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Instruction for use: Venlafaxine
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The Latin name of the substance Venlafaxine
Venlafaxinum (genus. Venlafaxini)
Chemical name
1- [2- (Dimethylamino) -1- (4-methoxyphenyl) ethyl] cyclohexanol (as hydrochloride)
Gross formula
C17H27NO2
Pharmacological group:
Antidepressants
The nosological classification (ICD-10)
F32 Depressive episode: Adynamic subdepression; Astheno-adynamic subdepressive states; Asthenodepressive disorder; Astheno-depressive disorder; Asthenodepressive state; Astheno-depressive state; Major Depressive Disorder; Vyaloapatichesky depression with retardation; Double depression; Depressive pseudodement; Depressive illness; Depressive mood disorder; Depressive disorder; Depressive mood disorder; Depressive state; Depressive disorders; Depressive syndrome; Depressive syndrome larviated; Depressive syndrome with psychoses; Depressed masks; Depression; Depression Depletion; Depression with the phenomena of inhibition within the framework of cyclothymia; Depression is smiling; Involutional depression; Involutionary melancholy; Involutional depression; Manic-depressive disorder; Masked Depression; Melancholic Attack; Neurotic depression; Neurotic depression; Shallow Depression; Organic depression; Organic depressive syndrome; Simple depression; Simple melancholic syndrome; Psychogenic depression; Reactive depression; Reactive depression with moderate psychopathological symptoms; Reactive depressive states; Reactive depression; Recurrent depression; Seasonal depressive syndrome; Severostatic depression; Senile Depression; Senile Depression; Symptomatic Depression; Somatogenic depression; Cyclotymic depression; Exogenous Depression; Endogenous depression; Endogenous Depressive Conditions; Endogenous Depression; Endogenous depressive syndrome
F33 Recurrent depressive disorder: Major depressive disorder; Secondary depression; Double Depression; Depressive pseudodement; Depressive mood disorder; Depressive disorder; Depressive mood disorder; Depressive state; Depressive syndrome; Depressed masks; Depression; Depression is smiling; Involutional depression; Involutional depression; Masked Depression; Melancholic Attack; Reactive depression; Reactive depression with moderate psychopathological symptoms; Reactive depressive states; Exogenous depression; Endogenous depression; Endogenous Depressive Conditions; Endogenous Depression; Endogenous depressive syndrome
CAS Code
93413-69-5
Characteristics of the substance Venlafaxine
Antidepressant. Inhibitor of reuptake of serotonin and norepinephrine.
Venlafaxine hydrochloride is a white or almost white crystalline substance. The solubility in water is 572 mg / ml. The octanol / water partition coefficient is 0.43. Molecular weight is 313.87.
Pharmacology
Pharmacological action - antidepressant.
The antidepressant effect of venlafaxine in humans is due to the increase in neurotransmitter activity in the central nervous system. In preclinical studies, venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODB), have been shown to be potent inhibitors of reverse neuronal seizure of serotonin and norepinephrine and weak inhibitors of dopamine reuptake. Venlafaxine and EFA in vitro have no significant affinity for muscarinic, histaminergic, alpha 1 -adrenergic receptors, do not have the ability to inhibit MAO.
Pharmacokinetics
After ingestion, venlafaxine is well absorbed and extensively metabolized in the liver. After taking a single dose, at least 92% is absorbed, absolute bioavailability is about 45% (due to presystemic metabolism). Eating does not significantly affect the absorption and biotransformation of venlafaxine.
The release of venlafaxine from a sustained-release dosage form occurs by diffusion through the spheroid membrane and is pH-independent. When receiving venlafaxine hydrochloride in the form of capsules with modified release (150 mg once a day), lower Cmax values (150 ng / ml for venlafaxine and 260 ng / ml for EFA) and higher Tmax values (5.5 h for venlafaxine and 9 h for EFA) than with immediate-release tablets (Cmax venlafaxine with 75 mg twice daily is 225 ng / ml, EFA - 290 ng / ml), Tmax - 2 h (venlafaxine) and 3 h ( EFA). When receiving equal daily doses of venlafaxine hydrochloride, either in the form of immediate-release tablets (as in two or three doses) or in the form of capsules with modified release of venlafaxine and EFA (AUC), the exposure was comparable in both dosing regimens, and plasma oscillations the levels of venlafaxine and EFA were slightly less when taken in capsule form. Therefore, the modified release capsules provide a lower rate, but the same degree of absorption of venlafaxine in comparison with the immediate release tablets.
Binding to plasma proteins is 27% ± 2% (venlafaxine, in the concentration range from 2.5 to 2215 ng / ml) and 30% ± 12% (EFA, in the concentration range from 100 to 500 ng / ml).
Metabolized mainly with the formation of a single pharmacologically active metabolite (EFA), as well as several inactive - N-desmethylvenlafaxine, N, O-didezmethylvenlafaxine, etc.
Extensive / Weak Metabolizans
In vitro studies have shown that the O-demethylation of venlafaxine with the formation of EFA occurs with the participation of the CYP2D6 isoenzyme. This was confirmed in a clinical study showing that patients with a low level of CYP2D6 ("weak metabolizing") had elevated plasma levels of venlafaxine and decreased levels of EFA compared to people with a normal CYP2D6 level ("extensive metabolizing"). However, clinically significant differences are not expected when using venlafaxine in weak and extensive metabolizing agents, the total venlafaxine and venerexine AUC (venlafaxine + EFA) exposure was similar in both groups, and the pharmacological activity and efficacy of venlafaxine and EFA are approximately the same.
Equilibrium plasma concentrations of both venlafaxine and EFA are achieved within 3 days of repeated administration. The pharmacokinetics of venlafaxine and EFA are linear in the range of daily doses taken 75-450 mg / day (every 8 hours). Plasma clearance, T1 / 2 and the volume of distribution in the equilibrium state were unchanged for both venlafaxine and for EFA after multiple doses. In the equilibrium state, the venlafaxine and EFA plasma clearance was 1.3 ± 0.6 l / h / kg and 0.4 ± 0.2 l / h / kg, T1 / 2 ± 5 ± 2 h and 11 ± 2 h, volume distribution - 7.5 ± 3.7 l / kg and 5.7 ± 1.8 l / kg, respectively.
