has no affinity to muskarinovy, cholinergic, histamine (H1) and α1-адренергическим to brain receptors. Venlafaksin does not suppress activity of monoamine oxidase (MAO). Has no affinity to opiate, benzodiazepine, fentsiklidinovy or N-methyl-d-aspartatnym (NMDA) to receptors.

Pharmacokinetics. Venlafaksin is well soaked up from digestive tract. After a single dose of 25 - 150 mg, the maximum concentration in a blood plasma reaches 33-172 ng/ml within about 2,4 hours. Is exposed to intensive metabolism at the first passing through a liver. Its main metabolite - the O-desmetil Venlafaksin (ODV).
The elimination half-life of a venlafaksin and ODV makes respectively 5 and 11 hours.
The maximum concentration of ODV in a blood plasma of 61-325 ng/ml is reached approximately in 4,3 hours after introduction. Linkng of a venlafaksin and ODV with proteins of a blood plasma makes respectively 27% and 30%. ODV and other metabolites, and also nemetabolizirovanny венлафаксин, are allocated with kidneys. At repeated introduction equilibrium concentration of a venlafaksin and ODV are reached within 3 days, In the range of daily doses of 75-450 mg, венлафаксин and ODV have linear kinetics. After administration of drug during food time of achievement of the maximum concentration in a blood plasma increases for 20-30 minutes, however sizes of the maximum concentration and absorption do not change.
Patients with cirrhosis have concentration in a blood plasma of a venlafaksin and ODV are increased, and the speed of their removal is reduced. At a moderate or heavy renal failure the general clearance of a venlafaksin and ODV decreases; and the elimination half-life is extended. Decrease in the general clearance to the main is observed at patients with clearance of creatinine lower than 30 ml/min. The age and a sex of the patient do not influence drug pharmacokinetics.

Indications to use:

Depressions of various etiology, treatment and prevention.

Route of administration and doses:

Velafaks's pill is recommended to be taken during food.
The recommended initial dose makes 75 mg in two steps (on 37,5 mg) daily.
If after several weeks of treatment considerable improvement is not observed, the daily dose can be raised to 150 mg (2 × 75 mg a day). If, according to the doctor, higher dose (the heavy depressive frustration or other states demanding hospitalization) is necessary, it is possible to appoint 150 mg in two steps at once (2 ×х 75 mg a day). After that it is possible to increase a daily dose by 75 mg each 2-3 days before achievement of desirable therapeutic effect. The maximum daily dose, drug of Velafaks makes 375 mg. After achievement of necessary therapeutic effect the daily dose can be gradually lowered to the minimum effective level. Maintenance therapy and prevention of a recurrence:
The supporting treatment can continue months and more. The minimal effective doses applied at treatment of a depressive episode are appointed. Renal failure: at a slight renal failure (the glomerular filtration rate (GFR) more than 30 ml/min.) correction of the mode of dosing is not required. At a moderate renal failure. (SKF of 10-30 ml/min.) should lower a dose by 25-50%. Due to the lengthening of an elimination half-life of a venlafaksin and its active metabolite (ODV), such patients should accept all dose once a day. It is not recommended to apply венлафаксин at a heavy renal failure (SKF less than 10 ml/min.) as reliable data on such therapy are absent. Patients on a hemodialysis can receive 50% of a usual daily dose of a venlafaksin after end of a hemodialysis.
Liver failure: at a slight liver failure (the prothrombin time (PT) less than 14 sec.) correction of the mode of dosing is not required. At a moderate liver failure (PV from 14 to 18 sec.) should lower a dose by 50%. It is not recommended to apply венлафаксин at a heavy liver failure as reliable data on such therapy are absent.
Elderly patients: advanced age of the patient in itself does not demand change of a dose, however (as well as at purpose of other medicines) at treatment of elderly patients care, for example, in connection with a possibility of a renal failure is required. It is necessary to apply the smallest effective dose. At increase in a dose the patient has to be under careful medical observation.

