Venlafaksin

General characteristics. Structure:

Active ingredient: 42,42 mg or 84,84 mg of a venlafaksin of a hydrochloride that there correspond 37,5 mg or 75 mg of a venlafaksin.

Excipients: cellulose microcrystallic, starch prezhelatinizirovanny, silicon dioxide colloid (aerosil), talc, magnesium stearate.

The drug appointed by the specialist doctor (usually the psychiatrist) at a mental depression. It is used both for prevention, and for treatment of depressions.

Venlafaksin does not worsen cognitive/intellectual functions and psychomotor function, and he practically has no sedation, however it is necessary to be careful at treatment by drug in case of simultaneous performance of potentially dangerous types of the works demanding the increased concentration of attention and speed of psychomotor reaction (including driving of the car and control of mechanisms). Pay attention that change of a dose and the termination treatment by drug should be carried out most gradually and carefully as drug has a withdrawal.

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 enantiomer. Venlafaksin and his main metabolite, O-desmetilvenlafaksin (ODV), are powerful inhibitors of the return serotonin reuptake and noradrenaline (in a short form: IOZSN or СИОЗСиН) and weak inhibitors of the return capture of dopamine. The mechanism of antidepressive action is connected with ability of drug to increase activity of neurotransmitters by transfer of nervous impulses in the central nervous system (CNS). Venlafaksin and ODV equally effectively influence the return capture of the above-named neurotransmitters, at the same time they have no affinity (in vitro was studied) with cholinergic (muskarinovy), histamine (H1), alfa1-adrenergic, opioid and benzodiazepine receptors, do not suppress activity of monoamine oxidase (MAO). On inhibition of the return serotonin reuptake венлафаксин concedes to the selective serotonin reuptake inhibitors (SSRI).

Pharmacokinetics. Absorption. Absorption from digestive tract good, about 92% for a single dose, quantitatively does not depend on meal.

Distribution. The general bioavailability – 40-45% that is connected with intensive presistemny metabolism in a liver. Venlafaksin and ODV contact proteins of plasma of the person for 27 and 30%, respectively; both of them get into breast milk. In the range of daily doses of a venlafaksin of 75-450 mg itself венлафаксин and ODV have linear kinetics. Time of achievement of the maximum concentration in a blood plasma (TCmax) of a venlafaksin and ODV – 2 and 3 h, respectively, after reception of tablets of Venlafaksin inside. In case of reception of the prolonged forms of a venlafaksin indicators of TCmax 5,5 and 9 of the h, respectively.

The elimination half-life (T1/2) made 5 ± 2 h and 11 ± 2 h, for a venlafaksin and ODV, respectively. Equilibrium concentration in plasma (Css) for a venlafaksin and ODV is reached after 3 days of multiple dose of therapeutic doses.

Metabolism. It is metabolized generally in a liver with participation of an isoenzyme of CYP2D6 to the only thing pharmacological of an active metabolite (ODV), and also to an inactive metabolite of N-desmetilvenlafaksina. Venlafaksin is weak inhibitor of an isoenzyme CYP2D6, does not inhibit CYP1A2, CYP2C9 or CYP3A4.

Removal. It is removed preferential by kidneys: about 87% of the accepted single dose are removed with urine during 48 h (5% in not changed look, 29% in the form of not conjugated ODV, 26% in the form of the conjugated ODV, 27% in the form of other inactive metabolites), and in 72 h kidneys remove 92% of drug.

Average value ± a standard deviation for plasma clearance of a venlafaksin and ODV makes 1.3 ±0.6 and 0.4 ±0.2 l/h/kg, respectively; the seeming elimination half-life of 5 ±2 and 11 ±2 hours, respectively; seeming (in an equilibrium state) the volume of distribution of 7.5 ±3.7 and 5.7 ±1.8 l/kg, respectively.

Special groups. Gender and age of the patient have no significant effect on pharmacokinetic parameters of a venlafaksin and ODV.