It is mainly excreted by the kidneys: approximately 87% of the dose is excreted in the urine for 48 hours (5% unchanged, 29% unconjugated EFA, 26% conjugated EFA, 27% other inactive metabolites).
Dependence of pharmacokinetics parameters on some factors
Age and gender
Data from the population pharmacokinetic analysis of 404 patients taking venlafaxine in two studies (including twice daily and three times daily) indicate that age and sex do not affect the pharmacokinetic parameters of venlafaxine.
Impaired liver function
In 9 patients with cirrhosis of the liver after receiving venlafaxine, the pharmacokinetic parameters were significantly altered: an elongation of T1 / 2 (about 30%) and a decrease in clearance (approximately 50%) of venlafaxine, for EFA-T1 / 2, increased by about 60%, clearance decreased by 30%. There was a wide variability in these parameters in patients. Three patients with severe cirrhosis experienced a greater reduction in venlafaxine clearance (about 90%).
In the second study, venlafaxine was used intravenously and intravenously in healthy subjects (n = 21), as well as in patients with mild (Child-Pugh A, n = 8) and moderate (Child-Pugh B, n = 11) degrees of hepatic impairment . When administered orally in patients with impaired hepatic function, an increase in bioavailability of 2-3 times, an increase in T1 / 2 by approximately 2-fold, and a decrease in clearance of more than 2-fold compared with healthy people were noted. There was a wide variability in these parameters in patients.
Impaired renal function
In patients with impaired renal function (glomerular filtration rate 10-70 ml / min), there was an increase in venlafaxine T1 / 2 by approximately 50% and a decrease in clearance by about 24%. The pharmacokinetic parameters of EFA varied as follows: T1 / 2 increased by about 40%, while clearance values remained normal. In dialysis patients, T1 / 2 venlafaxine elongated by about 180%, and the clearance decreased by 57%; for EFA, the T1 / 2 elongation was approximately 142% and the clearance decreased by approximately 56%. Variability of these parameters was observed.
Carcinogenicity, mutagenicity, effects on fertility
In studies of carcinogenicity in mice and rats, when venlafaxine was administered to animals at doses up to 120 mg / kg / day for 18 months (mouse) and 24 months (rats), there was no increase in incidence of tumors.
Venlafaxine and / or its metabolite EFA did not show mutagenic activity in a number of in vivo and in vitro tests, incl. in the Ames test using bacterial strains of Salmonella typhimurium, in the test of gene mutations on mammalian cells, in the sister chromatid exchange test, etc. However, the clastogenic effect in an in vivo test of chromosomal aberrations in bone marrow cells in male rats receiving doses equivalent to 200 MPhC (when calculating in mg / kg) or 50 MPHR (calculated in mg / m2); this effect was not manifested at doses equivalent to 67 MPhD (mg / kg) or 17 MPhR (mg / m2).
In studies on rats there was no effect on fertility in female and male rats when doses exceeding the MPD were increased to 8 times (mg / kg) or up to 2 times (mg / m2) by animals.
Abuse and dependence
In vitro studies have shown that venlafaxine does not actually have an affinity for opioid and benzodiazepine receptors, as well as for phencyclidine receptors and glutamate N-methyl-D-aspartate (NMDA) receptors. In experimental studies, there was no significant CNS stimulation (in rodents) and no significant excitatory or inhibitory effect on the central nervous system (in primates). During the clinical trials of venlafaxine, no cases of abuse were noted. However, these observations were not systematic, and careful monitoring of patients with a history of drug abuse is required.
Clinical trials
Tablets with immediate release
Short-term tests
The efficacy of venlafaxine hydrochloride in the treatment of depression was established in 5 placebo-controlled short-term trials. Four of these trials had a duration of 6 weeks and included outpatients with major depression (according to the DSM-III or DSM-III-R criteria): in 2 studies, the patient's doses were in the range of 75 to 225 mg / day ( reception three times a day); in the 3rd dose were fixed - 75; 225 and 375 mg / day (reception three times a day); in the 4th, doses of 25 were used; 75 and 200 mg / day (reception twice a day). The term of the 5th study was 4 weeks, the study included patients diagnosed with major depression with melancholia (according to the DSM-III-R criteria) undergoing inpatient treatment and receiving venlafaxine in doses of 150 to 375 mg / day (reception three times a day).
In these five studies, venlafaxine hydrochloride was significantly superior to placebo in at least two of the three psychometric scale scores: the Hamilton Grading Score for Depression Rating, the Hamilton Scale Rating and the Severity Score of the General Clinical Impression Score. In studies in outpatients, the doses from 75 to 225 mg / day were the most optimal (in comparison with placebo), while in patients in the hospital doses of about 350 mg / day were more effective. Data from 2 studies with fixed doses indicate a dose-response relationship in the dose range of 75-225 mg / day, whereas at doses above 225 mg / day no increase in efficacy was observed with increasing doses.
Analysis of the data obtained in clinical trials did not reveal the effect of the age or sex of patients on the effectiveness of treatment (no special efficacy studies were conducted in elderly patients, approximately 2/3 of the patients included in the study were female).
Long-term studies
The efficacy of venlafaxine hydrochloride (an immediate-release form of venlafaxine, tablets) as maintenance therapy in the treatment of recurrent depressive disorder in outpatients (who are responders after a 26-week initial treatment, ie responding to therapy, according to an assessment on psychometric scales) was evaluated in a single placebo-controlled study up to 52 weeks. Responders who continued with venlafaxine therapy at the same doses had significantly fewer relapses than in the placebo group.
Capsules with modified release
Major Depressive Disorder
Short-term tests
The efficacy of venlafaxine hydrochloride in the treatment of depression was established in two placebo-controlled, short-term (8- and 12-week) studies using different dose ranges in adult patients with major depression (according to the DSM-III-R or DSM-IV criteria) , treated out-patient. In a 12-week study, patients were given doses of 75 to 150 mg / day (the average dose calculated at the end of the study was 136 mg / day), an 8-week study used doses of 75-225 mg / day (mean dose at completion of the study - 177 mg / day). Severity of symptoms in patients was recorded using various scales (including the Hamilton Scale, the Montgomery-Asberg Scale, the Scale of General Clinical Impression). In both studies, venlafaxine hydrochloride was superior to placebo, and was significantly better than placebo in evaluating some of the Hamilton Scale indicators, including anxiety / somatization, cognitive impairment, retardation, and psychiatric anxiety.
