VENLAFAXINE PILLS 75MG

Mechanism of action

Venlafaxine - an antidepressant chemically not related to any class of antidepressants (tricyclic, tetracyclic, or others), is the racemate of two active enantiomers. Venlafaxine and its main metabolite, O-desmethylvenlafaxine (EFA), are potent inhibitors of serotonin reuptake and noradrenaline (abbreviated: IOSPN or SSRI) and weak inhibitors of dopamine reuptake.

The mechanism of antidepressant action is associated with the ability of the drug to enhance the activity of neurotransmitters during the transmission of nerve impulses in the central nervous system (CNS). Venlafaxine and EFA equally effectively affect the reuptake of the above-mentioned neurotransmitters, while they do not have affinity (studied in vitro) with cholinergic (muscarinic), histamine (H1alpha1-adrenergic, opioid and benzodiazepine receptors, do not inhibit the activity of monoamine oxidase (MAO). By inhibition of serotonin reuptake, venlafaxine is inferior to selective serotonin reuptake inhibitors (SSRIs).

Pharmacokinetics

Absorption

Absorption from the gastrointestinal tract is good, about 92% for a single dose, does not depend quantitatively on food intake.

Distribution

The total bioavailability is 40-45%, which is associated with intense presystemic metabolism in the liver. Venlafaxine and EFA bind to human plasma proteins by 27 and 30%, respectively; they both pass into breast milk.

In the range of daily doses of venlafaxine 75-450 mg, venlafaxine itself and EFA have linear kinetics. The time to reach maximum plasma concentration (TCmax) venlafaxine and EFA - 2 and 3 hours, respectively (after taking Venlafaxin pills inside). In the case of receiving prolonged forms of venlafaxine TC indicatorsmax 5.5 and 9 h, respectively.

T1/2 amounted to 5 &№177; 2 h and 11 &№177; 2 h, for venlafaxine and EFA, respectively.

Css in plasma for venlafaxine and EFA is achieved after 3 days of repeated administration of therapeutic doses.

Metabolism

Metabolized mainly in the liver with the participation of CYP2D6 isoenzyme to the only pharmacologically active metabolite (EFA), as well as to the inactive metabolite N-desmethylvenlafaxine.

Venlafaxine is a weak inhibitor of the isoenzyme CYP2D6, does not inhibit CYP1A2, CYP2C9 or CYP3A4.

Removal

Excreted mainly by the kidneys: approximately 87% of the single dose taken is excreted in the urine within 48 hours (5% unchanged, 29% as unconjugated EFA, 26% as conjugated EFA, 27% as other inactive metabolites), and after 72 h the kidneys excreted 92% of the drug.

The mean &№177; standard deviation for plasma clearance of venlafaxine and EFA is 1.3 &№177; 0.6 and 0.4 &№177; 0.2 l / h / kg, respectively; apparent half-life of 5 &№177; 2 and 11 &№177; 2 h, respectively; seeming (in equilibrium) Vd7.5 &№177; 3.7 and 5.7 &№177; 1.8 l / kg, respectively.

Special groups

Gender and age of the patient do not have a significant effect on the pharmacokinetic parameters of venlafaxine and EFA.

For elderly patients, a special dose adjustment based on age is not required.

Patients with low CYP2D6 isoenzyme activity do not need to select individual doses. Despite the multidirectional changes in concentrations taken separately, namely venlafaxine (increased) and EFA (reduced), the sum of the areas under the pharmacokinetic curves of these two active substances does not actually change due to a decrease in the activity of the CYP2D6 isoenzyme, and accordingly the dose adjustment is not required.

In patients with moderate to severe hepatic and renal failure, the metabolism of venlafaxine and the elimination of EFA decreases, increases Cmaxvenlafaxine and EFA, T extended1/2. The decrease in total clearance of venlafaxine is most pronounced in patients with creatinine (CK) clearance by the kidneys below 30 ml / min, as well as in patients on renal dialysis (T1/2 increases by 180% for venlafaxine and by 142% for EFA, and the clearance of both active substances decreases by about 57%). For such patients, especially on hemodialysis, an individual selection of the dose of venlafaxine and control of the kinetics is necessary taking into account the duration of treatment with this drug.

Although the data for patients with severe Child Failure insufficiency is limited, it should be borne in mind that individual variations in pharmacokinetics, in particular, the clearance of the drug and its T1/2are very diverse, which should be considered when prescribing venlafaxine to such patients.

In patients with class A for Child-Pugh (mild liver dysfunctions) and with class B for Child-Pugh (moderate disabilities) T1/2 venlafaxine and EFA are approximately 2 times longer than healthy patients, and clearance is reduced by more than half.

Indications

- depression: prevention and treatment.

