Venlafaksin

General characteristics. Structure:

Active ingredient: 37,5 mg or 75 mg of a venlafaksin.

Drug with the expressed antidepressive action.

Pharmacological properties:

Pharmacodynamics. Antidepressive action of a venlafaksin at the person is caused by strengthening of neuromediator activity in TsNS. In preclinical trials it is shown that венлафаксин and its active metabolite — O-dezmetilvenlafaksin (ODV) are strong inhibitors of the return neyronalny serotonin reuptake and noradrenaline and weak inhibitors of the return capture of dopamine. Venlafaksin and ODV in vitro have no significant affinity to muskarinovy, gistaminergichesky, alfa1-adrenergic receptors, have no ability to inhibit MAO.

Pharmacokinetics. After intake венлафаксин it is well absorbed and extensively metabolized in a liver. After reception of a single dose at least 92% are absorbed, absolute bioavailability makes about 45% (owing to presistemny metabolism). Meal has no significant effect on absorption and biotransformation of a venlafaksin.

Release of a venlafaksin with the slowed-down release comes from a dosage form by diffusion through a membrane of spheroids and does not depend on pH. At reception of a venlafaksin of a hydrochloride in the form of capsules with the modified release (150 mg of 1 times a day) lower Cmax values (150 ng/ml for a venlafaksin and 260 ng/ml for ODV) and higher Tmax values (5,5 h for a venlafaksin and 9 h for ODV) are usually noted, than at reception of tablets with immediate release (Cmax of a venlafaksin at reception of 75 mg twice a day makes 225 ng/ml, ODV — 290 ng/ml), Tmax — 2 h (венлафаксин) and 3 h (ODV). At reception of equal daily doses of a venlafaksin of a hydrochloride or in the form of tablets with immediate release (as in two, and in three steps), or in the form of capsules were comparable to the modified release of exposure (AUC) of a venlafaksin and ODV at both modes of dosing, and fluctuations of plasma levels of a venlafaksin and ODV were slightly less at reception in the form of capsules. Therefore, capsules with the modified release provide lower speed, but identical extent of absorption of a venlafaksin in comparison by stabletka with immediate release.

Linkng with proteins of plasma makes 27%±2% (венлафаксин, in the range of concentration from 2,5 to 2215 ng/ml) and 30%±12% (ODV, in the range of concentration from 100 to 500 ng/ml).

It is metabolized mainly with formation of the only thing pharmacological of an active metabolite (ODV), and also several inactive — N-dezmetilvenlafaksin, N, O-didezmetilvenlafaksin, etc.

Extensive/weak metabolizant. In in vitro researches it is shown that O-demethylation of a venlafaksin with formation of ODV happens to participation of an isoenzyme of CYP2D6. It was confirmed also in the clinical trial which showed that patients with the low CYP2D6 level ("weak metabolizant") had the increased plasma levels of a venlafaksin and the lowered ODV levels in comparison with people with the normal CYP2D6 level ("extensive metabolizant"). However clinically significant distinctions at use of a venlafaksin for weak and extensive metabolizant since the general exposure (AUC) of a venlafaksin and ODV (венлафаксин + ODV) was similar in both groups are not expected, and pharmacological activity and efficiency of a venlafaksin and ODV are approximately identical.

Equilibrium concentration in plasma of both a venlafaksin, and ODV are reached within 3 days of multiple dose. The pharmacokinetics of a venlafaksin and ODV has linear character in the range of accepted daily doses of 75-450 mg/days (at reception each 8 h). The plasma clearance, T1/2 and volume of distribution in an equilibrium state were invariable both for a venlafaksin, and for ODV after reception of repeated doses. In an equilibrium state the plasma clearance of a venlafaksin and ODV was made by 1,3±0,6 l/h/kg and 0,4±0,2 l/h/kg, T
1/2 — 5±2 h and 11±2 h, distribution volume — 7,5±3,7 l/kg and 5,7±1,8 l/kg respectively.

It is removed preferential by kidneys: about 87% of a 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).

Dependence of parameters of pharmacokinetics on some factors. Age and floor. Data of the population pharmacokinetic analysis at 404 patients accepting венлафаксин when carrying out 2 researches (including administration of drug twice and three times a day), demonstrate that the age and a floor do not exert impact on pharmacokinetic parameters of a venlafaksin.

Abnormal liver function. At 9 patients with cirrhosis after reception of a venlafaksin pharmacokinetic parameters were considerably changed: lengthening of T1/2 was observed (approximately for 30%) and decrease in clearance (approximately for 50%) a venlafaksina, for ODV — T1/2  was extended approximately for 60%, the clearance decreased by 30%. Wide variability of these parameters at patients was noted. At three patients with heavy cirrhosis more considerable decrease in clearance of a venlafaksin (about 90%) was observed.

In the second research венлафаксин applied inside and in/in at healthy faces (n=21), and also at persons with easy (Child-Pugh A, n=8) and average (Child-Pugh B, n=11) degree of a liver failure. At oral administration at patients with abnormal liver functions increase in bioavailability by 2–3 times, lengthening of T1/2 approximately twice and decrease in clearance more than twice in comparison with healthy people was noted. Wide variability of these parameters at patients was noted.

Renal failure. At patients with a renal failure (a glomerular filtration rate of 10-70 ml/min.) increase in T1/2 of a venlafaksin approximately for 50% and decrease in clearance approximately for 24% was noted. The ODV pharmacokinetic parameters changed as follows: T1/2 increased approximately by 40% whereas values of clearance remained normal. At the patients who are on dialysis, T1/2 of a venlafaksin was extended approximately for 180%, and the clearance decreased by 57%, for ODV were noted lengthening of T1/2 approximately for 142% and decrease in clearance approximately for 56%. Variability of these parameters was observed.

Carcinogenicity, mutagenicity, influence on fertility. In carcinogenicity researches on mice and rats at introduction the animal of a venlafaksin in doses to 120 mg/kg/days within 18 months (mouse) and 24 months (rat) did not note increase in frequency of developing of tumors.