The efficacy of venlafaxine in the form of modified release capsules in the treatment of depression in hospitalized patients has not been adequately studied.
Long-term studies
The efficacy of venlafaxine hydrochloride (a form of venlafaxine modified release capsules) in maintenance therapy for the treatment of depression (major depressive disorder according to the DSM-IV criteria) in outpatients (responding to the initial 8-week therapy with venlafaxine, the so-called responders, by appropriate scales) was evaluated in a single placebo-controlled study up to 26 weeks. Responders who continued with venlafaxine therapy had significantly fewer relapses than in the placebo group.
Generalized anxiety disorder (GAD)
The efficacy of venlafaxine hydrochloride in the form of modified release capsules in the treatment of GAD (DSM-IV criteria) in outpatients was established in two 8-week placebo-controlled studies with fixed doses (75, 150 and 225 mg / day in the first, second, 75 and 150 mg / day) and in two 6-month placebo-controlled trials, one with fixed doses, the other with a dose range.
Social phobias (SF)
The efficacy of venlafaxine hydrochloride in the form of modified release capsules was established in four double-blind 12-week multicenter, placebo-controlled trials, as well as in one double-blind, 6-month placebo-controlled study, in the treatment of CF (DSM-IV criteria) in adult patients on an outpatient basis using a range of doses of 75-225 mg / day.
Panic disorder
The efficacy of venlafaxine hydrochloride in the form of modified release capsules was established in two double-blind, 12-week, multicenter, placebo-controlled trials (using a dose range of 75-150 mg / day in one study and 75-225 mg / day in another) panic disorder with / without agoraphobia (DSM-IV criteria) in adult patients on an outpatient basis.
Use in elderly patients
In placebo-controlled premarketing trials, the efficacy of venlafaxine (in the form of modified release capsules) among patients with depression, GAD, SF and panic disorder was approximately 4% (14/357), 6% (77/1381), 1% (10/819 ) and 2% (16/1001) of patients were 65 years of age or older. In Phase 2 and Phase 3 studies, of the 2897 depressed patients receiving venlafaxine (in the form of immediate-release tablets), 12% (357) of patients were 65 years of age or older. In these studies, in general, there was no difference in the efficacy and safety of venlafaxine in patients of this age group compared with younger patients. However, it is impossible to exclude the possibility of hypersensitivity to drugs in some patients. As with the treatment with other antidepressants, several cases of hyponatremia and the syndrome of inadequate secretion of antidiuretic hormone (usually in elderly patients) were noted with venlafaxine.
Application of the substance Venlafaxine
According to the State Register1, venlafaxine hydrochloride in the form of tablets, prolonged-release tablets / capsules, modified-release capsules is indicated for depression (treatment, prevention of relapse).
According to the Physicians Desk Reference (2009) 2, venlafaxine hydrochloride in the form of immediate-release tablets is indicated for the treatment of depression. Venlafaxine hydrochloride in the form of capsules with modified release is indicated for the treatment of depression, generalized anxiety disorder, social phobia, panic disorder.
Contraindications
Hypersensitivity, simultaneous administration of MAO inhibitors (see "Precautions").
Restrictions on the use
Recently suffered myocardial infarction and unstable angina, changes in blood pressure, increased intraocular pressure and angle-closure glaucoma, manic conditions in the anamnesis, initially reduced body weight, renal / hepatic insufficiency, age to 18 years (safety and efficacy not established).
Application in pregnancy and lactation
During pregnancy, use is only possible in case of emergency (adequate and strictly controlled safety studies in pregnant women are not performed).
The action category for fetus by FDA is C.
Teratogenic effects. Venlafaxine did not cause developmental defects in the offspring of rats and rabbits receiving it in doses up to 11 times (rats) or 12 times (rabbits) exceeding the MPDR (calculated in mg / kg), or 2.5 times (rats) and 4 times (rabbits) above the MPDCH (when calculating in mg / m2). However, in rats (if venlafaxine was started to be given during pregnancy and continued until the end of the feeding period), the body weight of the calves decreased, the number of stillbirths increased, the mortality of the young increased in the first 5 days of feeding. The cause of these deaths is unknown, these effects were observed at doses of 10 times (mg / kg) or 2.5 times (mg / m2) exceeding the MPD. There was no effect on infant mortality in rats at doses exceeding the MPD 1.4 times (mg / kg) or 0.25 times MPDR (mg / m2).
Nonteratogenic effects. When appointing venlafaxine in the III trimester of pregnancy, the physician should carefully evaluate the potential risk and benefit from its use. In clinical practice, a number of adverse effects in newborns were noted if their mothers received venlafaxine, other serotonin and noradrenaline reuptake inhibitors, or SSRIs, before or immediately before childbirth, incl. respiratory distress, cyanosis, apnea, convulsions, unstable body temperature, vomiting, hypoglycemia, hyperreflexia, tremor, excitability, continuous crying. These adverse effects are associated with either direct toxic effects or, possibly, a manifestation of the discontinuation effects syndrome in a newborn. It should be noted that in some cases the clinical picture was similar to serotonin syndrome.
The effect of venlafaxine hydrochloride on labor and delivery in humans is unknown.
Venlafaxine and its active metabolite EFA penetrate the breast milk of women. Given the potential risk of serious side effects in breast-fed infants, lactating women should stop either breastfeeding or use of medicines (in accordance with the importance of drugs for the mother).
Side effects of venlafaxine
According to the Physicians Desk Reference (2009) 2
Tablets with immediate release
Side effects associated with discontinuation of treatment
19% of patients (537/2897) with depression receiving venlafaxine during phase 2 and phase 3 studies discontinued treatment due to side effects. The most common effects (≥1%) that were the cause of discontinuation of therapy and considered to be medication-mediated (ie, observed approximately 2 or more times more often with venlafaxine compared with placebo) were the following (in parentheses the percentage in the group placebo): drowsiness 3% (1%), insomnia 3% (1%), dizziness 3% (<1%), headache 3% (1%), anxiety 2% (1%), nervousness 2% (< 1%), asthenia 2% (<1%); dry mouth 2% (<1%), nausea 6% (1%), impaired ejaculation 3% (<1%), sweating 2% (<1%).