Dosage and administration

Inside

The drug Venlafaxine is taken with food, preferably at the same time, without chewing and squeezing fluid.

The recommended initial dose is 75 mg in two doses daily (37.5 mg twice a day). Depending on tolerability and effectiveness, the dose can be gradually increased to 150 mg / day. If necessary, increase the dose to 225 mg / day. Increasing the dose of 75 mg / day can be made at intervals of 2 weeks or more, in the case of clinical need, due to the severity of symptoms, it is possible to increase the dose in a shorter time, but not less than 4 days.

Higher doses (up to a maximum daily dose of 375 mg / day in 2-3 doses) require inpatient observation of patients. After achieving the desired therapeutic effect, the daily dose can be gradually reduced to the minimum effective level.

Supportive care and relapse prevention:maintenance treatment can last 6 months or more. Assigned to the minimum effective dose used in the treatment of a depressive episode.

Renal failure: atmild renal failure (glomerular filtration rate (GFR) of more than 30 ml / min) correction of the dosing regimen is not required. Atmoderate renal failure (GFR 10-30 ml / min)the dose should be reduced by 25-50%. Due to lengthening t1/2 venlafaxine and its active metabolite (EFA), such patients should take the entire dose once a day. It is not recommended to use venlafaxine whensevere renal failure (GFR less than 10 ml / min), since there is no reliable data on such therapy. Athemodialysis the daily dose should be reduced by 50%, the drug should be taken after the end of the hemodialysis session.

Liver failure: atmild hepatic failure(prothrombin time (PT) less than 14 sec) correction of the dosing regimen is not required. Atmoderate liver failure (PV from 14 to 18 seconds) the daily dose should be reduced by 50% or more. It is not recommended to use venlafaxine whensevere liver failurebecause there is no reliable data on such therapy.

Elderly patients: old age of the patient in the absence of any acute and chronic diseases does not require changing the dose, but (as with the appointment of other drugs) in the treatment of elderly patients requires caution. Older patients should use the lowest effective dose. At higher doses, the patient must be under close medical supervision.

Drug withdrawal

Discontinuation of the drug should be carried out gradually to minimize the risk associated with discontinuation of the drug. With a course of treatment for 6 weeks or more, the period of gradual withdrawal of the drug must be at least 2 weeks and depends on the dose, duration of therapy and the individual characteristics of the patient.

Side effect

Frequency of side effects: very often (≥1 / 10), often (≥1 / 100 to <1/10), infrequently (≥1 / 1000 to <1/100), rarely (≥1 / 10 000 to <1 / 1000), very rarely (<1/10 000), the frequency is not established (currently there are no data on the prevalence of adverse reactions).

Common symptoms:often - weakness, fatigue, chills; infrequently - angioedema, photosensitivity reactions; frequency not established - Anaphylactic reactions.

From the nervous system:very often - dry mouth, headache; often - unusual dreams, decreased libido, dizziness, insomnia, irritability, paresthesia, stupor, confusion, depersonalization, increased muscle tone, tremor; infrequently - apathy, agitation, hallucinations, myoclonus, impaired coordination of movements and balance; seldom - akathisia, psychomotor agitation, epileptic seizures, manic reactions; frequency not established - dizziness, malignant neuroleptic syndrome (ZNS), serotonin syndrome, delusions, extrapyramidal reactions (including dystonias and dyskinesia), late dyskinesia, suicidal thoughts and behavior, aggression.

From the gastrointestinal tract:very often nausea; often - loss of appetite (anorexia), constipation, vomiting; infrequently - bruxism, diarrhea; rarely, hepatitis; frequency is not installed - pancreatitis.

On the part of the respiratory system:often - yawning, bronchitis, shortness of breath; rarely, interstitial lung disease and eosinophilic pneumonia, chest pain.

Since the cardiovascular system:often - arterial hypertension, hyperemia of the skin; infrequently - postural hypotension, tachycardia, syncope; frequency not established - hypotension, prolongation of the QT interval, ventricular fibrillation, ventricular tachycardia (including bidirectional tachycardia).

From the hemopoietic system:infrequently - hemorrhages in the skin (ecchymosis), Gastrointestinal bleeding ; frequency not established - hemorrhages in mucous membranes, lengthening of bleeding time, thrombocytopenia, pathological changes in the blood (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia).

Metabolism:often - an increase in serum cholesterol levels, weight loss; infrequently - weight gain; very rarely, an increase in prolactin content; frequency not established - change in laboratory tests of liver function, hepatitis, hyponatremia, syndrome of insufficient secretion of antidiuretic hormone.

From the genitourinary system:often - ejaculatory / orgasm disorders (in men), erectile dysfunction (impotence), anorgasmia, dysuric disorders (mainly - difficulty in starting urination), pollakiuria, menstrual disorders associated with increased bleeding or increased irregular bleeding (menorrhagia, metrorrhagia); infrequently - violations of orgasm (in women), urinary retention; rarely urinary incontinence.