For elderly patients of special correction of a dose depending on age it is not required.

Patients with low activity of an isoenzyme of CYP2D6 have no need for selection of individual doses. Despite multidirectional change of the concentration taken separately namely the venlafaksina (raises) and ODV (decreases), the sum of the areas under pharmacokinetic curves of these two active agents actually does not change because of decrease of the activity of an isoenzyme of CYP2D6, according to correction of a dose it is not required.

At patients with a liver and renal failure from average metabolism of a venlafaksin and removal of ODV decreases to heavy degree, Cmax of a venlafaksin and ODV raises, T1/2 is extended. Decrease in the general clearance of a venlafaksin is most expressed at patients at the clearance of creatinine (CC) by kidneys lower than 30 ml/min., and also at the patients who are on renal dialysis (T1/2 increases by 180% for a venlafaksin and for 142% for ODV, and the clearance of both active agents decreases approximately by 57%). For such patients, especially on a hemodialysis, individual selection of a dose of a venlafaksin and control of kinetics taking into account treatment duration this drug is necessary.

Though data for patients with a liver failure of heavy degree on a scale of Chayld-Pyyu are limited, it is necessary to consider that individual variations of pharmacokinetics, in particular clearance of drug and its T1/2, have very various character which should be considered at purpose of a venlafaksin to such patients.

At patients with a class A on Chayld-Pyyu (easy abnormal liver functions) and with a class B on Chayld-Pyyu (average disturbances) of T1/2 of a venlafaksin and ODV it is extended approximately twice in comparison with healthy patients, and the clearance is reduced more than half.

Indications to use:

Depression. Prevention and treatment.

Route of administration and doses:

Inside. Drug Venlafaksin is accepted during food, it is desirable at the same time, without chewing and washing down with liquid. The recommended initial dose makes 75 mg in two steps daily (on 37.5 mg 2 times a day). Depending on portability and efficiency, the dose can be gradually increased to 150 mg/days. If necessary the dose is increased to 225 mg/days. Increase in a dose by 75 mg/days can be made at an interval of 2 weeks and more, in case of clinical need, in connection with weight of symptoms increase in a dose in shorter terms, but not less than 4 days is possible. Higher doses (to the maximum daily dose in 375 mg/days in 2-3 receptions) demand stationary observation of patients. 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 6 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.) the dose should be lowered 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 about such therapy are absent. At a hemodialysis the daily dose has to be lowered by 50%, it is necessary to accept drug after the end of a session 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.) the daily dose has to be lowered by 50% or more. It is not recommended to apply венлафаксин at a heavy liver failure as reliable data about such therapy are absent.

Elderly patients: advanced age of the patient in the absence of any acute and chronic diseases does not demand change of a dose, however (as well as at purpose of other medicines) at treatment of elderly patients care is required. Elderly patients should apply the smallest effective dose. At increase in a dose the patient has to be under careful medical observation.

Drug withdrawal. The termination of administration of drug should be carried out gradually to minimize the risk connected with drug withdrawal. At a course of treatment within 6 weeks and more period of gradual drug withdrawal has to be not less than 2 weeks and depends on a dose, duration of therapy and specific features of the patient.

Features of use:

It is not necessary to appoint венлафаксин to pregnant women and the nursing women since safety of drug during pregnancy and a lactation at the woman is not established sufficiently in view of the fact that there are no adequately conducted controlled clinical trials on rather big selection of such patients. It concerns health, both mothers, and, more, the fruit/child. Women of childbearing age have to be warned about it prior to treatment, it is necessary 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. In need of administration of drug in the period of a lactation the breastfeeding termination is necessary.