Side effects observed in controlled trials
The most common side effects associated with taking venlafaxine hydrochloride (frequency of occurrence 5% or more) are not equivalent in the frequency of occurrence in the placebo group, i.e. when taking venlafaxine hydrochloride were observed at least 2 times more often than in the placebo group (see Table 1), asthenia, sweating, nausea, constipation, anorexia, vomiting, drowsiness, dry mouth, dizziness, nervousness, anxiety, tremor, blurred vision, impaired ejaculation / orgasm and impotence in men.
Side effects observed with a frequency of ≥1% in patients treated with venlafaxine hydrochloride (Table 1). Table 1 shows the side effects observed in patients receiving venlafaxine hydrochloride in the form of tablets at doses of 75-375 mg / day for short-term trials (4- and 8-week). These effects were observed with a frequency of ≥1% and exceeded the placebo frequency. The table shows the percentage of patients in each group who have had at least one incidental side effect during the treatment period. Side effects are grouped using the standard terminology dictionary COSTART.
Table 1
Side effects observed in 4-8 weeks of placebo-controlled clinical trials in the treatment of patients with depression
| Body Systems / Side Effects | Venlafaxine (n=1033), % | Placebo (n=609), % |
| Organism as a whole | ||
| Headache | 25 | 24 |
| Asthenia | 12 | 6 |
| Infection | 6 | 5 |
| Chills | 3 | - |
| Chest pain | 2 | 1 |
| Injury | 2 | 1 |
| The cardiovascular system | ||
| Vasodilation | 4 | 3 |
| Increased blood pressure / hypertension | 2 | - |
| Tachycardia | 2 | - |
| Orthostatic hypotension | 1 | - |
| Leather | ||
| Sweating | 12 | 3 |
| Rash | 3 | 2 |
| Itching | 1 | - |
| Gastrointestinal tract | ||
| Nausea | 37 | 11 |
| Constipation | 15 | 7 |
| Anorexia | 11 | 2 |
| Diarrhea | 8 | 7 |
| Vomiting | 6 | 2 |
| Dyspepsia | 5 | 4 |
| Flatulence | 3 | 2 |
| Metabolism | ||
| Weight loss | 1 | - |
| Nervous system | ||
| Drowsiness | 23 | 9 |
| Dry mouth | 22 | 11 |
| Dizziness | 19 | 7 |
| Insomnia | 18 | 10 |
| Nervousness | 13 | 6 |
| Anxiety | 6 | 3 |
| Tremor | 5 | 1 |
| Unusual dreams | 4 | 3 |
| Hypertension | 3 | 2 |
| Paresthesia | 3 | 2 |
| Decreased libido | 2 | - |
| Agitation | 2 | - |
| Confusion of consciousness | 2 | 1 |
| Violation of the thinking process | 2 | 1 |
| Depersonalization | 1 | - |
| Depression | 1 | - |
| Delayed urination | 1 | - |
| Twitching of muscles | 1 | - |
| Respiratory system | ||
| Yawn | 3 | - |
| Sense organs | ||
| Blurred vision | 6 | 2 |
| Perversion of taste | 2 | - |
| Tinnyt | 2 | - |
| Mydriasis | 2 | - |
| Genitourinary system | ||
| Violation of ejaculation / orgasm | 12* | -* |
| Impotence | 6* | -* |
| Increasing urination | 3 | 2 |
| Violation of urination | 2 | - |
| Violation of orgasm | 2** | -** |
Dependence of side effects on dose. The extent of side effects in patients receiving venlafaxine hydrochloride was evaluated in a comparative study with fixed doses: 75 mg / day (n = 89), 225 mg / day (n = 89), 375 mg / day (n = 88), and placebo (n = 92). Effects were observed that occurred at a frequency of 5% or more in at least one of the venlafaxine-treated groups and were observed at least 2-fold more frequently than in the placebo group.
To assess the potential dose-dose-response trend, the Cochran-Armitage test was used with a two-sided criterion, P <0.05 for the level of statistical significance. The analysis shows the dose-dependence of some effects, including the following: chills, hypertension, anorexia, nausea, agitation, dizziness, drowsiness, tremor, yawning, sweating, ejaculation.
Adapting to some side effects
During the 6-week period of therapy, cases of adaptation to some side effects (for example, dizziness and nausea) were noted, to a lesser extent - to other effects (eg, ejaculation, dry mouth).
Capsules with modified release
Data obtained in short-term placebo-controlled studies are presented.
Side effects associated with discontinuation of treatment
According to the results of clinical trials, almost 11% of the 357 patients with a large depressive episode receiving venlafaxine hydrochloride discontinued treatment due to side effects, compared to 6% of the 285 patients who received the placebo. In patients with GAD, a similar rate was 18% of 1,381 patients (placebo - 12% out of 555), in patients with SF - 15% of 819 patients (placebo - 5% of 695), in patients with panic disorder - 7% of 1001 (placebo - 6% out of 662).
Side effects that led to discontinuation of treatment and were associated with drug administration (i.e., leading to discontinuation in at least 1% of patients and occurring at least twice as often as placebo), depending on the diagnosis were the following (percentage in the placebo group in brackets):
in patients with depression - nausea 4% (<1%), anorexia 1% (<1%), dry mouth 1% (0%), dizziness 2% (1%), insomnia 1% (<1%), drowsiness 2% (<1%);
in patients with GAD-asthenia 3% (<1%), nausea 8% (<1%), dry mouth 2% (<%), vomiting 1% (<%), insomnia 3% (<1%), drowsiness 3% (<1%), nervousness 2% (<1%), tremor 1% (0%), sweating 2% (<1%);
in patients with SF-asthenia 1% (<1%), headache 2% (<1%), nausea 4% (0%), dizziness 2% (0%), insomnia 3% (<1%), drowsiness 2% (<1%), anxiety 1% (<1%), sweating 1% (0%), impotence 3% (0%).
