Instructions for Lafaxin XR tablets 75 mg N28
Composition
active ingredient: venlafaxine hydrochloride;
1 tablet contains venlafaxine hydrochloride 84.85 mg, which is equivalent to venlafaxine base 75 mg;
Excipients: microcrystalline cellulose, hypromellose 2208, ethylcellulose, magnesium stearate, colloidal anhydrous silicon dioxide, coating (ethylcellulose aqueous dispersion, dibutyl sebacate, hypromellose, macrogol 400.
Dosage form
Extended-release tablets.
Main physicochemical properties: white, convex, capsule-shaped tablets, coated.
Pharmacotherapeutic group
Antidepressants. ATX code N06A X16.
Pharmacological properties
Pharmacodynamics
Mechanism of action
The mechanism of antidepressant action of venlafaxine in humans is thought to be related to its potentiation of neurotransmitter activity in the central nervous system (CNS). Preclinical studies have shown that venlafaxine and its major metabolite O-desmethylvenlafaxine (ODV) are serotonin and norepinephrine reuptake inhibitors (SNRIs). Venlafaxine also weakly inhibits dopamine reuptake. Venlafaxine and its active metabolite reduce β-adrenergic reactivity after single (single dose) and chronic administration. Venlafaxine and ODV are very similar in their overall effects on neurotransmitter reuptake and receptor binding.
Venlafaxine has little affinity for muscarinic, cholinergic, H1-histaminergic, and α1-adrenergic receptors in rat brain in vitro. Pharmacological actions at these receptors may be associated with a variety of adverse effects seen with other antidepressants, such as anticholinergic, sedative, and cardiovascular adverse effects.
Venlafaxine does not exhibit inhibitory activity against monoamine oxidase (MAO).
In vitro studies have shown that venlafaxine has almost no affinity for opiate or benzodiazepine receptors.
Clinical efficacy and safety
Major depressive episodes
The efficacy of immediate-release venlafaxine for the treatment of major depressive episodes has been demonstrated in five randomized, double-blind, placebo-controlled, short-term studies of 4 to 6 weeks duration at doses up to 375 mg/day. The efficacy of extended-release venlafaxine for the treatment of major depressive episodes has been demonstrated in two short-term, placebo-controlled studies of 8 to 12 weeks duration at doses of 75 to 225 mg/day. In a longer-term study, adult outpatients who responded to venlafaxine during an 8-week open-label trial of venlafaxine extended-release (75, 150, or 225 mg) were randomized to continue venlafaxine at the same dose or placebo with a follow-up period for relapse for up to 26 weeks.
In a second, longer-term study, the efficacy of venlafaxine in preventing recurrence of depressive episodes over 12 months was established in a placebo-controlled, double-blind clinical trial in adult outpatients with recurrent depressive episodes who had responded to venlafaxine treatment (100-200 mg/day, administered twice daily) for a previous depressive episode.
Generalized anxiety disorders
The efficacy of venlafaxine extended-release for the treatment of generalized anxiety disorder (GAD) was established in two placebo-controlled, fixed-dose (75-225 mg/day) studies of 8 weeks duration, one placebo-controlled, fixed-dose (75-225 mg/day) study of 6 months duration, and one placebo-controlled, variable-dose (37.5, 75, and 150 mg/day) study of 6 months duration in adult outpatients.
Despite evidence of superiority over placebo for the 37.5 mg/day dose, this dose was not as consistently effective as the higher dose.
Social anxiety disorders
The efficacy of venlafaxine extended-release for the treatment of social anxiety disorder was established in four double-blind, multicenter, placebo-controlled, variable-dose, parallel-group studies of 12 weeks duration and one double-blind, placebo-controlled, fixed/variable-dose, parallel-group study of 6 months duration in adult outpatients. Patients received doses ranging from 75 to 225 mg/day. There was no evidence of greater efficacy in the 150-225 mg/day group compared with the 75 mg/day group over the 6-month study period.