Venlafaksin and/or his metabolite ODV did not show mutagen activity in a number of in the vivo and in vitro tests, including in Ames's test with use of bacterial strains of Salmonella typhimurium, in the test of genovariations on cells of mammals, in the test of exchange of sister chromatids, etc. However the clastogene effect in in vivo the test of aberation chromosomes on marrow cells at males of the rats receiving the doses equivalent 200 MRDCh (is noted when calculating in mg/kg) or 50 MRDCh (when calculating in mg/sq.m); this effect was not shown at the doses equivalent of 67 MRDCh (mg/kg) or 17 MRDCh (mg/sq.m).

In researches on rats influence on fertility at females and males of rats is not revealed at introduction by an animal in the doses exceeding MRDCh to 8 times (mg/kg) or to 2 times (mg/sq.m).

Abuse and dependence. In the researches in vitro it is shown what венлафаксин actually has no affinity to opioid and benzodiazepine receptors, and also to receptors of phencyclidine and glutamate N-methyl - D-aspartate (NMDA) - to receptors. In pilot studies significant stimulation of TsNS was not revealed (at rodents), and also the significant exciting or oppressing action on TsNS is noted (at primacies). During clinical trials of a venlafaksin abuse cases were not noted. However these observations were not systematic therefore attentive observation of patients at whom in the anamnesis abuse of medicines is noted is required.

Clinical tests. Tablets with immediate release. Short-term tests. Efficiency of a venlafaksin of a hydrochloride at treatment of a depression was established in 5 placebos - controlled short-term tests. Four of these tests had duration of 6 weeks and included ambulatory patients with a big depression (according to criteria of DSM-III or DSM-III-R): in 2 researches the doses accepted by patients were in the range from 75 to 225 mg/days (reception three times a day); in the 3rd doses were fixed — 75; 225 and 375 mg/days (reception three times a day); in the 4th used doses 25; 75 and 200 mg/days (reception twice a day). The term of the 5th research made 4 weeks, the research included the patients with the diagnosis a big depression with melancholy (according to criteria of DSM-III-R) who were undergoing treatment in a hospital and receiving венлафаксин in doses from 150 to 375 mg/days (reception three times a day).

In these five researches of a venlafaksin the hydrochloride considerably surpassed placebo at least in two of three estimates on psychometric scales: total on Hamilton Scale for depression assessment, a mood assessment indicator on Hamilton Scale and a disease severity assessment indicator on the Scale of the general clinical impression. In researches ambulatories the most optimum (in comparison with placebo) had doses from 75 to 225 mg/days while patients in a hospital had more effective doses about 350 mg/days. Data of 2 researches with the fixed doses confirm interrelation "dose answer" in the range of doses of 75-225 mg/days whereas at doses over 225 mg/days of increase in efficiency at increase in a dose were not observed.

The analysis of the data obtained in clinical trials did not reveal influence of age or a sex of patients on efficiency of treatment (special researches of efficiency at elderly patients were not conducted; about 2/3 patients included in researches were female).

Long researches. Efficiency of a venlafaksin of a hydrochloride (a form of a venlafaksin with immediate release, tablets) as a maintenance therapy at treatment of recurrent depressive frustration at ambulatories (being responders after 26 weeks initial treatment, i.e. answered therapy, according to assessment on psychometric scales) was estimated in one placebo - a controlled research lasting up to 52 weeks. At the responders which continued therapy venlafaksiny in the same doses, a recurrence was significantly less, than in group of the patients receiving placebo.

Capsules with the modified release. Big depressive frustration. Short-term tests. Efficiency of a venlafaksin of a hydrochloride at treatment of a depression was established in two placebos - controlled, short-term (8-and 12 weeks) researches with use of various ranges of doses at the adult patients with a big depression (according to criteria of DSM-III-R or DSM-IV) treated on an outpatient basis. In a 12 weeks research to patients doses from 75 to 150 mg/days (the average dose calculated at the end of the research made 136 mg/days) were appointed, in a 8 weeks research used doses of 75-225 mg/days (an average dose at the end of the research — 177 mg/days). Expressiveness of symptomatology at patients was registered with use of various rating scales (including. Hamilton scale, Montgomery's Scale — Asberg, the Scale of the general clinical impression). In both researches of a venlafaksin the hydrochloride surpassed placebo, and also was much better than placebo at assessment of some indicators on Hamilton Scale, including an indicator of alarm/somatization, cognitive disturbances, retardation, mental alarm.

Efficiency of use of a venlafaksin in the form of capsules with the modified release at treatment of a depression at the hospitalized patients is not studied adequately.

Long researches. Efficiency of a venlafaksin of a hydrochloride (a form of a venlafaksin of the modified release, capsules) in a maintenance therapy at treatment of a depression (big depressive frustration by criteria of DSM-IV) at the ambulatories (who answered initial 8 weeks therapy venlafaksiny, so-called responders, according to assessment on the corresponding scales) was estimated in one placebo - a controlled research lasting up to 26 weeks. At the responders which continued therapy venlafaksiny of a recurrence was significantly less, than in group of placebo.

Generalized Alarming Frustration (GAF). Efficiency of a venlafaksin of a hydrochloride in the form of capsules with the modified release at treatment of GTR (by criteria of DSM-IV) at ambulatory patients was established in two 8 weeks placebos - controlled researches with the fixed doses (in the first — 75, 150 and 225 mg/days; in the second — 75 and 150 mg/days) and in two 6-month placebos - controlled researches, one of which was with the fixed doses, another — with use of range of doses.

Social Phobias (SP). Efficiency of a venlafaksin of a hydrochloride in the form of capsules with the modified release was established in four double blind people 12 weeks multicenter, placebo - controlled tests, and also in one double blind 6-month placebo - a controlled research, at treatment of the Federation Council (by criteria of DSM-IV) at adult patients in out-patient conditions with use of range of doses of 75-225 mg/days.