Side effects observed in controlled trials with a frequency of ≥2% in patients treated with venlafaxine hydrochloride (Table 2).
Table 2 shows the side effects observed in patients receiving venlafaxine hydrochloride during placebo-controlled clinical trials in emergency therapy of a major depressive episode (up to 12 weeks, a range of doses from 75 to 225 mg / day), GAD (up to 8 weeks, range of doses from 37,5 to 225 mg / day), SF (up to 12 weeks, range of doses from 75 to 225 mg / day), panic disorder (up to 12 weeks, range of doses from 37.5 to 225 mg / day). These effects were observed with a frequency of ≥2% and exceeded the frequency of placebo. The table shows the percentage of patients in each group who have had at least one incidental side effect during the treatment period. Side effects are grouped using the standard terminology dictionary COSTART.
The most common side effects associated with taking venlafaxine hydrochloride (incidence of 5% or more) that are not equivalent in the placebo group (ie, when taking venlafaxine hydrochloride were observed at least 2 times more often than in the placebo group) in the conduct of clinical trials, depending on the diagnosis, were the following (see also Table 2):
Patients with depression in all placebo-controlled trials were noted, in particular: ejaculation disorder, gastrointestinal disorders (nausea, dry mouth and anorexia), CNS disorders (dizziness, drowsiness, unusual dreams), sweating. In two placebo-controlled trials in the United States, n = 192 were additionally noted: impairment of sexual function (impotence in men, anorgasmia in women, decreased libido), gastrointestinal disorders (constipation and flatulence), CNS disorders (insomnia, nervousness and tremor), impaired vision, cardiovascular disorders (hypertension and vasodilation), yawning.
In patients with GAD, during all placebo-controlled trials, violations of sexual function (impaired ejaculation and impotence), gastrointestinal disorders (nausea, dry mouth, anorexia, constipation), visual impairment, sweating were noted.
In patients with SF in placebo-controlled trials, asthenia, gastrointestinal disorders (anorexia, dry mouth, nausea, constipation), CNS disorders (insomnia, decreased libido, nervousness, drowsiness, tremor), violations of sexual function ejaculation, impotence), yawning, sweating.
table 2
The side effects observed in placebo-controlled clinical trials in the treatment of patients with depression, generalized anxiety disorder (GAD) and social phobias (SF)
| Body Systems / Side Effects | Depression | ÃÒÐ | ÑÔ | |||
| Venlafaxine (n=357), % | Placebo (n=285), % | Venlafaxine (n=1381), % | Placebo (n=555), % | Venlafaxine (n=819), % | Placebo (n=695), % | |
| Organism as a whole | ||||||
| Asthenia | 8 | 7 | 12 | 8 | 19 | 9 |
| Headache | - | - | - | - | 38 | 34 |
| Accidental injury | - | - | - | - | 4 | 3 |
| Abdominal pain | - | - | - | - | 6 | 4 |
| The cardiovascular system | ||||||
| Vasodilation (mainly hot flashes) | 4 | 2 | 4 | 2 | 3 | 2 |
| Hypertension | 4 | 1 | - | - | 5 | 3 |
| Palpitation | - | - | - | - | 3 | 1 |
| Digestive system | ||||||
| Nausea | 31 | 12 | 35 | 12 | 31 | 9 |
| Constipation | 8 | 5 | 10 | 4 | 9 | 3 |
| Anorexia | 8 | 4 | 8 | 2 | 17 | 2 |
| Vomiting | 4 | 2 | 5 | 3 | - | - |
| Flatulence | 4 | 3 | - | - | - | - |
| Diarrhea | - | - | - | - | 8 | 6 |
| Dyspepsia | - | - | - | - | 7 | 6 |
| Metabolism | ||||||
| Weight loss | 3 | 0 | - | - | 2 | <1 |
| Nervous system | ||||||
| Dizziness | 20 | 9 | 16 | 11 | 16 | 8 |
| Drowsiness | 17 | 8 | 14 | 8 | 20 | 8 |
| Insomnia | 17 | 11 | 15 | 10 | 24 | 8 |
| Dry mouth | 12 | 6 | 16 | 6 | 17 | 4 |
| Nervousness | 10 | 5 | 6 | 4 | 10 | 5 |
| Unusual dreams (mostly bright dreams, nightmares, sleep with dreams) | 7 | 2 | 3 | 2 | 3 | <1 |
| Anxiety | - | - | - | - | 5 | 4 |
| Tremor | 5 | 2 | 4 | <1 | 5 | 2 |
| Hypertension | - | - | 3 | 2 | - | - |
| Paresthesia | 3 | 1 | 2 | 1 | - | - |
| Decreased libido | 3 | <1 | 4 | 2 | 8 | 2 |
| Agitation | 3 | 1 | - | - | 3 | 1 |
| Depression | 3 | <1 | - | - | - | - |
| Twitching of muscles | - | - | - | - | 3 | <1 |
| Respiratory system | ||||||
| Pharyngitis | 7 | 6 | - | - | - | - |
| Yawn | 3 | 0 | 3 | <1 | 5 | <1 |
| Leather | ||||||
| Sweating | 14 | 3 | 10 | 3 | 13 | 4 |
| Sense organs | ||||||
| Visual impairment (including blurred vision) | 4 | <1 | 5 | <1 | 4 | 2 |
| Genitourinary system | ||||||
| Violation of ejaculation (including ejaculation delay) * | 16 | <1 | 11 | <1 | 19 | <1 |
| Impotence* | 4 | <1 | 5 | <1 | 6 | <1 |
| Orgasmic disorders (including orgasm arrest, anorgasmia) ** | 3 | <1 | 2 | 0 | 5 | <1 |
-lessthan2%
* was recorded only in men
** was recorded only in women
Side effects observed in placebo-controlled clinical trials in the treatment of patients with panic disorder (the percentage of occurrence of this side effect in the group receiving venlafaxine [n = 1001] was indicated next to the name, in brackets - in the placebo group [n = 662]) :
The body as a whole: asthenia - 10% (8%).
Cardiovascular system: hypertension - 4% (3)%, vasodilation (mainly tides) - 3% (2%).