In practice cases of purpose of a venlafaksin to mothers meet during pregnancy and shortly before childbirth when in a specific situation the expected advantage for mother exceeds potential risk for a fruit. In these cases at newborns complications which demanded were often observed: increase in terms of hospitalization, maintenance of breath and feeding via the probe. These complications can develop right after childbirth and are characteristic also in case of reception of other antidepressants from group of IOZSN or SIOZS (which are not containing a venlafaksin). In similar cases it was reported about the following clinical symptoms at newborns: frustration of external respiration, cyanosis, apnoea, spasms, instability of temperature, difficulty of feeding, vomiting, hypoglycemia, muscular hypertension or hypotonia, hyperreflexia, tremor, trembling, irritability, slackness, constant crying, drowsiness or sleeplessness. Similar disturbances can demonstrate serotonergic effects of drug Venlafaksin. If венлафаксин it was applied during pregnancy, and treatment of mother was complete shortly before childbirth, the newborn can have a withdrawal. At such newborn it is necessary to exclude existence of a serotoninovy syndrome or malignant antipsychotic syndrome. Epidemiological data demonstrate that use of SIOZS during pregnancy, especially on late durations of gestation, can increase risk of persistent pulmonary hypertensia of newborns.

Suicide and suicide behavior. The depression is connected with the increased risk of emergence of suicide thoughts, drawings to itself injuries and a suicide (suicide behavior). This risk remains up to approach of the expressed remission. As within the first several weeks of therapy or even a bigger period of improvement it can not be observed, before such improvement it is necessary to carry out careful observation of patients. According to the accumulated clinical experience the risk of a suicide can increase at early stages of recovery.

Patients with suicide attempts in the anamnesis or with the high level of reflection on suicide subjects prior to treatment are more subject to risk of suicide thoughts or attempts of a suicide, for such patients it is necessary to carry out careful observation. Placebo meta-analysis - controlled clinical trials of antidepressants with participation of adult patients with mental disturbances showed that at reception of antidepressants in comparison with reception of placebo at patients more young than 25 years the risk of suicide behavior is increased. Drug treatment of these patients and, in particular, patients with a suicide high risk, has to be followed by careful observation, especially at an early stage of therapy and at dose adjustment. Patients (and the persons who are looking after such patients) should be warned about need to control any manifestations of clinical deterioration, suicide behavior or thoughts, and also unusual changes in behavior, and to ask immediately for medical care at emergence of these symptoms.

At a small amount of the patients accepting antidepressants, including венлафаксин during an initiation of treatment, change of a dose or the termination of treatment aggression can be observed.

The clinical trials conducted 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, and also for the patients having such symptoms in the anamnesis.

Special groups of patients. Venlafaksin is not allowed for use for children. At patients with the aggression observed earlier венлафаксин it is necessary to apply with care. Patients with affective frustration, bipolar disorder at treatment with antidepressants, including venlafaksiny, can have hypomaniacal and 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.

At therapy venlafaksiny there can be convulsive frustration. As well as all antidepressants, венлафаксин it is necessary to apply with care at patients with convulsive frustration in the anamnesis, for such patients it is necessary to establish careful control. Treatment has to be stopped at development of spasms.

Akathisia. Use of a venlafaksin was connected with development of an akathisia which is characterized by feeling of internal motive concern, unpleasant for the patient, and shown in inability of the patient long to sit quietly in one pose or to be left long without the movement. This state can be observed in an initiation of treatment and within the first weeks of treatment. At patients who appeared such symptoms increase in a dose is not recommended.

Bipolar disorder. Prior to treatment, it is necessary to define those patients who are in risk group of bipolar disorder. Such check has to include detailed studying of the anamnesis, including family, for identification of cases of suicide, bipolar disorder. It should be noted that венлафаксин it is not recommended for use at treatment of a bipolar depression.

Use for patients with associated diseases. Clinical experience of use of a venlafaksin for patients with associated diseases is limited.

It is necessary to apply with care at patients with those diseases which have an action of a venlafaksin on hemodynamic indicators and/or metabolism can be significant.

Patients should be warned about the immediate address to the doctor at emergence of rash, urtikarny elements or other allergic reactions.