Panic frustration. Efficiency of a venlafaksin of a hydrochloride in the form of capsules with the modified release was established in two double blind 12 weeks multicenter placebos - controlled tests (with use of range of doses of 75-150 mg/days in one research and 75–225 mg/days — in another) at treatment of panic frustration with/without agoraphobia (by criteria of DSM-IV) at adult patients in out-patient conditions.

Use for patients of advanced age. In placebo - controlled premarketingovy tests of efficiency of a venlafaksin (in the form of capsules with the modified release) among patients with a depression, GTR, the Federation Council and panic frustration about 4% (14/357), 6% (77/1381), 1% (10/819) and 2% (16/1001) of patients were at the age of 65 years and are more senior. When carrying out researches of the Phase 2 and Phase of 3 of 2897 patients with a depression receiving венлафаксин (in the form of tablets with immediate release), 12% (357) patients were at the age of 65 years and are more senior. In these researches in general distinctions in efficiency and safety of use of a venlafaksin for patients of this age group in comparison with patients of young age were not observed. However it is impossible to exclude a possibility of hypersensitivity to HP at some patients. As well as at treatment other antidepressants, against the background of reception of a venlafaksin noted several cases of development of a hyponatremia and a syndrome of inadequate secretion of antidiuretic hormone (as a rule, at elderly patients).

Indications to use:

According to the State registry 1, a venlafaksin the hydrochloride in the form of tablets, tablets/capsules of the prolonged action, capsules with the modified release is shown at a depression (treatment, prevention of a recurrence).

According to Physicians Desk Reference (2009) 2, a venlafaksin the hydrochloride in the form of tablets with immediate release is shown for treatment of a depression. Venlafaksina the hydrochloride in the form of capsules with the modified release is shown for treatment of a depression, generalized alarming frustration, social phobias, panic frustration.

Route of administration and doses:

Inside, along with meal. The mode of dosing is selected individually, purpose of minimal effective doses is desirable. The recommended initial dose — 75 mg/days (tablets — a daily dose divide into 2–3 receptions, capsules — 1 times/days, approximately at the same time days — in the morning or in the evening). For some patients the starting dose of 37,5 mg/days can be desirable (within 4–7 days).

If necessary increase in a dose (gradually, on 75 mg/days, 1 time in 4 days is possible and more) to 225 mg/days (the recommended dose at a depression of moderate severity), in a hospital (at a heavy depression) increase in a dose to maximum — 375 mg/days is possible.

Decrease in a daily dose by 50% is required from patients with an abnormal liver function from easy to moderate severity, at cirrhosis — and more than 50%. Against the background of a renal failure (a glomerular filtration rate — 10–70 ml/min.) the dose decline for 25–50% is necessary, at a hemodialysis — for 50%, it is necessary to accept drug after a hemodialysis.

It is not required from patients of advanced age of special correction of doses, however it is necessary to be careful at treatment of this category of patients, especially at increase in a dose.

Features of use:

Use at pregnancy and feeding by a breast. At pregnancy use is possible only in urgent cases (adequate and strictly controlled researches of safety of use for pregnant women are not conducted). Category of action on a fruit on FDA — C.

Teratogenic effects. Venlafaksin did not cause malformations in posterity of the rats and rabbits receiving it in doses, to 11 times (rat) or 12 times (rabbits) of the exceeding MRDCh (when calculating in mg/kg), or by 2,5 times (rat) and 4 times (rabbits) MRDCh (is higher when calculating in mg/sq.m). However at rats (if венлафаксин began to give during pregnancy and continued before the end of the period of feeding) decrease in body weight of cubs, increase in number of mortinatus cubs, increase in mortality of cubs in the first 5 days of feeding was noted. The reason of these death is unknown, these effects were observed at doses by 10 times (mg/kg) or 2,5 times (mg/sq.m) of the exceeding MRDCh. Influence on mortality of cubs at rats at the doses exceeding MRDCh by 1,4 times (mg/kg) or by 0,25 times of MRDCh (mg/sq.m) was not noted.

Not teratogenic effects. At purpose of a venlafaksin in the III trimester of pregnancy the doctor has to estimate carefully potential risk and advantage of its use. In clinical practice a number of adverse effects at newborns was noted if their mothers accepted венлафаксин, other inhibitors of the return serotonin reuptake and noradrenaline or SIOZS, to or just before childbirth, including a respiratory distress, cyanosis, an apnoea, spasms, unstable body temperature, vomiting, a hypoglycemia, a hyperreflexia, a tremor, excitability, continuous crying. These adverse effects are connected or with direct toxic impact or, perhaps, are manifestation of a withdrawal (discontinuation effects) at the newborn. It should be noted that in certain cases the clinical picture was similar to a serotoninovy syndrome.

The effect of a venlafaksin of a hydrochloride on childbirth and delivery at the person is unknown. Venlafaksin and his active metabolite ODV get into breast milk of women. Considering potential risk of serious side effects at the children who are on breastfeeding, the feeding women should stop either breastfeeding, or use of HP (according to importance of HP for mother).

Clinical deterioration and risk of a suicide. In short-term researches of big depressive frustration on criteria of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders (4th ed.) — The reference book on diagnosis and statistics of mental disorders, the 4th edition) and other mental diseases increase in a suitsidalnost (risk of suicide intentions or attempts of a suicide) at reception of antidepressants in comparison with placebo at children, teenagers and people of young age (from 18 to 24 years) was observed. At purpose of a venlafaksin or any other antidepressant patients of these age groups should estimate possible risk. In short-term researches at adults 24 years are more senior it is shown that the risk of a suitsidalnost at reception of antidepressants in comparison with placebo does not increase, and at patients 65 years are more senior — decreases. The depression and some other mental diseases are associated with the increased risk of a suicide. At therapy by antidepressants, especially in an initiation of treatment, careful observation of patients of any age is necessary for timely detection of clinical deterioration, a suitsidalnost or unusual change of behavior. The relatives of patients and persons who are looking after them need to know about need of attentive observation of patients and timely informing the doctor.