Termination of administration of drug of Velafaks:
Upon termination of administration of drug of Velafaks it is recommended to reduce gradually a drug dosage, at least, within a week and to watch a condition of the patient to minimize the risk connected with drug withdrawal (see below).
The period demanded for complete cessation of administration of drug depends on its dosage, duration of a course of treatment and specific features of the patient.

Features of use:

Drug withdrawal of Velafaks: As well as at treatment by other antidepressants, the sharp termination of therapy venlafaksiny - especially after high doses of drug - can cause cancellation symptoms in this connection it is recommended to lower gradually before drug withdrawal its dose. Duration of the period necessary for a dose decline depends on the size of a dose, therapy duration, and also individual sensitivity of the patient.

At purpose of tablets of Velafaks patients with a lactose intolerance should consider the content of lactose (56,62 mg in each tablet of 25 mg; 84,93 mg in each tablet of 37,5 mg; 113,24 mg in each tablet of 50 mg, 169,86 mg in each tablet of 75 mg).
At patients with depressive frustration before any medicinal therapy it is necessary to consider probability of suicide attempts. Therefore for decrease in risk of overdose the initial dose of drug has to be whenever possible low, and the patient has to be under careful medical observation.
Patients with affective frustration at treatment by antidepressants, including venlafaksiny, can have hypomaniacal or maniacal states.
As well as other antidepressants, венлафаксин it has to be appointed with care the patient with a mania in the anamnesis. Such patients need medical observation.
As well as other antidepressants, венлафаксин it has to be appointed with care the patient with epileptic seizures in the anamnesis. Treatment venlafaksiny has to be interrupted when developing epileptic seizures.
Patients should be warned about need to see immediately a doctor when developing rash, urtikarny elements or other allergic reactions.
At some patients during reception венлафаксин and dozo-dependent increase in arterial pressure in this connection regular control of arterial pressure, especially during specification or increase in a dosage is recommended is noted.
There can be an increase in frequency of a cordial rhythm, especially during reception of high doses. Care at a tachyarrhythmia is recommended.
Patients, especially elderly, have to be warned about possibility of dizziness and disturbance of sense of equilibrium.
As well as other inhibitors of the return serotonin reuptake, венлафаксин the risk of hemorrhages in skin and mucous membranes can raise, At treatment of the patients predisposed to such states care is necessary.
During reception of a venlafaksin. especially in the conditions of dehydration or decrease in volume of blood (including at the elderly patients and patients accepting diuretics), the hyponatremia and/or a syndrome of insufficient secretion of antidiuretic hormone can be observed.
During administration of drug the mydriasis in this connection control of intraocular pressure at the patients inclined to its increase or having closed-angle glaucoma is recommended can be observed.
Venlafaksin is not investigated at the patients who recently had a myocardial infarction and having dekompensirovanny heart failure. Such patients should appoint drug with care.
The clinical tests which are carried out so far did not reveal tolerance to a venlafaksin or dependence on it. Despite it, as well as at treatment by other drugs operating on the central nervous system, the doctor has to establish careful observation of patients for identification of signs of abuse of drug. Careful control and observation are necessary for the patients having such symptoms in the anamnesis.
Women of childbearing age have to apply, the corresponding methods of contraception during reception of a venlafaksin.
In spite of the fact that венлафаксин does not influence psychomotor and cognitive functions, it is necessary to consider that any medicinal therapy by psychoactive drugs can reduce ability of removal of judgments, thinking or performance of motive functions. It is necessary to warn the patient about it before begun treatments.
At emergence of such effects degree and duration of restrictions have to be established by the doctor. Also alcohol intake is not recommended.