At some patients during reception of a venlafaksin dozozavisimy increase in arterial pressure and/or increase in heart rate therefore regular control of arterial pressure and an ECG, especially during specification or increase in a dosage of a venlafaksin is recommended is noted. In experience of post-marketing use of a venlafaksin (at overdose) lethal cardiac arrhythmias were registered. Before purpose of a venlafaksin patients with high risk of development of serious violations of a cordial rhythm should estimate a ratio of probable advantage to possible risk at use.

Patients, especially elderly, have to be warned about possibility of dizziness and disturbance of sense of equilibrium for the purpose of traumatism prevention.

During reception of a venlafaksin, especially in the conditions of dehydration or decrease in volume of the circulating 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.

Venlafaksin is not investigated on the patients who had recently a myocardial infarction and having dekompensirovanny heart failure. Such patients should appoint drug with care.

Reception of SIOZS or venlafaksin by patients with a diabetes mellitus can cause change of level of glucose in a blood plasma. Dose adjustment of insulin and/or antidiabetic medicines can be required.

During treatment it is recommended to abstain from reception of any alkogolsoderzhashchy drinks.

Safety and efficiency of use of a venlafaksin in combination with the medicines losing body weight (including phentermine) were not established. The concomitant use of a venlafaksin and the medicines losing body weight is not recommended.

Women of childbearing age have to apply the corresponding methods of contraception during reception of a venlafaksin.

Explanations of special symptoms and states which emergence is possible at treatment by drug. Dryness in a mouth is noted at 10% of the patients receiving венлафаксин. It can increase risk of development of caries. Patients have to observe hygiene of an oral cavity carefully.

Use of a venlafaksin can cause to move development of the akathisia which is characterized by subjective unpleasant feelings or motive concern and need often that often is followed by inability to sit or stand still. Generally it occurs within the first several weeks of treatment. Increase in a dose can cause undesirable effects in patients at whom the specified symptoms develop.

In placebo - controlled clinical tests at 5,3% of patients clinically significant increase in content of cholesterol in blood serum was registered. Control of level of cholesterol at prolonged treatment is necessary.

Withdrawal. During the termination of treatment the withdrawal, especially, is widespread if this sharp termination. The risk of a withdrawal can depend on several factors, including the treatment duration, size of therapeutic doses and speed of their decrease. It is very seldom reported about these symptoms at patients who accidentally missed administration of drug.

Withdrawal symptoms usually come during the first several days after the treatment termination. Usually these symptoms pass within 2 weeks though some people can have them 2-3 months and more. It is recommended to reduce gradually a dose of a venlafaksin at the termination of administration of drug - within several weeks or months, depending on expressiveness of clinical symptoms of a disease.

Serotoninovy syndrome. Reception of a venlafaksin, as well as other serotonergic drugs, can cause a serotoninovy syndrome, potentially life-threatening state, in particular at simultaneous use of other medicines which can affect serotonergic neuromediator systems, such as, MAO inhibitors (see the section "Interactions with Other Medicines").

Symptoms of a serotoninovy syndrome can include changes of the mental status (excitement, hallucinations, a coma), vegetative instability (tachycardia, lability of arterial pressure, a hyperthermia), neuromuscular frustration (a hyperreflexia, a lack of coordination) and/or gastrointestinal symptoms (nausea, vomiting, diarrhea).

Data on possible influence of drug on ability to manage vehicles, mechanisms. During treatment it is necessary to be careful when performing potentially dangerous types of the works demanding the increased concentration of attention and speed of psychomotor reaction (including driving of the car and control of mechanisms).

Side effects:

Frequency of side effects: very often (≥ 1/10), it is frequent (≥ 1/100 to <1/10), infrequently (≥ 1/1000 to <1/100), is rare (≥ 1/10000 to <1/1000), is very rare (<1/10000), frequency is not established (now data on prevalence of side reactions are absent).

General symptoms: often - weakness, increased fatigue, a fever; infrequently - a Quincke's edema, reactions of a photosensitization; frequency is not established - anaphylactic reactions.