The efficacy of venlafaxine extended-release in the treatment of panic disorder was established in two double-blind, multicenter, placebo-controlled studies of 12 weeks duration in adult outpatients with panic disorder, with or without agoraphobia. The initial dose of the drug in the treatment of panic disorder in the studies was 37.5 mg/day for 7 days. Thereafter, patients received fixed doses of 75 or 150 mg/day in one study and 75 or 225 mg/day in the other study. Efficacy was also established in one long-term, double-blind, placebo-controlled, parallel-group study of long-term safety, efficacy, and relapse prevention in adult outpatients who responded to open-label treatment. Patients continued to receive the same dose of venlafaxine extended-release that they were taking at the end of the open-label phase (75, 150, or 225 mg).
Cardiac electrophysiology
It is known that in a dedicated QTc study in healthy volunteers, venlafaxine did not prolong the QT interval to any clinically significant extent at a supratherapeutic dose of 450 mg/day (225 mg twice daily). However, cases of QTc prolongation/TdP and ventricular arrhythmia have been reported, particularly with overdose or in patients with other risk factors for QTc prolongation/TdP (see sections 4.4, 4.8 and 4.8).
Pharmacokinetics
Venlafaxine is extensively metabolized, primarily to the active metabolite ODV. The mean ± standard deviation (SD) half-lives for venlafaxine and ODV from plasma are 5±2 hours and 11±2 hours, respectively. Steady-state concentrations of venlafaxine and ODV are achieved within 3 days of multiple oral administration. Venlafaxine and ODV show linear kinetics over the dose range of 75 to 450 mg/day.
Absorption
At least 92% of venlafaxine is absorbed after a single oral dose of immediate-release venlafaxine. Absolute bioavailability is 40–45%, which is due to first-pass metabolism. Following a dose of immediate-release venlafaxine, peak plasma concentrations of venlafaxine and ODV are observed at 2 and 3 hours, respectively. Following a dose of extended-release venlafaxine, peak plasma concentrations of venlafaxine and ODV are achieved at 5.5 and 9 hours, respectively. When given the same daily doses of immediate-release or extended-release venlafaxine, the extended-release dosage form provides a slower rate of absorption with a similar extent of absorption compared to the immediate-release tablets. Food intake does not affect the bioavailability of venlafaxine and ODV.
Distribution
Venlafaxine and ODV are minimally bound to human plasma proteins at therapeutic concentrations (27% and 30%, respectively). The volume of distribution of venlafaxine at steady state is 4.4±1.6 L/kg after intravenous administration.
Biotransformation
Venlafaxine undergoes extensive hepatic metabolism. In vitro and in vivo studies indicate that venlafaxine is biotransformed by CYP2D6 to form its major active metabolite, ODV. In vitro and in vivo studies indicate that venlafaxine is metabolized by CYP3A4 to form its minor, less active metabolite, N-desmethylvenlafaxine. In vitro and in vivo studies indicate that venlafaxine is a weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP1A2, CYP2C9, or CYP3A4.
Breeding
Venlafaxine and its metabolites are primarily excreted by the kidneys. Approximately 87% of a venlafaxine dose is excreted in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). The mean ± SD steady-state plasma clearances of venlafaxine and ODV are 1.3 ± 0.6 L/h/kg and 0.4 ± 0.2 L/h/kg, respectively.
Special populations
Age and gender
The patient's age and gender do not significantly affect the pharmacokinetics of venlafaxine and ODV.
CYP2D6 extensive/poor metabolizers
Plasma concentrations of venlafaxine are higher in CYP2D6 poor metabolizers than in extensive metabolizers. Since the total exposure (AUC) to venlafaxine and ODV is similar in poor and extensive metabolizers, there is no need for different venlafaxine dosing regimens for these two patient groups.
Liver dysfunction
In patients with Child-Pugh Class A (mild hepatic impairment) and Child-Pugh Class B (moderate hepatic impairment), the elimination half-life of venlafaxine and ODV was prolonged compared with patients with normal hepatic function. The oral clearance of venlafaxine and ODV was reduced, with a wide degree of inter-patient variability. Data on the use of the drug in patients with severe hepatic impairment are limited.
In patients on dialysis, the half-life of venlafaxine was prolonged by approximately 180% and clearance was reduced by approximately 57% compared to patients with normal renal function, while the half-life of ODV was prolonged by approximately 142% and clearance was reduced by approximately 56%. Dosage adjustment is required in patients with severe renal impairment and in patients requiring hemodialysis (see Dosage and Administration).