From the senses:often - accommodation disturbances, mydriasis, visual impairment; infrequently - a violation of taste, noise or tinnitus; frequency not set - angle-closure glaucoma.

From the skin:very often - sweating; infrequently - alopecia, rapid rash; frequency not established - erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, pruritus, urticaria.

From the musculoskeletal system:frequency not established - rhabdomyolysis.

When you stop taking venlafaxine, abruptly cancel or while reducing the dose, you may experience symptoms related to the so-called withdrawal syndrome: fatigue, asthenia, headache, dizziness, sleep disorders (drowsiness or insomnia, difficulty falling asleep, the appearance of unusual dreams), hypomania, anxiety, agitation (increased nervous irritability and irritability),confusion, paresthesia (spontaneously unpleasant sensation of numbness, tingling, burning, crawling, etc.), increased sweating, dry mouth, decreased appetite, nausea, vomiting, diarrhea (most of these reactions are mild and do not require treatment ).

Contraindications

- hypersensitivity to venlafaxine or to any of the excipients;

- simultaneous use with MAO inhibitors ;

- severe renal dysfunction (glomerular filtration rate (GFR) less than 10 ml / min);

- severe abnormal liver function;

- taking the drug at the age of under 18 years;

- during pregnancy and lactation.

Carefully: recent myocardial infarction, unstable stenocardia, arterial hypertension, arrhythmias (especially tachycardia), history of convulsions, increased intraocular pressure, closed-angle glaucoma, a history of manic, suicidal tendencies, prejudice to bleeding ischemic ischemic, they are hemorrhagic, history of manic, history of suicide body weight, hyponatremia, dehydration, concurrently with diuretics, or with drugs used to treat obesity.

Use during pregnancy and lactation

Do not assign venlafaxine to pregnant and lactating women, because the safety of the drug during pregnancy and lactation in a woman has not been established to a sufficient extent, due to the fact that there are no adequately conducted controlled clinical studies on a sufficiently large sample of such patients. This concerns the health of both the mother and, to a greater extent, the fetus / child.

Women of childbearing age should be warned about this before starting treatment; they should immediately consult a doctor if they become pregnant or are planning a pregnancy during the period of drug treatment. Venlafaxine and its metabolite (EFA) are excreted in breast milk. If necessary, taking the drug during lactation is necessary to stop breastfeeding.

In practice, there are cases of prescribing venlafaxine to mothers during pregnancy and shortly before delivery, when in a particular situation the expected benefits to the mother outweigh the potential risk to the fetus.In these cases, newborns often observed complications that required: an increase in the length of hospitalization, maintenance of breathing, and feeding through a tube. These complications can develop immediately after childbirth and are also characteristic in the case of taking other antidepressants from the group of SSRIs or SSRIs (not containing venlafaxine). In such cases, the following clinical symptoms were reported in newborns: external respiratory disorders, cyanosis, apnea, convulsions, temperature instability, feeding difficulties, vomiting, hypoglycemia, muscle hypertension or hypotension, hyperreflexia, tremor, tremors, irritability, lethargy, constant crying, drowsiness or insomnia. Such violations may indicate the serotonergic effects of the drug Venlafaxine.

If venlafaxine was used during pregnancy, and treatment of the mother was completed shortly before birth, the newborn may experience withdrawal syndrome. In such a newborn, the presence of serotonin syndrome or a neuroleptic malignant syndrome should be excluded. Epidemiological data suggest that using SSRIs during pregnancy, especially in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn.

special instructions

Suicide and suicidal behavior

Depression is associated with an increased risk of suicidal thoughts, personal injury and suicide (suicidal behavior). This risk persists until the onset of severe remission. Since there may be no improvement during the first few weeks of therapy or even a longer period of time, it is necessary to carefully monitor patients before such an improvement occurs. According to clinical experience, the risk of suicide may increase during the early stages of recovery.

Patients with a history of suicidal attempts or a high level of reflection on suicidal topics are more at risk of suicidal thoughts or attempted suicide before treatment, and such patients should be closely monitored. A meta-analysis of placebo-controlled clinical trials of antidepressants with the participation of adult patients with mental disorders showed that when taking antidepressants compared with taking placebo in patients younger than 25 years of age, the risk of suicidal behavior is increased.Drug treatment of these patients and, in particular, patients with a high risk of suicide should be accompanied by careful observation, especially at an early stage of therapy and with dose adjustment. Patients (and those caring for such patients) should be warned about the need to control any manifestations of clinical deterioration, suicidal behavior or thoughts, as well as unusual changes in behavior, and seek medical help immediately when these symptoms appear.