From a nervous system: very often - dryness in a mouth, a headache; often - unusual dreams, decrease a libido, dizziness, sleeplessness, a hyperexcitability, paresthesias, a stupor, confusion of consciousness, depersonalization, increase in a muscle tone, a tremor; infrequently – apathy, agitation, hallucinations, a myoclonus, a lack of coordination of movements and balance; seldom - an akathisia, psychomotor excitement, epileptic seizures, maniacal reactions; frequency is not established – dizziness, the malignant antipsychotic syndrome (MAS), a serotoninovy syndrome, nonsense, extrapyramidal reactions (including dystonias and dyskinesia), late dyskinesia, suicide thoughts and behavior, aggression.

From digestive tract: very often - nausea; often - a loss of appetite (anorexia), a lock, vomiting; infrequently - a bruxism, diarrhea; seldom - hepatitis; frequency is not established - pancreatitis.

From a respiratory organs: often – yawning, bronchitis, short wind; seldom: intersticial diseases of lungs (IDL) and eosinophilic pneumonia, stethalgia.

From cardiovascular system: often - arterial hypertension, a hyperemia of integuments; infrequently - postural hypotension, tachycardia, a syncope; frequency is not established - hypotonia, lengthening of an interval of QT, fibrillation of ventricles, ventricular tachycardia (including bidirectional tachycardia).

From system of a hemopoiesis: infrequently - hemorrhages in skin (ecchymomas), gastrointestinal bleedings; frequency is not established - hemorrhages in mucous membranes, lengthening of a bleeding time, thrombocytopenia, pathological changes of blood (including an agranulocytosis, aplastic anemia, a neutropenia and a pancytopenia).

From a metabolism: often - increase in level of cholesterol in blood serum, decrease in body weight; infrequently - increase in body weight; very seldom - increase in content of prolactin; frequency is not established - change of laboratory liver function tests, hepatitis, a hyponatremia, a syndrome of insufficient secretion of antidiuretic hormone.

From urinogenital system: often - disturbances of an ejaculation/orgasm (at men), erectile dysfunction (impotence), an anorgazmiya, dysuric frustration (generally - difficulties at the beginning of an urination), a pollakiuria, the disturbances of periods connected with the increased bleeding or the increased irregular bleeding (a menorrhagia, a metrorrhagia); infrequently - disturbances of an orgasm (at women), an ischuria; seldom - an urine incontience.

From sense bodys: often - accommodation disturbances, a mydriasis, a vision disorder; infrequently - disturbance of flavoring feelings, noise or a ring in ears; frequency is not established - closed-angle glaucoma.

From integuments: very often – perspiration; infrequently - the alopecia fast-passing rash; frequency is not established - a mnogoformny erythema, a toxic epidermal necrolysis, Stephens-Johnson's syndrome, an itch, a small tortoiseshell.

From a musculoskeletal system: frequency is not established - рабдомиолиз.

At the termination of reception of a venlafaksin, sharp cancellation or at a dose decline symptoms which belong to a so-called withdrawal can be observed: increased fatigue, an adynamy, a headache, dizziness, sleep disorders (drowsiness or sleeplessness, backfilling difficulty, emergence of unusual dreams), a hypomania, uneasiness, agitation (the increased nervous irritability and irritability), confusion of consciousness, paresthesia (spontaneously arising unpleasant feeling of numbness, a pricking, burning, crawling of goosebumps, etc.), the increased sweating, dryness in a mouth, a loss of appetite, nausea, vomiting, diarrhea (the majority of these reactions are expressed slightly and do not demand treatment).

Interaction with other medicines:

Venlafaksin, itself without possessing the increased communication with proteins of a blood plasma, practically does not increase concentration of at the same time accepted medicines of which high communication with proteins of plasma is characteristic. Clinically significant interaction with anti-hypertensive (many pharmacological groups, including beta-blockers, inhibitors of an angiotensin-converting enzyme and diuretics) and antidiabetic drugs is not revealed. It is necessary to show care at co-administration with other drugs influencing the central nervous system (CNS) as combinations of a venlafaksin with all such drugs are not studied.