Indication
Treatment of major depressive episodes.
Prevention of recurrence of major depressive episodes.
Treatment of generalized anxiety disorders.
Treatment of social anxiety disorder (social phobia).
Treatment of panic disorder with or without agoraphobia.
Contraindication
Hypersensitivity to venlafaxine or to any of the excipients of the drug.
Concomitant treatment with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serotonin syndrome with symptoms such as agitation, tremor and hyperthermia. Venlafaxine should not be started for at least 14 days after discontinuation of irreversible MAOI treatment.
Venlafaxine treatment should be discontinued at least 7 days before starting therapy with irreversible MAO inhibitors.
Interaction with other medicinal products and other types of interactions
MAO inhibitors
Irreversible non-selective MAO inhibitors
Venlafaxine should not be used in combination with irreversible non-selective MAO inhibitors. Venlafaxine should not be started for at least 14 days after discontinuation of treatment with irreversible non-selective MAO inhibitors. Venlafaxine treatment should be discontinued at least 7 days before initiation of therapy with irreversible non-selective MAO inhibitors (see sections "Contraindications" and "Special Instructions").
Reversible selective MAO-A inhibitor (moclobemide)
Due to the risk of serotonin syndrome, the combined use of venlafaxine with reversible selective MAO inhibitors such as moclobemide is not recommended. After completion of treatment with the reversible MAO inhibitor, a shorter withdrawal period (less than 14 days) may be used before starting treatment with venlafaxine. It is recommended to stop taking venlafaxine at least 7 days before starting treatment with the reversible MAO inhibitor (see section "Special instructions").
Reversible nonselective MAO inhibitor (linezolid)
The antibiotic linezolid is a weak reversible non-selective MAO inhibitor and should not be administered to patients receiving venlafaxine (see section "Special warnings and precautions for use").
Serious adverse reactions have been reported in patients who have recently discontinued MAO inhibitors and started treatment with venlafaxine, or who have recently discontinued venlafaxine before starting treatment with an MAO inhibitor. These reactions have included tremor, myoclonus, profuse sweating, nausea, vomiting, flushing, dizziness, and hyperthermia with features suggestive of neuroleptic malignant syndrome (NMS), convulsions, and death.
Serotonin syndrome
As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with venlafaxine treatment, especially with concomitant use of other drugs that may affect the serotonergic neurotransmitter system (including triptans, selective serotonin reuptake inhibitors (SSRIs), SNRIs, tricyclic antidepressants, amphetamines, lithium, sibutramine, St. John's wort (Hypericum perforatum), opioids [e.g., fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, pethidine, methadone, pentazocine, buprenorphine, and buprenorphine/naloxone combination]), with drugs that disrupt serotonin metabolism, such as MAO inhibitors (e.g., methylene blue), or with serotonin precursors (such as tryptophan supplements), or with antipsychotics or other dopamine antagonists (see sections "Contraindications" and "Special instructions for use").
If there is a clinical indication for the concomitant use of venlafaxine with an SSRI or SNRI or a serotonin receptor agonist (triptan), close monitoring of the patient is recommended, especially at the beginning of treatment and when the dose of the drug is increased. The simultaneous use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended (see section "Special instructions").
Active substances that affect the CNS
The risk of using venlafaxine in combination with other CNS-active substances has not been systematically studied. Therefore, caution is recommended when using venlafaxine in combination with other CNS-active substances.
Ethanol
Patients should be advised to avoid alcohol, given its effects on the CNS and potential clinical worsening of psychiatric disorders, as well as the potential for adverse interactions with venlafaxine, including CNS depressant effects.
The risk of QTc prolongation and/or ventricular arrhythmias (e.g. TdP) is increased by concomitant use with other medicinal products that prolong the QTc interval. Concomitant use of such medicinal products should be avoided (see section 4.4).
Relevant classes include:
Class Ia and III antiarrhythmics (e.g. quinidine, amiodarone, sotalol, dofetilide);
some neuroleptics (e.g. thioridazine);
some macrolides (e.g. erythromycin);
some antihistamines;
some quinolone antibiotics (e.g. moxifloxacin).