Digestive system: nausea - 21% (14%), dry mouth - 12% (6%), constipation - 9% (3%), anorexia - 8% (3%).
Nervous system: insomnia 17% (9%), drowsiness - 12% (6%), dizziness - 11% (10%), tremor - 5% (2%).
Skin: sweating - 10% (2%).
Genitourinary system: decreased libido - 4% (2%), violation of ejaculation (including delayed ejaculation) - 8% (<1%) and impotence 4% (<1%) in men; orgasmic disorders (including delayed orgasm, anorgasmia) in women - 2% (<1%).
It should be borne in mind that side effect data obtained in placebo-controlled studies can not be used to predict the occurrence of side effects in routine medical practice, because the status of patients and other factors differ from those that prevailed in clinical trials. Similarly, the frequency of occurrence of side effects (in percent) in the tables may differ from those obtained by other clinical researchers, since each drug test can be conducted with a different set of conditions. However, these figures give the doctor an idea of the relative contribution of the substance itself and other factors (not related to drugs), to the development of side effects when using drugs in the population.
Changing vital functions
Tablets with immediate release
In clinical trials, it was found that, when taking venlafaxine, the pulse rate was increased by about 3 beats per minute, the average for all groups of patients receiving different doses (compared with placebo, where there were no such changes). In studies with a range of doses of 200-375 mg / day (average dose - more than 300 mg / day), the pulse rate was increased by an average of 2 beats per minute (compared to placebo, where there was a decrease of 1 beat per minute).
In controlled clinical trials with the use of venlafaxine, an increase in DAD in the range 0.7-2.5 mm Hg was associated. (for all groups of patients) compared with placebo, where there was a decrease in DAD in the range of 0.9-3.8 mm Hg. In this case, the increase in blood pressure was dose-dependent (see "Precautions", persistent hypertension).
Capsules with modified release
In premarketing placebo-controlled trials in patients with a large depressive episode who received venlafaxine hydrochloride for up to 12 weeks, by the time the therapy ended, an average pulse rate of 2 beats per minute was observed compared with placebo (1 ppm increase) . Similar results were obtained in premarketing placebo-controlled trials in patients with GAD (up to 8 weeks of treatment). In premarketing placebo-controlled trials in patients with SF who received venlafaxine for up to 12 weeks, the pulse rate was increased by an average of 3 beats per minute (in the placebo group, an increase of 1 beat per minute). In premarketing placebo-controlled trials in patients with panic disorder who received venlafaxine for up to 12 weeks, the pulse rate was increased by an average of 1 beat per minute (in the placebo group, a decrease of less than 1 beat per minute).
Change in laboratory indicators
According to the results of laboratory monitoring performed during the clinical trials of venlafaxine (tablets, capsules), statistically significant differences (in comparison with placebo) were observed in the serum cholesterol level. Thus, in the treatment of venlafaxine (tablets) in patients with depression for at least 3 months, a clinically significant increase in cholesterol was recorded in 5.3% of patients compared with 0% placebo (based on 12-month placebo-controlled trials).
ECG change
Comparison of ECG in patients receiving venlafaxine hydrochloride (n = 769) and placebo (n = 450) in controlled clinical trials showed that a statistically significant difference was only an increase in heart rate with venlafaxine.
Interaction
Incompatible with MAO inhibitors (see "Precautions").
Simultaneous application of cimetidine and venlafaxine in 18 healthy volunteers at equilibrium concentrations of both substances led to inhibition of the metabolism of venlafaxine during "first passage" through the liver, a decrease in clearance of venlafaxine by approximately 43%, and an increase in AUC and Cmax by 60%, while cimetidine did not affect the pharmacokinetics of EFA (which is present in the systemic blood stream in a much larger amount than venlafaxine); the total pharmacological activity of venlafaxine + EFA increased only slightly; the interaction of venlafaxine and cimetidine may be more pronounced in patients on the background of hypertension, impaired liver function and in elderly people (caution should be exercised).
There was no interaction between diazepam and its active metabolite, desmethyldiazepam and venlafaxine and its metabolite (EFA), in 18 healthy volunteers with a single dose of diazepam against venlafaxine in equilibrium conditions.
The administration of a single oral dose of haloperidol against venlafaxine in equilibrated conditions in 24 healthy volunteers led to a change in the pharmacokinetic parameters of haloperidol: a decrease in the total clearance of haloperidol by 42%, an increase in AUC by 70%, and Cmax by 80%; while T1 / 2 remained unchanged.
A single oral lithium intake did not affect the pharmacokinetics of venlafaxine (and also EFA) in equilibrium in 12 healthy men. Venlafaxine also did not alter the pharmacokinetic parameters of lithium.
Venlafaxine did not increase free concentrations in the blood of other, concomitantly receiving drugs with high binding to proteins (due to low binding of venlafaxine and EFA to plasma proteins).
In vitro studies have shown that venlafaxine is a weak inhibitor of the CYP2D6 isoenzyme and does not inhibit the isoenzymes CYP3A4, CYP1A2, CYP2C9, CYP2C19.
Venlafaxine does not affect the pharmacokinetics of imipramine and its active metabolite; similarly, imipramine does not affect the pharmacokinetics of venlafaxine and its active metabolite.
A single oral risperidone intake against venlafaxine in equilibrated conditions was accompanied by a 32% increase in risperidone AUC due to a slight inhibition of CYP2D6-mediated metabolism of risperidone to the active metabolite (9-hydroxy-risperidone), while the overall pharmacological activity (risperidone + metabolite) did not change.
In clinical trials, no interaction of venlafaxine with drugs metabolized with the participation of CYP3A4 (including alprazolam, diazepam, terfenadine) has been identified.
The administration of a single oral dose of indinavir against the background of venlafaxine in an equilibrium state in 9 healthy volunteers reduced the AUC and Cmax of indinavir by 28% and 36%, respectively (the clinical significance of the phenomenon is unknown).
A single dose of ethanol (0.5 g / kg) had no effect on the pharmacokinetics of venlafaxine and EFA when taking venlafaxine 150 mg / day (in 15 healthy men).