Inhibitors of a monoaminooxidase (MAO). Contraindicated simultaneous use of a venlafaksin with MAO inhibitors, and also within 14 days after their cancellation (the risk of development of heavy side effects up to a lethal outcome is probable). It is possible to appoint therapy MAO inhibitors not less than in 7 days after drug withdrawal Venlafaksin. Administration of drug Venflaksin has to be stopped at least in 7 days prior to reception of the MAO reversible selection inhibitors (моклобемид). Poorly reversible and non-selective inhibitor Maolinezolid (antimicrobic HP) and methylene blue (an intravenous dosage form) are also not recommended for simultaneous use with venlafaksiny.

Serotonergic means. It is necessary to treat with care simultaneous use of medicines which influence serotoninovy system of mediators, such as triptanes (суматриптан, золмитриптан, etc.), the selective serotonin reuptake inhibitors (SSRI) and IOZSN (long spasms), tricyclic antidepressants, lithium, сибутрамин or fentanyl (and its analogs dextromethorphan, трамадол, etc. were noted), and also surplus of sources of tryptophane in view of strengthening of potential risk of emergence of a serotoninovy syndrome.

Alcohol. During treatment venlafaksiny it is necessary to exclude alcohol completely. Alcohol strengthens disturbances of psychomotor functions which can cause венлафаксин.

Lithium. Drugs of lithium do not exert considerable impact on pharmacokinetics of a venlafaksin.

Diazepam. Influence of orally appointed diazepam on pharmacokinetics of a venlafaksin and ODV is not revealed, and, on the contrary, венлафаксин did not change pharmacokinetics of diazepam and its metabolite of a desmetildiazepam. Besides, purpose of both of these drugs does not worsen the psychomotor and psychometric effects caused by diazepam.

Cimetidinum. Co-administration of Cimetidinum and venlafaksin was shown in a metabolism delay at "the first passing" of a venlafaksin. The clearance of a venlafaksin at intake decreased by 43%, and the area under pharmacokinetic curve (AUC) and the maximum concentration (Cmax) of this drug increased by 60%. However, similar influence was not shown concerning ODV. As the general activity of a venlafaksin and ODV, as expected, will increase at the same time only in small degree, correction of a dose for most of ordinary patients will not be required. However to patients with the available (revealed) hypertensia, to elderly patients and those who has an abnormal liver function or kidneys correction of a dose of a venlafaksin is possible.

Haloperidol. In a research where венлафаксин it was appointed in a stage of equilibrium concentration at a dose of 150 mg/day, decrease in the general clearance of a peroral haloperidol by 42% after a dose of 2 mg inside was observed; at the same time the area under pharmacokinetic curve (AUC) increased for 70%, and Cmax increased for 88%, at the same time the elimination half-life of a haloperidol (T 1/2) did not change. It should be considered for a right choice of a dose of a haloperidol.

Imipraminum. Venlafaksin does not worsen pharmacokinetics of Imipraminum and 2 hydroxyimipraminums. However AUC, Cmax and Cmin of a desipramin (an active metabolite of Imipraminum) increased approximately for 35% at a concomitant use of a venlafaksin. Also from 2,5 to 4,5 times increase (depending on a dose of a venlafaksin: 37,5 mg for 12 hours or 75 mg for 12 hours) concentration of a 2-gidroksidesipramin, but clinical value of this fact are not known.

Metoprolol. At simultaneous use of a metoprolol and venlafaksin it is necessary to be careful as owing to pharmacokinetic interaction concentration of a metoprolol in a blood plasma increases approximately by 30-40%, without change of concentration of its active metabolite of a α-gidroksimetoprolol. The clinical importance of this interaction is not investigated. Metoprolol does not influence AUC of a venlafaksin and ODV.