The list of drugs above is not exhaustive, and other known individual drugs that significantly prolong the QT interval should be avoided.
Effects of other drugs on venlafaxine
Ketoconazole (CYP3A4 inhibitor)
A pharmacokinetic study of ketoconazole in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) resulted in increases in venlafaxine AUC (70% and 21% in CYP2D6 EMs and EMs, respectively) and AUC (33% and 23% in CYP2D6 EMs and EMs, respectively) following ketoconazole administration. Concomitant use of CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, voriconazole, posaconazole, ketoconazole, nelfinavir, ritonavir, saquinavir, telithromycin) and venlafaxine may increase venlafaxine and AUC levels. Therefore, caution is advised if a patient is receiving concomitant therapy with a CYP3A4 inhibitor and venlafaxine.
Effect of venlafaxine on other drugs
Lithium
Serotonin syndrome may develop when venlafaxine and lithium are used concomitantly (see section on serotonin syndrome).
Diazepam
Venlafaxine does not affect the pharmacokinetics and pharmacodynamics of diazepam and its active metabolite, desmethyldiazepam. Diazepam is unlikely to affect the pharmacokinetics of either venlafaxine or ODV. It is unknown whether pharmacokinetic and/or pharmacodynamic interactions exist with other benzodiazepines.
Imipramine
Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. A dose-dependent increase in the AUC of 2-OH-desipramine of 2.5- to 4.5-fold was observed when venlafaxine was administered at doses of 75 to 150 mg once daily.
Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this interaction is unknown. Caution should be exercised when venlafaxine and imipramine are coadministered.
Haloperidol
A pharmacokinetic study of venlafaxine with haloperidol showed a 42% decrease in total oral clearance, a 70% increase in AUC, and an 88% increase in Cmax, but the half-life of haloperidol remained unchanged. This should be considered in patients receiving concomitant treatment with haloperidol and venlafaxine. The clinical significance of this interaction is unknown.
Risperidone
Venlafaxine increased the AUC of risperidone by 50%, but did not significantly alter the pharmacokinetic profile of the total active component (risperidone plus 9-hydroxyrisperidone). The clinical significance of this interaction is unknown.
Metoprolol
Concomitant administration of venlafaxine and metoprolol to healthy volunteers in a pharmacokinetic interaction study for both drugs resulted in an increase in plasma concentrations of metoprolol by approximately 30–40% without changes in plasma concentrations of its active metabolite, α-hydroxymetoprolol. The clinical significance of these findings in patients with hypersensitivity is unknown. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, ODV. Caution should be exercised when venlafaxine and metoprolol are coadministered.
Indinavir
A pharmacokinetic study with indinavir showed a 28% decrease in AUC and a 36% decrease in Cmax of indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this interaction is unknown.
Drugs metabolized by cytochrome P450
In vivo isoenzyme studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP3A4 (alprazolam and carbamazepine), CYP1A2 (caffeine), and CYP2C9 (tolbutamide) or CYP2C19 (diazepam) in vivo.
Oral contraceptives
It is known that in post-marketing experience, cases of unintended pregnancy have been reported in individuals taking oral contraceptives while being treated with venlafaxine. There is no clear evidence that these pregnancies were the result of a drug interaction with venlafaxine. Interaction studies with hormonal contraceptives have not been conducted.
Application features
Overdose
Patients should be advised to avoid alcohol, given its effects on the CNS and the potential for clinical worsening of psychiatric disorders, as well as the potential for adverse interactions with venlafaxine, including CNS depressant effects (see section 4.5).
Venlafaxine should be prescribed at the lowest dose with appropriate monitoring of the patient's condition to reduce the risk of overdose (see section "Overdose").
Suicide/suicidal thoughts or clinical worsening
Depression is associated with an increased risk of thoughts of harming oneself and of suicide (suicidality). The risk persists until significant remission occurs. As improvement may not occur during the first few weeks of treatment or longer, patients should be closely monitored until improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Other psychiatric disorders for which venlafaxine is indicated may also be associated with an increased risk of suicidal behaviour. In addition, these conditions may coexist with major depressive disorder. The precautions observed in the treatment of patients with major depressive disorder should also be observed in the treatment of patients with other psychiatric disorders.