It is necessary to prick up the ears at emergence of alarm, agitation, the panic attacks, an insomniya, irritability, aggression, hostility, an akathisia, a hypomania or a mania, other symptoms of unusual behavior of patients as well as at emergence of tendency to suicide and immediately to report about these symptoms to the attending physician.

Venlafaksin do not apply at patients aged up to 18 years (see. "Restrictions to use").

Combination to MAO inhibitors (see. "Contraindications"). Treatment venlafaksiny should be begun not earlier than in 14 days after the end of reception of MAO inhibitors, in turn treatment by MAO inhibitors can be begun not earlier than in 7 days after cancellation of a venlafaksin. At a concomitant use of a venlafaksin and MAO inhibitors development of heavy side reactions is possible (including a tremor, a myoclonus, plentiful sweating, nausea, vomiting, rush of blood to the person, dizziness; a hyperthermia with the signs similar to an antipsychotic malignant syndrome; spasms, up to a lethal outcome).

Persistent hypertensia. At some patients in the course of treatment the persistent venlafaksin-induced hypertensia defined as increase in diastolic pressure in a prone position (DADL) of ≥90 mm of mercury develops. and ≥10 mm of mercury. in relation to basic (initial) level at measurement during three consecutive visits to the doctor.

In premarketingovy researches when using of three fixed doses of a venlafaksin — 75, 225 and 375 mg/days in the form of tablets with immediate release in comparison with placebo average value of increase in DADL in group of the patients receiving 375 mg/days by the end of the 6th week made 7,2 mm of mercury., whereas in groups of the patients accepting doses of 75 and 225 mg/days, essential changes were not (in group of placebo decrease in DADL by 2,2 mm of mercury was noted.). The analysis which is carried out at the patients answering to criterion of existence of persistent hypertensia revealed dozozavisimy increase in frequency of its emergence. At doses of a venlafaksin less than 100 mg/days persistent hypertensia was noted in 3% of cases, 101–200 mg/days — 5%, 201–300 mg/days — 7%, more than 300 mg/days — 13% (placebo — 2%). The analysis at patients with existence of persistent hypertensia and 19 patients who stopped treatment in connection with development of hypertensia (less than 1% of total number of the patients accepting венлафаксин) revealed that most often DADL increased by 10–15 mm of mercury. Nevertheless long increase in DADL can have adverse effects. Therefore regular monitoring of the ABP at the patients accepting венлафаксин is recommended. In cases of long increase in the ABP it is necessary either to lower a dose, or to resolve an issue of drug withdrawal.

In premarketingovy researches at the patients with big depressive frustration receiving a venlafaksin a hydrochloride in the form of capsules with the modified release in doses of 75-375 mg/days in 3% of cases (19/705) persistent hypertensia was noted. At the patients with generalized alarming frustration accepting венлафаксин in doses of 37,5-225 mg/days, persistent hypertensia was noted in 0,5% of cases (5/1011). At the patients with social phobias receiving doses of 75-225 mg/days, persistent hypertensia was noted in 1,4% of cases (4/277). The number of patients in these researches receiving doses over 300 mg/days was insufficient for assessment of frequency of increase in the ABP at the highest doses.

Mydriasis. As it was reported about development of a mydriasis at treatment venlafaksiny, it is necessary to apply with care it at patients with the increased intraocular pressure or with risk of development of a bad attack of closed-angle glaucoma.

Insomniya and nervousness. The integrated analysis of short-term, double blind people, placebo - controlled researches at patients with a depression showed that the alarm of 6% (3%), nervousness of 13% (6%), an insomniya of 18% (10%) were the most cumulative effects connected with reception of a venlafaksin in the form of tablets with immediate release (n=1033) in comparison with placebo (n=609), in brackets the percent in group of placebo is specified. In the Phase 2 and the Phase of 3 researches at patients with a depression the alarm, nervousness and an insomniya led to the termination of treatment at 2%, 2% and 3% of patients, respectively.

The integrated analysis of short-term researches at patients with a depression, generalized alarming frustration and social phobias showed that the insomniya and nervousness were the most cumulative effects connected with reception of a venlafaksin in the form of capsules with the modified release in comparison with placebo (in brackets the percent in group of placebo is specified). Insomniya was marked out in 17% of cases (11%), nervousness – 10% (5%) is at patients with a depressive episode (n=357) in comparison with placebo (n=285); Patients have 15% (10%) and 6% (4%) with generalized alarming frustration (n=1381) in comparison with placebo (n=555); Patients have 23% (7%) and 11% (3%) with social phobias (n=277) in comparison with placebo (n=274), respectively.

At treatment of patients with a depressive episode of 0,9% of patients stopped treatment because of emergence of an insomniya and 0,9% — because of emergence of nervousness. At patients with generalized alarming frustration at treatment during up to 8 weeks the insomniya and nervousness were the reason of the termination of therapy in 3 and 2% of cases, lasting treatment up to 6 months — in 2 and 0,7% of cases respectively. At patients with social phobias at treatment up to 12 weeks the insomniya was the reason of cancellation of a venlafaksin in 3% of cases, nervousness was not the reason of drug withdrawal.

Change of appetite and body weight. By results of short-term, double blind people, placebo - controlled researches at patients with a depression it was most often reported about the anorexia arising at reception of a venlafaksin (11% of a tablet / 8 capsule %) in comparison with placebo (2% of a tablet / 4 capsule %). Dozozavisimy decrease in body weight was often noted at the patients accepting венлафаксин within several weeks. Essential decrease in body weight, especially at the patients with a depression having too small weight can be undesirable effect of treatment venlafaksiny. Decrease in body weight by 5% was also more observed against the background of a venlafaksin at 6% of patients (tablet) of/7% (capsule) in comparison with placebo (1%/2%) and at 3% of the patients accepting other antidepressant. The termination of decrease in body weight under the influence of a venlafaksin (tablet) was noted seldom — in 0,1% of cases when carrying out researches of the Phase 2 and Phase 3 at patients with a depression. Patients with a depression at reception of capsules also had a small termination of progressing of anorexia and a degrowth of a body — 1 and 0,1% respectively.