Risperidon. At simultaneous use with risperidony (despite increase in AUC of a risperidon) the pharmacokinetics of couple of active molecules (a risperidon and a 9-gidroksirisperidona) significantly does not change at a combination with venlafaksiny.

Clozapine. During post-marketing studying of a venlafaksin it is found out that at simultaneous use with clozapine its concentration in a blood plasma increases. It was shown by strengthening of side effects of clozapine, especially concerning the frequency of developing of spasms.

Indinavir. At simultaneous use the pharmacokinetics of an indinavir changes (AUC decreases by 28%, and Cmax decreases by 36%). At a venlafaksin of change of pharmacokinetics it is not observed. Clinical value of this fact is unknown.

Ketokonazol. The pharmacokinetics research at a combination with ketokonazoly showed increase in plasma concentration of a venlafaksin and ODV at subjects at which initial metabolism with participation of an isoenzyme of CYP2D6 is both good (H-Met), and bad (P-Met). In particular, Cmax of a venlafaksin increased for 26% at H-Met and for 48% at P-Met. ODV Cmax values increased for 14% and 29% at subjects H-Met and P-Met, respectively. AUC of a venlafaksin increased for 21% at H-Met and for 70% at P-Met. AUC ODV values increased by 23% and 33% at subjects H-Met and P-Met, respectively.

The means influencing coagulability of blood and function of thrombocytes (NPVP, drugs of acetylsalicylic acid and other anticoagulants). The serotonin which is emitted with thrombocytes plays an important role in a hemostasis (a bleeding stop). Epidemiological researches show interrelation between reception of psychotropic drugs which interfere with the return serotonin reuptake, and the frequency of bleedings in upper parts of digestive tract. This interrelation amplifies if non-steroidal anti-inflammatory drugs (NPVP), drugs with the content of acetylsalicylic acid or other anticoagulants are at the same time used. It is proved the risk of bleedings at purpose of SIOZS and IOZSN increases (including венлафаксин) along with warfarin. Patients to whom warfarin is appointed have to is under careful control of a prothrombin time and/or partial tromboplastinovy time, especially when combined use with venlafaksiny begins or comes to an end.

Interaction with other medicines at the level of the studied metabolism with P450 cytochrome isoenzymes. The main ways of metabolism of a venlafaksin include isoenzymes of CYP2D6 and CYP3A4: the first of them turns венлафаксин into its active metabolite ODV, and the second is less important in metabolism of a venlafaksin in comparison with CYP2D6 and forms N-desmetilvenlafaksin product with small pharmacological activity. Preclinical trials showed, and then it was confirmed clinically that венлафаксин is rather weak CYP2D6 inhibitor. Therefore even at appointment with the medicines which are moderately suppressing activity of this enzyme (see above an example with Imipraminum), or in case of patients with genetically caused depression of function of CYP2D6, dose adjustment of a venlafaksin is not required as total concentration of active agent and an active metabolite (a venlafaksina and ODV) at the same time significantly does not change. It positively characterizes венлафаксин when comparing with other antidepressants. It is necessary to show care at co-administration with such CYP2D6 inhibitors as quinidine, пароксетин, fluoxetine, a haloperidol, Perfenazinum, levomepromazinum as in this case венлафаксин can potentially increase plasma concentration of these CYP2D6 substrates. In combination with the drugs oppressing both enzymes (CYP2D6 and CYP3A4) it is required to observe extra care. Such medicinal interactions are still insufficiently investigated, and in this case such combination of drugs is not recommended.

Besides венлафаксин does not suppress activity of CYP3A4, CYP1A2 and CYP2C9 enzymes therefore with such drugs as to alprozola, caffeine, carbamazepine, diazepam, Tolbutamidum, терфенадин significant interaction is not observed.

Interaction with ketokonazoly is described above. Such CYP3A3/4 inhibitors as итраконазол, ритонавир can exert similar impact.

Other interactions with various accompanying therapeutic factors and food. Against the background of use 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.