Patients with a history of suicidal behaviour or patients who demonstrate a significant degree of suicidal ideation prior to initiation of treatment are known to be at greater risk of suicidal thoughts or suicide attempts and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared with placebo in patients aged <25 years.
Close monitoring of patients, especially those at high risk, should be undertaken in conjunction with drug therapy, particularly early in treatment and after dose changes. Patients and caregivers should be alerted to the need to monitor for any clinical worsening, suicidal behaviour or thoughts, and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Children
Suicidal behaviour (suicidal thoughts or suicide attempts) and hostility (predominantly aggression, oppositional behaviour and anger) were observed more frequently in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, due to clinical need, a decision to treat is nevertheless made, patients should be closely monitored for the development of suicidal symptoms. In addition, long-term safety data on growth, maturation and cognitive and behavioural development in children and adolescents are lacking.
Serotonin syndrome
As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with venlafaxine treatment, especially with concomitant use of other drugs that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, SNRIs, tricyclic antidepressants, amphetamines, lithium, sibutramine, St. John's wort (Hypericum perforatum), opioids [e.g. fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, pethidine, methadone, pentazocine, buprenorphine and buprenorphine/naloxone combination]), with drugs that disrupt serotonin metabolism, such as MAO inhibitors (e.g. methylene blue), or with serotonin precursors (such as tryptophan supplements), or with antipsychotics or other dopamine antagonists (see section 4.4). sections "Contraindications" and "Interaction with other medicinal products and other types of interactions").
Symptoms of serotonin syndrome may include changes in the patient's mental status (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form, may resemble CNS depression, including hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuations in vital signs and changes in mental status.
If concomitant treatment with venlafaxine and other drugs that may affect the serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, close monitoring of patients is recommended, especially at the beginning of treatment and during dose increases.
Concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended.
Narrow-angle glaucoma
Mydriasis may occur with venlafaxine. Close monitoring is recommended in patients with elevated intraocular pressure or at increased risk of developing acute narrow-angle glaucoma (angle-closure glaucoma).
Dose-related increases in blood pressure have been commonly reported with venlafaxine. In post-marketing experience, several cases of severe hypertension requiring immediate treatment have been reported. All patients should be monitored closely for the development of high blood pressure, and pre-existing hypertension should be controlled before initiating treatment. Blood pressure should be monitored periodically after initiation of treatment and after dose increases. Caution should be exercised in patients with underlying medical conditions that may predispose them to increased blood pressure, such as those with impaired cardiac function.
Heart rate
An increase in heart rate may occur, especially at higher doses. Caution should be exercised when treating patients whose underlying conditions may be predisposed to an increase in heart rate.
Heart disease and the risk of developing arrhythmia
Venlafaxine has not been studied in patients with a recent myocardial infarction or a history of unstable heart disease. Therefore, this drug should be used with caution in these patients.
In post-marketing experience with venlafaxine, cases of QTc prolongation, Torsade de Pointes (TdP), ventricular tachycardia, and fatal cardiac arrhythmias have been reported with venlafaxine, particularly in overdose or in patients with other risk factors for QTc prolongation/TdP. The risk-benefit ratio should be considered before prescribing venlafaxine to patients at high risk of developing serious cardiac arrhythmias or QTc prolongation (see section 5.1).
Convulsions
Convulsions may occur during treatment with venlafaxine. As with all antidepressants, venlafaxine should be initiated cautiously in patients with a history of seizures; these patients should be closely monitored. Treatment should be discontinued in any patient who develops a seizure.
Hyponatremia
Hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur with venlafaxine. These events have been reported most frequently in patients who are dehydrated or debilitated. Elderly patients, patients taking diuretics, and patients who are otherwise hypovolemic are at greater risk of developing these events.
Abnormal bleeding
Serotonin reuptake inhibitors may cause decreased platelet function. Bleeding events associated with the use of SSRIs and SNRIs have ranged from ecchymoses, hematomas, epistaxis and petechiae to gastrointestinal and life-threatening haemorrhages. Patients taking venlafaxine may be at increased risk of haemorrhage. As with other SSRIs, venlafaxine should be used with caution in patients with a predisposition to bleeding, including patients receiving anticoagulants and platelet inhibitors. SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see sections 4.8 and 4.8).