In short-term (to 8 weeks) researches at the patients with generalized alarming frustration receiving венлафаксин in the form of capsules, anorexia was noted in 8% of cases (placebo — 2%). Decrease in body weight by 7% was also more observed at 3% of the patients receiving венлафаксин in the form of capsules during the period up to 6 months (placebo — 1%). The termination of progressing of anorexia and a degrowth of a body at reception of capsules during the period to 8 weeks was observed at 0,9% and 0,3% of patients respectively.

In researches at the patients with social phobias receiving венлафаксин in the form of capsules during the period to 12 weeks, anorexia was noted in 20% of cases (placebo – 2%). Decrease in body weight by 7% was not observed at the patients receiving венлафаксин in the form of capsules during the period up to 12 months in group of placebo also any more. The termination of progressing of anorexia and a degrowth of a body at reception of capsules during the period to 12 weeks made 0,4% and 0,0% respectively.

Activation of a mania/hypomania. At a small number of patients with the disturbances of mood receiving antidepressants the mania or a hypomania can develop. By results of all premarketingovy tests of a venlafaksin at patients with a depression the mania/hypomania was noted in 0,5% (tablet) and 0,3% (capsule) of cases (placebo of 0%). As well as other antidepressants, венлафаксин patients should appoint with care with a mania in the anamnesis.

Hyponatremia. It must be kept in mind that against the background of a venlafaksin development of a hyponatremia and syndrome of inadequate secretion of antidiuretic hormone, especially at patients with a hypovolemia, dehydration, at elderly people is possible, and also at a concomitant use of diuretics.

Spasms. During premarketingovy tests of a spasm were noted at 0,26% (8/3082) patients receiving венлафаксин (tablets) most of which part (5 of 8) was observed at the patients accepting doses of 150 mg/days and less. At reception of a venlafaksin in the form of capsules at patients with a depressive episode (n=705), generalized alarming frustration (n=1381) and social phobias (n=277) of spasms it was not noted. Nevertheless it is necessary to appoint with care венлафаксин to patients with the instruction to spasms in the anamnesis. At development of an attack it is necessary to stop administration of drug.

Hemorrhages. There are messages on emergence against the background of a venlafaksin of abnormal skin hemorrhages (in most cases ecchymomas — extensive hemorrhages in skin or a mucous membrane). Relationship of cause and effect of this phenomenon is not established with reception of a venlafaksin, however disturbance of aggregation of thrombocytes was noted (perhaps owing to reduction of content of serotonin in them).

Increase in level of serumal cholesterol (see. "Side effects" Change of laboratory indicators).

At long therapy measurement of level of serumal cholesterol (during clinical tests clinically significant increase in this indicator at the patients receiving венлафаксин is noted) is recommended.

Use for patients with associated diseases. Clinical experience of use of a venlafaksin in the presence at patients of associated diseases is limited. It is necessary to be careful at a number of diseases and states, including followed disturbance of a hemodynamics or metabolism (see. "Restrictions to use").

Systematic observations at patients with recently postponed myocardial infarction or unstable stenocardia since these patients were excluded from many clinical premarketingovy trials were not made. However the analysis of an ECG at the patients receiving венлафаксин shows that administration of drug is not connected with development of clinically significant deviations on an ECG.

Treatment termination venlafaksiny. It was reported about emergence in patients of the effects caused by the treatment termination venlafaksiny (discontinuation effects). In this regard cancellation of a venlafaksin should be carried out gradually, by a dose decline to reduce risk of emergence of reactions of cancellation, at the same time observation of a condition of the patient is recommended. Time of the period of cancellation can depend on a dose, duration of therapy and specific features of the patient. At treatment venlafaksiny during 6 weeks and more period of drug withdrawal has to be not less than 2 weeks.

Manifestations of reaction of cancellation at the patients treated venlafaksiny were systematized when carrying out the prospective analysis of results of clinical tests of a venlafaksin at generalized alarming frustration and the retrospective review of tests at a depression. It was revealed that the sharp termination of reception of a venlafaksin or decrease in its dose (at various doses) are associated with emergence of symptoms which frequency increased with increase in a dose and duration of treatment. Noted symptoms included the following: agitation, anorexia, alarm, confusion of consciousness, an incoordination, diarrhea, dizziness, dryness in a mouth, a dysphoria, fascicular twitchings, fatigue, a headache, a hypomania, an insomniya, nausea, nervousness, nightmares, spasms, sensitivity disturbance (including feeling of blow by electric current), drowsiness, perspiration, a tremor, вертиго, vomiting.

Maintenance therapy. In the carried-out clinical tests there is no enough the data specifying how it is long possible to accept венлафаксин at treatment of a depression, generalized alarming frustration and social phobias.

Though венлафаксин did not strengthen influence of ethanol on psychomotor reactions at volunteers, it is necessary to avoid a concomitant use of a venlafaksin and alcohol.

In researches on healthy volunteers clinically significant decrease in cogitative activity and speed of psychomotor reactions against the background of a venlafaksin was not noted. However, as any psychoactive drug can exert impact on TsNS, patients have to be warned about need to be careful during the work with potentially dangerous mechanisms and when driving the car.

Side effects:

According to ^{Physicians Desk Reference (2009)2}

Tablets with immediate release. The side effects connected with the treatment termination. 19% of the patients (537/2897) with a depression receiving венлафаксин when carrying out researches of the Phase 2 and Phase 3 stopped treatment in connection with emergence of side effects. The following (in brackets the percent in group of placebo is specified) were the most cumulative effects (≥1%) which were the reason of the termination of therapy and considered as caused by drug intake (i.e. observed approximately in 2 and more times is more often at reception of a venlafaksin in comparison with placebo): drowsiness of 3% (1%), insomniya of 3% (1%), dizziness of 3%.