Significant influence of different types of food on absorption of a venlafaksin and its subsequent transformation into ODV is not revealed. Food (as a rule, with the high content of protein, for example: firm cheeses, fish roe, a turkey), and also the nutritional supplements and fitness diets which are the raised tryptophane source potentially promotes бóльшей to development in a serotonin organism that can strengthen side serotonergic effects of a venlafaksin.

Undesirable pharmakodinamichesky interaction can take place at Venlafaksin's reception along with a medicinal plant the St. John's Wort which is made a hole (a grass or any drugs from it), such combination is not recommended.

The patients accepting венлафаксин, and even in several days after cancellation of a venlafaksin have messages on false positive results of an immunokhromatografichesky rapid test of urine (test strip) for phencyclidine and amphetamines. It can be explained with insufficient specificity of this test. To distinguish венлафаксин from phencyclidine and amphetamines only the confirmatory test in specialized anti-doping laboratory can.

According to the data which are available today, венлафаксин did not prove as the drug causing medicinal abuse or addiction (as at a preclinical trial of affinity to receptors, and in clinical practice).

Contraindications:

Hypersensitivity to a venlafaksin or to any of excipients, simultaneous use with MAO inhibitors (see also section "Interaction with Other Medicines"), heavy renal failures and/or a liver (the glomerular filtration rate (GFR) less than 10 ml/min.).

Administration of drug is contraindicated aged 18 years are younger, at pregnancy and in the period of a lactation.

With care. Recently postponed myocardial infarction, unstable stenocardia, arterial hypertension, arrhythmias (especially tachycardia), a convulsive syndrome in the anamnesis, increase in intraocular pressure, closed-angle glaucoma, maniacal states in the anamnesis, suicide tendencies, predisposition to bleedings from integuments and mucous membranes, initially reduced body weight, a hyponatremia, dehydration, along with diuretics or with the medicines (M) applied to treatment of obesity

Overdose:

Overdose symptoms: consciousness disturbance (from drowsiness to a coma), agitation, is possible vomiting, diarrhea; tremor, decrease or (weak) increase in arterial pressure, golokruzheniye, mydriasis, convulsive states, sinus or ventricular tachycardia or bradycardia; changes on an ECG (lengthening of an interval of Q-T, blockade of legs of a ventriculonector, expansion of the QRS complex).

Post-marketing experience of use specifies that most often the overdose of a venlafaksin happened at a concomitant use of alcohol and/or to other psychotropic drugs. There are numerous messages on deaths.

The published references on retrospective researches of overdoses of a venlafaksin report that such increased risk of fatal outcomes can be inherent in a venlafaksin at its comparison with the SIOZS group antidepressants which are available in a medical turn, however this risk is lower, than the risk inherent in tricyclic antidepressants. Epidemiological researches showed that those patients who are treated venlafaksiny have бóльшую burdeness concerning risk of commission of a suicide in comparison with those patients who are treated SIOZS (other than a venlafaksin). However still remained obscure to what degree such high percent of deaths (because of overdose of a venlafaksin) are caused by toxic properties of the drug or special characteristics of that group of patients who are treated venlafaksiny. According to clinical experience, it is recommended in recipes on венлафаксин to write out minimum possible amount of the drug sufficient only prior to the next visit of the patient, for the purpose of decrease in risk of intended overdose (see also section "Special Instructions").

Treatment: the symptomatic and maintenance therapy is carried out. Specific antidotes are unknown. Continuous control of the vital functions (breath, blood circulation and a heart rhythm) is recommended. At overdose the immediate gastric lavage, reception of absorbent carbon for decrease in absorption of drug is recommended. It is not recommended to cause vomiting at risk of aspiration of emetic masses. The artificial diuresis, dialysis, hemotransfusion are inefficient.

Storage conditions:

To store in the place protected from light at a temperature not above 30 °C. To store in the place, unavailable to children. Period of validity 3 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets on 37,5 mg or 75 mg. On 10 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 1, 2, 3, 4 or 5 blister strip packagings together with the application instruction place in a pack from a cardboard.