Serum cholesterol level
Clinically significant increases in serum cholesterol were reported in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients for at least 3 months in placebo-controlled clinical trials. During long-term treatment, serum cholesterol levels should be considered.
Sexual dysfunction
SSRIs may cause symptoms of sexual dysfunction (see section 4.8). In some cases, these symptoms have persisted after discontinuation of treatment.
Concomitant use with weight loss products
The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Concomitant use of venlafaxine and weight loss agents is not recommended. Venlafaxine is not prescribed for weight loss alone or in combination with other drugs.
Mania/hypomania
Mania/hypomania may occur in a small percentage of patients with mood disorders treated with antidepressants, including venlafaxine. As with other antidepressants, venlafaxine should be prescribed with caution in patients with a history or family history of bipolar disorder.
Aggression
Aggression may occur in a small number of patients treated with antidepressants, including venlafaxine. This phenomenon has been reported after initiation of treatment, dose changes, and discontinuation of treatment.
As with other antidepressants, venlafaxine should be used with caution in patients with a history of aggression.
Antidepressants are known to have withdrawal effects and these effects can sometimes be prolonged and serious. Suicide/suicidal thoughts and aggression have been reported in patients during changes in venlafaxine dosing regimens, including when treatment is discontinued. Therefore, patients should be closely monitored during dose reduction or when treatment is discontinued (see section 4.4 - Suicide/suicidal thoughts or clinical worsening and Aggression). (see section 4.8). In clinical trials, adverse events on discontinuation of treatment (dose tapering and after dose tapering) were observed in approximately 31% of patients treated with venlafaxine and 17% of patients treated with placebo.
The risk of withdrawal symptoms may depend on several factors, including the duration of treatment and dose, and the rate of dose reduction. The most commonly reported reactions are: dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and deep sleep), agitation or anxiety, nausea and/or vomiting, tremor and headache, visual disturbances and hypertension. These symptoms are usually mild to moderate in severity, but in some patients they may be severe in intensity. These events usually occur within the first few days after discontinuation of treatment, but there have been isolated reports of such symptoms in patients who inadvertently missed a dose.
In general, these symptoms resolve spontaneously, usually within 2 weeks, although in some patients they may persist longer (2-3 months or longer). Therefore, when discontinuing treatment, the dose of venlafaxine should be gradually reduced over several weeks or months, depending on the patient's needs (see section 4.2). In some patients, discontinuation of treatment may take months or longer.
Akathisia/psychomotor agitation
The use of venlafaxine has been associated with the development of akathisia, characterized by a subjectively unpleasant or distressing restlessness and need to move frequently, accompanied by an inability to sit or stand still. This phenomenon is more likely to occur during the first few weeks of treatment. In patients who develop these symptoms, increasing the dose of the drug may be harmful.
Dry mouth
Dry mouth has been reported in 10% of patients treated with venlafaxine. This may increase the risk of caries, and patients should be advised of the importance of maintaining good oral hygiene.
Diabetes mellitus
In patients with diabetes mellitus, treatment with SSRIs or venlafaxine may affect glycemic control. The doses of insulin and/or oral antidiabetic drugs may need to be adjusted.
Drug and laboratory test interactions
False-positive results of urine immunoassays for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to the lack of specificity of the screening tests. False-positive test results can be expected for several days after discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, can distinguish venlafaxine from PCP and amphetamine.
Use during pregnancy or breastfeeding
Pregnancy
There are no adequate data from the use of venlafaxine in pregnant women.
Animal studies have shown reproductive toxicity. The potential risk to humans is unknown. Venlafaxine should be administered to pregnant women only if the expected benefit outweighs the potential risk.
As with other SSRIs/NSAIDs, withdrawal symptoms may occur in newborn infants if venlafaxine is used before or shortly before birth. Some newborn infants exposed to venlafaxine late in the third trimester have developed complications requiring parenteral nutrition, assisted ventilation, or prolonged hospitalization. These complications may occur immediately after birth.