The side effects observed in controlled tests. By the most frequent side effects connected with reception of a venlafaksin of a hydrochloride (frequency of occurrence of 5% and more), not equivalent on occurrence frequency in group of placebo, i.e. at reception of a venlafaksin of a hydrochloride were observed at least twice more often than in group of placebo (see tab. 1), there were an adynamy, perspiration, nausea, a lock, anorexia, vomiting, drowsiness, dryness in a mouth, dizziness, nervousness, alarm, a tremor, a sight illegibility, disturbance of an ejaculation/orgasm and impotence at men.

The side effects observed with a frequency of 1% at patients, treated a venlafaksina a hydrochloride (tab. 1). The side effects noted at the patients receiving a venlafaksin a hydrochloride in the form of tablets in doses of 75-375 mg/days when carrying out short-term tests are presented in table 1 (4-and 8 weeks). These effects were observed with a frequency of 1% and exceeded on placebo frequency. In the table the percent of patients in each group at whom one case of separate side effect during treatment was noted at least is specified. Side effects are grouped with use of the standard terminological COSTART dictionary.

Table 1. The by-effects observed in 4-8 weeks placebos - controlled clinical tests at treatment of patients with a depression

Systems of an organism / Side effects	Venlafaksin (n=1033), %	Placebo (n=609), %
Organism in general
Headache	25	24
Adynamy	12	6
Infection	6	5
Fever	3	-
Stethalgia	2	1
Injury	2	1
Cardiovascular system
Vazodilatation	4	3
Increase ABP/hypertensia	2	-
Tachycardia	2	-
Orthostatic hypotension	1	-
Skin
Perspiration	12	3
Rash	3	2
Itch	1	-
Digestive tract
Nausea	37	11
Lock	15	7
Anorexia	11	2
Diarrhea	8	7
Vomiting	6	2
Dyspepsia	5	4
Meteorism	3	2
Metabolism
Decrease in body weight	1	-
Nervous system
Drowsiness	23	9
Dryness in a mouth	22	11
Dizziness	19	7
Insomniya	18	10
Nervousness	13	6
Alarm	6	3
Tremor	5	1
Unusual dreams	4	3
Hypertensia	3	2
Paresthesia	3	2
Decrease in a libido	2	-
Agitation	2	-
Confusion of consciousness	2	1
Disturbance of process of thinking	2	1
Depersonalization	1	-
Depression	1	-
Urination delay	1	-
Twitchings of muscles	1	-
Respiratory system
Yawning	3	-
Sense bodys
Sight misting	6	2
Food faddism	2	-
Tinnit	2	-
Mydriasis	2	-
Urinogenital system
Disturbance of an ejaculation/orgasm	12 *	-*
Impotence	6 *	-*
Increase of an urination	3	2
Disturbance of an urination	2	-
Disturbance of an orgasm	2 **	-**

- less than 1%

The adverse effects noted at least at 1% of the patients accepting a venlafaksin a hydrochloride and the placebos observed with a frequency equal or smaller, included the following: pain, including abdominal pain, a dorsodynia, a mialgiya, an arthralgia, a grippopodobny syndrome, fever, heartbeat, increase in appetite, amnesia, a hypesthesia, rhinitis, pharyngitis, sinusitis, strengthening of cough, a dysmenorrhea (at women).

Dependence of side effects on a dose. Assessment of degree of manifestation of side effects at the patients receiving a venlafaksin a hydrochloride was carried out in a comparative research with the fixed doses: 75 mg/days (n=89), 225 mg/days (n=89), 375 mg/days (n=88) and placebo (n=92). Effects which met frequency of 5% and more at least in one of groups of the patients receiving венлафаксин and were observed at least twice more often than in group of placebo were considered.

For assessment of a tendency of potential dependence "a dose - side effect" used Kokhrana-Armitage's test with bilateral criterion, took P for the level of the statistical importance

Adaptation to some side effects. During the 6 weeks period of therapy cases of adaptation to some side effects (for example, dizziness and nausea), to a lesser extent — to other effects were noted (for example, disturbance of an ejaculation, dryness in a mouth).

Capsules with the modified release. The data obtained in short-term placebos - controlled researches are submitted.

The side effects connected with the treatment termination. By results of clinical tests, nearly 11% from 357 patients with a big depressive episode receiving a venlafaksin a hydrochloride interrupted treatment because of emergence of side effects, in comparison with 6% from 285 patients receiving placebo. At patients with GTR the similar indicator made 18% from 1381 patients (placebo — 12% from 555), at patients with the Federation Council are 15% from 819 patients (placebo — 5% from 695), at patients with panic frustration are 7% from 1001 (placebo — 6% from 662).

The following (in brackets the percent in group of placebo is specified) were side effects which led to the termination of treatment and were connected with drug intake (i.e. the placebos leading to the drug intake termination at least at 1% of patients, and meeting at least twice more often) depending on the diagnosis:

patients with a depression have a nausea of 4%;

patients with GTR have an adynamy of 3%;

patients with the Federation Council have an adynamy of 1%.

The side effects observed in controlled tests with a frequency of 2% at patients, treated a venlafaksina a hydrochloride (tab. 2).

The side effects noted at the patients receiving a venlafaksin a hydrochloride during placebo - controlled clinical tests at the emergency therapy of a big depressive episode (to 12 weeks, the range of doses from 75 to 225 mg/days) are presented to GTR in table 2 (to 8 weeks, the range of doses from 37,5 to 225 mg/days), the Federation Council (to 12 weeks, the range of doses from 75 to 225 mg/days), panic frustration (to 12 weeks, the range of doses from 37,5 to 225 mg/days). These effects were observed with a frequency of 2% and exceeded on placebo frequency. In the table the percent of patients in each group at whom one case of separate side effect during treatment was noted at least is specified. Side effects are grouped with use of the standard terminological COSTART dictionary.