Side effects:

The majority of the listed below side effects depend on a dose. At prolonged treatment weight and frequency of the majority of these effects decreases, and there is no need of cancellation of therapy.
As decrease in frequency: frequent> 1%, infrequent> 0,1% - <1%, rare> 0,01% - <0,1%, very rare <0,01%.
General symptoms: weakness, increased fatigue,
From digestive tract: a loss of appetite, a lock, nausea, vomiting, dryness in a mouth, seldom hepatitis.
From a metabolism: increase in level of cholesterol of blood serum, weight reduction of a body; infrequent: change of laboratory liver function tests, hyponatremia, syndrome of insufficient secretion of antidiuretic hormone.
From cardiovascular system: arterial hypertension, hyperemia of integuments; infrequent: postural hypotension, tachycardia,
From a nervous system: unusual dreams, dizziness, sleeplessness, hyperexcitability, paresthesias, stupor, increase in a muscle tone, tremor, yawning; dirty: apathy, hallucinations, spasms of muscles, serotoninovy syndrome; rare: epileptic seizures, maniacal reactions, and also the symptoms reminding the malignant antipsychotic syndrome (MAS).
From urinogenital system: disturbances of an ejaculation, an erection, an anorgazmiya, dysuric frustration (generally - difficulties at the beginning of an urination); infrequent: decrease libido, menorrhagia, ischuria.
From sense bodys: accommodation disturbances, mydriasis, vision disorder; infrequent: disturbance of flavoring feelings.
From integuments: perspiration; infrequent: reactions of a photosensitivity; rare: mnogoformny erythema, Stephens-Johnson's syndrome.
From system of a hemopoiesis: infrequent: hemorrhages in skin (ecchymomas) and mucous membranes, thrombocytopenia; rare; lengthening of a bleeding time.
Hypersensitivity reactions: infrequent: skin rash; very rare: anaphylactic reactions.
After sharp cancellation of a venlafaksin or decrease in its dose can be observed: fatigue, drowsiness, a headache, nausea, vomiting, anorexia, dryness in a mouth, dizziness, a diarrhea, sleeplessness, alarm, an acrimony, a disorientation, a hypomania, paresthesias, perspiration. These symptoms are usually poorly expressed and pass without treatment. Because of probability of emergence of these symptoms it is very important to reduce a drug dose gradually.

Interaction with other medicines:

Simultaneous use of monoamine oxidase inhibitors (MAO) and venlafaksin contraindicated. It is possible to begin administration of drug of Velafaks not less than in 14 days after the end of therapy with MAO inhibitors. If the MAO reversible inhibitor was applied (моклобемид), this interval can be shorter (24 hours). It is possible to begin therapy with MAO inhibitors not less than in 7 days after drug withdrawal of Velafaks.
Venlafaksin does not influence lithium pharmacokinetics.
At simultaneous use with Imipraminum the pharmacokinetics of a venlafaksin and its metabolite O-dezmetilvenlafaksina (ODV) does not change.
Haloperidol: the effect of the last can amplify because of increase in level of drug in blood at combined use.
At simultaneous use with diazepam the pharmacokinetics of drugs and their main metabolites, significantly do not change. Also influence on psychomotor and psychometric effects of diazepam is not revealed.
At simultaneous use with clozapine increase in its level in a blood plasma and development of side effects can be observed (for example, epileptic seizures).
At simultaneous use with risperidony (despite increase in AUC of a risperidon) the pharmacokinetics of the sum of active components (a risperidon and its active metabolite) significantly did not change.
Strengthens influence of alcohol on psychomotor reactions.
Against the background of reception of a venlafaksin it is necessary to observe extra care at electroconvulsive therapy as experience of use of a venlafaksin in these conditions is absent.
Medicines, metaboliziruyemy isoenzymes of P 450 cytochrome:
CYP2D6 enzyme of system of P 450 cytochrome will transform венлафаксин to active metabolite O-desmetil венлафаксин (ODES In). Unlike many other antidepressants, the dose of a venlafaksin can be not reduced at simultaneous introduction with the drugs suppressing activity of CYP2D6 or patients with genetically caused decrease of the activity have CYP2D6 as total concentration of active agent and a metabolite (a venlafaksina and ODV) at the same time will not change.
The main way of removal of a venlafaksin includes metabolism with participation of CYP2D6 and CYP3A4; therefore it is necessary to observe extra care at purpose of a venlafaksin in combination with the medicines oppressing both of these enzymes. Such medicinal interactions are not investigated yet.
Venlafaksin - rather weak CYP2D6 inhibitor also does not suppress activity of isoenzymes of CYP1A2, CYP2C9 and CYP3A4; therefore it is not necessary to expect it interaction with other drugs in which metabolism these liver enzymes participate.
Cimetidinum suppresses metabolism of "the first passing" of a venlafaksin and does not exert impact on pharmacokinetics O-dezmetilvenlafaksina. At most of patients only slight increase of the general pharmacological activity of a venlafaksin and O-dezmetilvenlafaksina is expected (it is more expressed at elderly patients and at an abnormal liver function).
Clinically significant interactions of a venlafaksin with anti-hypertensive (including beta-blockers APF inhibitors and diuretics) and antidiabetic drugs are not found.
The medicines connected with proteins of a blood plasma: linkng with proteins of plasma makes 27% for a venlafaksin and 30% for ODV. Therefore does not influence concentration of the medicines in a blood plasma possessing high extent of linkng with proteins.
At a concomitant use with warfarin, the anticoagulating effect of the last can amplify.
At a concomitant use with indinaviry the pharmacokinetics of an indinavir changes (with 28% reduction of the area under curve AUC and 36% decrease in the maximum concentration of Cmax), and the pharmacokinetics of a venlafaksin and ODV does not change. However clinical value of this effect is unknown.