Overdose
Symptoms: changes in the ECG (prolongation of the QT interval, blockage of the bundle of the bundle, expansion of the QRS complex, etc.), sinus and ventricular tachycardia, bradycardia, hypotension, dizziness, impaired consciousness of varying severity (from drowsiness to coma), seizures, outcome.
Treatment: the use of activated charcoal, induction of vomiting, gastric lavage (to reduce absorption). Maintenance of airway patency for adequate ventilation and oxygenation. It is recommended to closely monitor and monitor the rhythm of the heart and other vital functions, symptomatic and supportive therapy. The effectiveness of such activities as forced diuresis, dialysis, hemoperfusion and exchange blood transfusion is unlikely. There is no specific antidote.
In post-marketing studies, cases of venlafaxine overdose have been noted primarily with simultaneous use of alcohol and / or other medications.
Routes of administration
Inside, while eating.
Precautions for the substance Venlafaxine
Clinical impairment and risk of suicide
In short-term studies of major depressive disorder according to the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders (4th ed.) - Diagnostic and Statistical Manual of Mental Disorders, 4th edition) and other mental illnesses, there was an increase in suicidal (risk of suicidal intent or attempts at suicide) with antidepressants compared with placebo in children, adolescents and young people (18-24 years old). When prescribing venlafaxine or any other antidepressant, patients of these age groups should assess the possible risk. In short-term studies in adults over 24 years of age, it has been shown that the risk of suicidality with antidepressants compared with placebo does not increase, and in patients over 65 years of age it decreases. Depression and some other mental illnesses are associated with an increased risk of suicide. When antidepressant therapy, especially at the beginning of treatment, requires careful monitoring of patients of any age for the timely detection of clinical deterioration, suicidal or unusual behavioral changes. Relatives of patients and persons caring for them need to be aware of the need for close monitoring of patients and timely informing the doctor.
Should be alerted to when anxiety, agitation, panic attacks, insomnia, irritability, aggressiveness, hostility, akathisia, hypomania or mania, other symptoms of unusual behavior of patients, as well as a suicidal tendencies, and immediately report these symptoms to the treating doctor.
Venlafaxine is not used in patients under the age of 18 (see "Restrictions on Use").
The combination with MAO inhibitors (see "Contraindications")
Treatment with venlafaxine should be started no earlier than 14 days after the end of the intake of MAO inhibitors, in turn, treatment with MAO inhibitors can begin no earlier than 7 days after the withdrawal of venlafaxine. With simultaneous administration of venlafaxine and MAO inhibitors, it is possible to develop severe adverse reactions (including tremor, myoclonus, excessive sweating, nausea, vomiting, flushing, dizziness, hyperthermia with signs similar to neuroleptic malignant syndrome, seizures, up to and including lethal outcome).
Persistent hypertension
In some patients, persistent venlafaxin-induced hypertension develops during the treatment, defined as an increase in the diastolic pressure in the prone position (dADL) ≥90 mm Hg. Art. and ≥ 10 mm Hg. Art. in relation to the baseline (baseline) level when measured during three consecutive visits to the physician.
In premarketing studies, using three fixed doses of venlafaxine-75, 225 and 375 mg / day in the form of immediate-release tablets compared with placebo, the mean increase in dADL in the 375 mg / day group was 7 at the end of the 6th week , 2 mm Hg. whereas in the groups of patients taking doses of 75 mg and 225 mg / day, there were no significant changes (in the placebo group there was a decrease in the doppler by 2.2 mm Hg). The analysis carried out in patients who meet the criterion of the presence of persistent hypertension, revealed a dose-dependent increase in the incidence of its occurrence. At doses of venlafaxine less than 100 mg / day, persistent hypertension was observed in 3% of cases, 101-200 mg / day - 5%, 201-300 mg / day - 7%, more than 300 mg / day - 13% (placebo - 2%). . Analysis in patients with persistent hypertension and 19 patients who stopped treatment due to the development of hypertension (less than 1% of the total number of patients taking venlafaxine), found that most of the time the DADL increased by 10-15 mm Hg. Art. Nevertheless, a prolonged increase in the DADL may have adverse consequences. Therefore, regular monitoring of blood pressure in patients taking venlafaxine is recommended. In cases of prolonged blood pressure, either a dose reduction or a decision to discontinue the drug should be taken.
In premarketing studies in patients with major depressive disorder, venlafaxine hydrochloride in the form of capsules with modified release in doses of 75-375 mg / day in 3% of cases (19/705), persistent hypertension was noted. In patients with generalized anxiety disorder, taking venlafaxine in doses of 37.5-225 mg / day, persistent hypertension was noted in 0.5% of cases (5/1011). In patients with social phobias who received doses of 75-225 mg / day, persistent hypertension was noted in 1.4% of cases (4/277). The number of patients in these studies, who received doses above 300 mg / day, was insufficient to estimate the frequency of BP elevation at the highest doses.
Mydriasis
Since it was reported on the development of mydriasis in the treatment of venlafaxine, caution should be used in patients with increased intraocular pressure or with the risk of developing an acute attack of angle-closure glaucoma.
Insomnia and nervousness
A combined analysis of short-term, double-blind, placebo-controlled trials in patients with depression showed that the most common effects associated with taking venlafaxine in the form of immediate-release tablets (n = 1033) compared with placebo (n = 609) were an anxiety of 6% 3%), nervousness 13% (6%), insomnia 18% (10%), in brackets the percentage in the placebo group is indicated. In Phase 2 and Phase 3 studies in patients with depression, anxiety, nervousness and insomnia led to discontinuation of treatment in 2%, 2%, and 3% of patients, respectively.
A combined analysis of short-term studies in patients with depression, generalized anxiety disorder and social phobias showed that the most common effects associated with taking venlafaxine in the form of modified-release capsules were insomnia and nervousness compared with placebo (percentage in the placebo group in brackets). Insomnia was noted in 17% of cases (11%), nervousness - 10% (5%) in patients with depressive episode (n = 357) compared with placebo (n = 285); 15% (10%) and 6% (4%) in patients with generalized anxiety disorder (n = 1381) compared with placebo (n = 555); 23% (7%) and 11% (3%) in patients with social phobias (n = 277) compared with placebo (n = 274), respectively.