 (Frequency of occurrence of 5% and more), not equivalent on occurrence frequency in group of placebo (i.e. at reception of a venlafaksin of a hydrochloride were observed at least twice more often than in group of placebo) at carrying out clinical tests, depending on the diagnosis, the following (see also tab. 2) was the most frequent side effects connected with reception of a venlafaksin of a hydrochloride:

At patients with a depression in all placebos - controlled tests were noted, in particular: disturbance of an ejaculation, gastrointestinal frustration (nausea, dryness in a mouth and anorexia), disturbances from TsNS (dizziness, drowsiness, unusual dreams), perspiration. In two placebos - the controlled tests which are carried out to the USA in addition were noted (n=192): disturbances of sexual function (impotence at men, an anorgazmiya at women, decrease in a libido), gastrointestinal frustration (a lock and a meteorism), disturbances from TsNS (an insomniya, nervousness and a tremor), a vision disorder, cardiovascular disturbances (hypertensia and a vazodilatation), yawning.

At patients with GTR during all placebos - controlled tests were noted: disturbances of sexual function (disturbance of an ejaculation and impotence), gastrointestinal frustration (nausea, dryness in a mouth, anorexia, a lock), a vision disorder, perspiration.

At patients with the Federation Council in placebo - controlled tests the adynamy, gastrointestinal frustration (anorexia, dryness in a mouth, nausea, a lock), disturbances were noted from TsNS (an insomniya, decrease a libido, nervousness, drowsiness, a tremor), disturbances of sexual function (disturbance of an ejaculation, impotence), yawning, perspiration.

Table 2. The side effects observed in placebo - controlled clinical tests at treatment of patients with a depression, the generalized alarming frustration (GAF) and the social phobias (SP)

Systems of an organism / Side effects	Depression		GTR		FEDERATION COUNCIL
	Venlafaksin (n=357), %	Placebo (n=285), %	Venlafaksin (n=1381), %	Placebo (n=555), %	Venlafaksin (n=819), %	Placebo (n=695), %
Organism in general
Adynamy	8	7	12	8	19	9
Headache	-	-	-	-	38	34
Accidental injury	-	-	-	-	4	3
Abdominal pain	-	-	-	-	6	4
Cardiovascular system
Vazodilatation (mainly inflows)	4	2	4	2	3	2
Hypertensia	4	1	-	-	5	3
Heartbeat	-	-	-	-	3	1
Alimentary system
Nausea	31	12	35	12	31	9
Lock	8	5	10	4	9	3
Anorexia	8	4	8	2	17	2
Vomiting	4	2	5	3	-	-
Meteorism	4	3	-	-	-	-
Diarrhea	-	-	-	-	8	6
Dyspepsia	-	-	-	-	7	6
Metabolism
Decrease in body weight	3	0	-	-	2
Nervous system
Dizziness	20	9	16	11	16	8
Drowsiness	17	8	14	8	20	8
Insomniya	17	11	15	10	24	8
Dryness in a mouth	12	6	16	6	17	4
Nervousness	10	5	6	4	10	5
Unusual dreams (mainly bright dreams, nightmares, a dream with dreams)	7	2	3	2	3
Alarm	-	-	-	-	5	4
Tremor	5	2	4		5	2
Hypertension	-	-	3	2	-	-
Paresthesia	3	1	2	1	-	-
Decrease in a libido	3		4	2	8	2
Agitation	3	1	-	-	3	1
Depression	3		-	-	-	-
Twitchings of muscles	-	-	-	-	3
Respiratory system
Pharyngitis	7	6	-	-	-	-
Yawning	3	0	3		5
Skin
Perspiration	14	3	10	3	13	4
Sense bodys
Vision disorder (including sight misting)	4		5		4	2
Urinogenital system
Disturbance of an ejaculation (including ejaculation delay) *	16		11		19
Impotence *	4		5		6
Orgazmichesky frustration (including orgasm delay, anorgazmiya) **	3		2	0	5

- less than 2%
* it was fixed only at men
** it was fixed only at women

The side effects observed in placebo - controlled clinical tests at treatment of patients with panic frustration (near the name the percent of occurrence of this side effect in the group receiving венлафаксин [n=1001]), in brackets — in group of placebo [n=662] is specified):

Organism in general: an adynamy — 10% (8%).

Cardiovascular system: hypertensia — 4% (3) %, a vazodilatation (mainly inflows) — 3% (2%).

Alimentary system: nausea — 21% (14%), dryness in a mouth — 12% (6%), a lock — 9% (3%), anorexia — 8% (3%).

Nervous system: an insomniya of 17% (9%), drowsiness — 12% (6%), dizziness — 11% (10%), a tremor — 5% (2%).

Skin: perspiration — 10% (2%).

Urinogenital system: decrease in a libido — 4% (2%), disturbance of an ejaculation (including an ejaculation delay) — 8%.

It must be kept in mind that the data on side effects obtained in placebo - controlled researches, cannot be used for forecasting of emergence of side effects in customary medical practice since the condition of patients and other factors differ from those which prevailed in clinical tests. In this way, the figures of frequency of occurrence of side effects specified in tables (as a percentage) can differ from received by other clinical researchers since each testing of HP can be carried out with various set of conditions. However the provided figures give to the doctor an idea of a relative contribution of the substance and other factors (which are not connected with HP), in development of side effects at use of HP in population.

Change of the vital functions. Tablets with immediate release. When carrying out clinical tests it is revealed that against the background of reception of a venlafaksin pulse rate was increased approximately on 3 beats per minute — average value for all groups of the patients receiving various doses (in comparison with placebo where such changes were not noted). In researches with a range of doses of 200-375 mg/days (average value of a dose — more than 300 mg/days) pulse rate was increased on average on 2 beats per minute (in comparison with placebo where decrease by 1 beat per minute was noted).

In controlled clinical tests increase in DAD in the range of 0,7-2,5 mm hg (for all groups of patients) in comparison with placebo where decrease in DAD in the range of 0,9–3,8 mm hg was noted was connected with reception of a venlafaksin. At the same time increase in the ABP was dozozavisimy (see. "Precautionary measures", persistent hypertensia).