Contraindications:

• Hypersensitivity.
• A concomitant use of MAO inhibitors (see also section "Interaction").
• Heavy renal failures and/or liver (glomerular filtration rate (GFR) less than 10 ml/min.).
• Age up to 18 years (safety and efficiency for this age group are not proved).
• The established or suspected pregnancy.
• Lactation period.

With care: recently postponed myocardial infarction, unstable stenocardia, arterial hypertension, tachycardia, a convulsive syndrome in the anamnesis, increase in intraocular pressure, closed-angle glaucoma, maniacal states in the anamnesis, predisposition to bleedings from integuments and mucous membranes, initially reduced body weight.

Pregnancy and period of a lactation
Safety of use of a venlafaksin at pregnancy is not proved therefore use during pregnancy (or alleged pregnancy) is possible in only if the potential advantage for mother surpasses possible risk for a fruit. Women of childbearing age have to be warned about it prior to treatment and have to see immediately a doctor in case of approach of pregnancy or planning of pregnancy during treatment by drug. Venlafaksin and his metabolite (ODV) are allocated in breast milk. Safety of these substances for newborn children is not proved therefore reception of a venlafaksin during breastfeeding is not recommended. In need of administration of drug in the period of a lactation it is necessary to resolve an issue of the breastfeeding termination. If treatment of mother was complete shortly before childbirth, the newborn can have drug withdrawal symptoms.

Overdose:

Symptoms: changes of an ECG (lengthening of an interval of QT, blockade of a leg of a ventriculonector, expansion of the QRS complex), sinus or ventricular tachycardia; bradycardia, hypotension, convulsive states, consciousness change (decrease in level of wakefulness). At overdose of a venlafaksin at a concomitant use with alcohol and/or other psychotropic drugs, it was reported about death.

Treatment: symptomatic. Specific antidotes are unknown. Continuous control of the vital functions (breath and blood circulation) is recommended.
Purpose of absorbent carbon for decrease in absorption of drug. It is not recommended to cause vomiting in connection with danger of aspiration, Venlafaksin and ODV are not removed at dialysis.

Storage conditions:

Period of validity 2 years. Not to use after the period of validity specified on packaging. At a temperature not above 30 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

On 14 tablets in the blister from a film of PVC and aluminum foil.
On 2 or 4 blisters together with the application instruction in a cardboard pack.