In the treatment of patients with a depressive episode, 0.9% of patients discontinued treatment due to insomnia and 0.9% because of the appearance of nervousness. In patients with generalized anxiety disorder, during treatment for up to 8 weeks, insomnia and nervousness caused the discontinuation of therapy in 3 and 2% of cases, with treatment duration of up to 6 months in 2 and 0.7% of cases, respectively. In patients with social phobias, up to 12 weeks of treatment, insomnia caused 3% of venlafaxine withdrawal, and nervousness was not the reason for discontinuing the drug.
Changes in appetite and body weight
Based on the results of short-term, double-blind, placebo-controlled studies in patients with depression, the most common reported occurrence of venlafaxine anorexia (11% tablet / 8% capsule) was compared with placebo (2% tablet / 4% capsule). Dose-dependent weight loss was often observed in patients taking venlafaxine for several weeks. Significant weight loss, especially in depressed patients who are too small, may be an undesirable effect of venlafaxine treatment. Body weight loss of 5% or more was observed against venlafaxine in 6% of patients (tablets) / 7% (capsules) compared with placebo (1% / 2%) and 3% of patients taking another antidepressant. The cessation of weight loss under the influence of venlafaxine (tablets) was rare - in 0.1% of cases in Phase 2 and Phase 3 studies in patients with depression. The cessation of progression of anorexia and weight loss in patients with depression when taking capsules was also small - 1 and 0.1%, respectively.
In short-term (up to 8 weeks) studies in patients with generalized anxiety disorder who received venlafaxine in the form of capsules, anorexia was noted in 8% of cases (placebo - 2%). A decrease in body weight of 7% or more was observed in 3% of patients receiving venlafaxine in the form of capsules for up to 6 months (placebo - 1%). The cessation of progression of anorexia and weight loss with capsules for a period of up to 8 weeks was observed in 0.9% and 0.3% of patients, respectively.
In studies in patients with social phobias who received venlafaxine in capsule form for up to 12 weeks, anorexia was noted in 20% of cases (placebo - 2%). A decrease in body weight of 7% or more was not observed in patients who received venlafaxine in the form of capsules for up to 12 months, or in the placebo group. The cessation of progression of anorexia and a decrease in body weight when taking capsules for up to 12 weeks was 0.4% and 0.0%, respectively.
Activation of mania / hypomania
A small number of patients with mood disorders receiving antidepressants may develop mania or hypomania. According to the results of all premarketing trials of venlafaxine in patients with depression, mania / hypomania was noted in 0.5% (tablets) and 0.3% (capsules) of cases (placebo 0%). Like other antidepressants, venlafaxine should be administered with caution to patients with a history of mania.
Hyponatremia
It should be borne in mind that against the background of venlafaxine, the development of hyponatremia and the syndrome of inadequate secretion of antidiuretic hormone is possible, especially in patients with hypovolemia, dehydration, in the elderly, and also with simultaneous diuretics.
Convulsions
During premarketing tests, seizures were noted in 0.26% (8/3082) of patients receiving venlafaxine (tablets), most of which (5 of 8) were observed in patients taking doses of 150 mg / day or less. When venlafaxine was administered in the form of capsules, seizures were not observed in patients with a depressive episode (n = 705), generalized anxiety disorder (n = 1381) and social phobias (n = 277). Nevertheless, caution should be used to appoint venlafaxine to patients with a history of seizures. If the seizure develops, stop taking the drug.
Hemorrhages
There are reports of an anomalous skin hemorrhage on the background of venlafaxine (in most cases, ecchymoses - extensive hemorrhage into the skin or mucous membrane). The cause-and-effect relationship of this phenomenon with venlafaxine was not established, but there was a violation of platelet aggregation (possibly due to a decrease in the serotonin content in them).
Increase serum cholesterol (see "Side effects" Change in laboratory indicators).
With prolonged therapy, it is recommended to measure the serum cholesterol level (clinical trials showed a clinically significant increase in this parameter in patients receiving venlafaxine).
Use in patients with concomitant diseases
Clinical experience with venlafaxine in patients with concomitant diseases is limited. Care must be taken in a number of diseases and conditions, including. accompanied by a violation of hemodynamics or metabolism (see "Restrictions on use").
There were no systematic observations in patients with recent myocardial infarction or unstable angina, these patients were excluded from many clinical premarketing studies. However, ECG analysis in patients receiving venlafaxine shows that the drug is not associated with the development of clinically significant abnormalities in the ECG.
Termination of venlafaxine treatment
It was reported that patients had effects due to discontinuation of treatment with venlafaxine (discontinuation effects). In this regard, the cancellation of venlafaxine should be carried out gradually, by lowering the dose to reduce the risk of withdrawal reactions, while monitoring the patient's condition is recommended. The period of cancellation may depend on the dose, the duration of therapy, and the individual characteristics of the patient. When treatment with venlafaxine for 6 weeks or more, the withdrawal period should be at least 2 weeks.
Manifestations of the withdrawal reaction in patients treated with venlafaxine were systematized in a prospective analysis of the results of clinical trials of venlafaxine in generalized anxiety disorder and a retrospective review of depression trials. It was found that a sharp discontinuation of venlafaxine or a decrease in its dose (at different doses) is associated with the appearance of symptoms, whose frequency increased with increasing dose and duration of treatment. The symptoms included the following: agitation, anorexia, anxiety, confusion, impaired coordination, diarrhea, dizziness, dry mouth, dysphoria, fascicular twitching, fatigue, headache, hypomania, insomnia, nausea, nervousness, nightmares, convulsions, (including the feeling of an electric shock), drowsiness, sweating, tremor, vertigo, vomiting.
Supportive therapy
In the clinical trials conducted, there is not enough evidence indicating how long it takes to take venlafaxine in the treatment of depression, generalized anxiety disorder and social phobias.
Although venlafaxine did not increase the effect of ethanol on psychomotor reactions in volunteers, simultaneous administration of venlafaxine and alcohol should be avoided.
In studies on healthy volunteers, there was no clinically significant decrease in mental activity and the rate of psychomotor reactions against venlafaxine. However, since any psychoactive drug can affect the central nervous system, patients should be warned about the need to be careful when working with potentially dangerous mechanisms and when driving a car.