Capsules with the modified release. In premarketingovy placebos - controlled researches at the patients with a big depressive episode receiving a venlafaksin a hydrochloride during the period to 12 weeks by the time of the end of therapy increase in pulse rate on average on 2 beats per minute in comparison with placebo was noted (increase on 1 beat per minute). Similar results were received in premarketingovy placebos - controlled researches at patients with GTR (to 8 weeks of treatment). In premarketingovy placebos - controlled researches at patients from the Federation Councils receiving венлафаксин during the period to 12 weeks, pulse rate was increased on average on 3 beats per minute (in group of placebo — increase on 1 beat per minute). In premarketingovy placebos - controlled researches at the patients with panic frustration receiving венлафаксин during the period to 12 weeks, pulse rate was increased on average on 1 beat per minute (in group of placebo — decrease less than on 1 beat per minute).

Change of laboratory indicators. By results of the monitoring of laboratory indicators which is carried out during clinical tests of a venlafaksin (a tablet, the capsule), statistically significant distinctions (in comparison with placebo) were noted in the level of serumal cholesterol. So, at treatment venlafaksiny (tablets) of patients with a depression at least within 3 months clinically significant increase in level of cholesterol was registered at 5,3% of patients in comparison with 0% of placebo (by results of carrying out 12-month placebos - controlled tests).

Change of an ECG. Comparison of an ECG at the patients receiving a venlafaksin a hydrochloride (n=769) and placebo (n=450) in controlled clinical tests showed that increase in ChSS against the background of reception of a venlafaksin was statistically significant difference only.

Interaction with other medicines:

It is incompatible with MAO inhibitors (see. "Precautionary measure").

Simultaneous use for 18 healthy volunteers of Cimetidinum and venlafaksin at achievement of equilibrium concentration of both substances led to inhibition of metabolism of a venlafaksin at "the first passing" through a liver, to decrease in clearance of a venlafaksin approximately for 43% and to increase in AUC and Cmax by 60%, at the same time Cimetidinum did not influence ODV pharmacokinetics (which is present in at a system blood-groove in much bigger quantity, than венлафаксин); the general pharmacological activity "венлафаксин + ODV" increased only slightly; interaction of a venlafaksin and Cimetidinum can have more expressed character at patients against the background of hypertensia, an abnormal liver function and at people of advanced age (it is necessary to be careful).

Interaction between diazepam and its active metabolite dezmetildiazepamy and venlafaksiny and its metabolite (ODV) at 18 healthy volunteers is not revealed at use of a single dose of diazepam against the background of a venlafaksin in equilibrium conditions.

Reception of a single peroral dose of a haloperidol against the background of a venlafaksin in equilibrium conditions at 24 healthy volunteers led to change of pharmacokinetic parameters of a haloperidol: to decrease in the general clearance of a haloperidol by 42%, increase in AUC by 70% and Cmax by 80%; at this T1/2 was left without changes.

Single oral administration of lithium did not influence pharmacokinetics of a venlafaksin (and also ODV) in an equilibrium state at 12 healthy men. Venlafaksin also did not change pharmacokinetic parameters of lithium.

Venlafaksin did not increase free concentration in blood of another, at the same time accepted HP with high linkng with proteins (in view of low linkng of a venlafaksin and ODV with proteins of plasma).

In the researches in vitro it is shown what венлафаксин is weak inhibitor of an isoenzyme CYP2D6 and does not inhibit isoenzymes of CYP3A4, CYP1A2, CYP2C9, CYP2C19.

Venlafaksin does not influence pharmacokinetics of Imipraminum and its active metabolite, similar to Imipraminum does not influence pharmacokinetics of a venlafaksin and its active metabolite.

Single oral administration of a risperidon against the background of a venlafaksin in equilibrium conditions was followed by increase in AUC of a risperidon for 32% owing to low inhibition of CYP2D6 - the mediated metabolism of a risperidon to an active metabolite (9-hydroxy-risperidon), at the same time the general pharmacological activity (рисперидон + a metabolite) did not change.

In clinical trials interaction of a venlafaksin with the HP which are metabolized with the participation of CYP3A4 is not revealed (including alprazola, diazepam, терфенадин).

Reception of a single peroral dose of an indinavir against the background of a venlafaksin in an equilibrium state at 9 healthy volunteers led to decrease in AUC and Cmax of an indinavir by 28% and 36% respectively (clinical value of the revealed phenomenon is unknown).

The single dose of ethanol (0,5 g/kg) did not exert impact on pharmacokinetics of a venlafaksin and ODV at reception of a venlafaksin in a dose of 150 mg/days (at 15 healthy men).

Contraindications:

Hypersensitivity, concomitant use of MAO inhibitors (see. "Precautionary measures").

Restrictions to use. Recently postponed myocardial infarction and unstable stenocardia, changes of the ABP, the increased intraocular pressure and closed-angle glaucoma, maniacal states in the anamnesis, initially a body underweight, a renal/liver failure, age up to 18 years (safety and efficiency of use are not established).

Overdose:

Symptoms: changes of an ECG (lengthening of an interval of QT, blockade of legs of a ventriculonector, expansion of the QRS complex, etc.), sinus and ventricular tachycardia, bradycardia, hypotension, dizziness, disturbance of consciousness of various degree of manifestation (from drowsiness to a coma), spasms, up to a lethal outcome.

Treatment: use of absorbent carbon, induction of vomiting, a gastric lavage (for absorption reduction). Maintenance of passability of respiratory tracts for ensuring adequate ventilation and oxygenation. Careful observation and monitoring of a heart rhythm and other vital functions, a symptomatic and maintenance therapy is recommended. Efficiency of such actions as an artificial diuresis, dialysis, hemoperfusion and exchange hemotransfusion is improbable. There is no specific antidote.

In post-market researches cases of overdose of a venlafaksin were noted preferential at a concomitant use of alcohol and/or other medicines.

Storage conditions:

To store at a temperature of 15-25 °C, in dry, protected from light and 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 of 37,5 mg, 75 mg. 20 tablets (for a dose of 37,5 mg) or 10 tablets (for a dose of 75 mg) in each blister, on one, two or three blisters together with the application instruction in cardboard packaging.