Cymlafax XR 225 225 mg XR capsules.

Cymlafax XR 225 is indicated for the treatment of depression, including depression with associated anxiety. Cymlafax XR 225 is indicated for the prevention of relapses of an episode of depression in patients responding to an initial six to eight weeks of treatment. In patients responding to six months of relapse prevention, Cymlafax XR 225 may be used to prevent recurrence. Safety and efficacy beyond one year have not been demonstrated. When Cymlafax XR 225 is used for long-term it should periodically be re-evaluated for the usefulness of the product in the individual patient. Cymlafax XR 225 is indicated for the treatment of generalised anxiety disorder and for the treatment of Social Anxiety Disorder. The effectiveness of Cymlafax XR 225 in the treatment of Social Anxiety Disorder for more than 12 weeks has not been demonstrated.

The usual recommended dose for Cymlafax XR 225 is 75 mg, given once daily. If after several weeks further clinical improvement is required, the dose may be increased to 150 mg, given once daily. If needed, the dose can be further increased up to 225 mg given once daily. Dose increments should be made at intervals of approximately 2 weeks or more, but not less than 4 days. The dose for depressed patients may be further increased, if needed, up to 375 mg, given once daily.

Cymlafax XR 225 should be administered once daily, at approximately the same time either in the morning or in the evening. The extended-release formulation contains spheroids, which release the medicine slowly into the digestive tract. The insoluble portion of these spheroids are eliminated and may be seen in stools.

Depressed patients, who are currently being treated at a therapeutic dose with immediate release formulation may be switched to Cymlafax XR 225 at the nearest equivalent dose (mg/day). Individual dosage adjustments may however be necessary.

Patients with renal impairment should receive lower doses of Cymlafax XR 225. The total daily dose of Cymlafax XR 225 should be reduced by 25 to 50 % for patients with renal impairment with a glomerular filtration rate (GFR) of 10 to 70 mL/min. The total daily dose of Cymlafax XR 225 should be reduced by 50 % in haemodialysis patients. Because of individual variability in clearance in these patients, individualisation of dosage may be desirable.

Patients with hepatic impairment should receive lower doses of Cymlafax XR 225. The total daily dose of Cymlafax XR 225 should be reduced by 50 % in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been studied; therefore, caution should be used if considering treating these patients with Cymlafax XR 225 and a further reduction should be considered. Since there is a variability in clearance between hepatically impaired patients, individualisation of dosing, including further dose reductions (> 50 %), may be desirable in some patients.

Children: Not for use in children under 18 years (see section 4.3).

Elderly patients: No specific dosage adjustments of Cymlafax XR 225 are recommended based on patient age.

Maintenance, continuation and extended treatment: The need for long-term therapy with Cymlafax XR 225 must be periodically reassessed. Whether the dose of antidepressant needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.

Discontinuing Cymlafax XR 225: Dose tapering is recommended whenever possible when discontinuing Cymlafax XR 225 therapy (see sections 4.4 & 4.8). Tapering over at least a two-week period is recommended if Cymlafax XR 225 has been used for more than 6 weeks. In clinical trials with venlafaxine extended-release capsules, tapering was achieved by reducing the daily dose by 75 mg at one week intervals. The period required for tapering may depend on the dose, duration of therapy and the individual patient. Patients should be advised to consult their doctor before abruptly discontinuing Cymlafax XR 225 (see section 4.4 & 4.8).

Method of administration: It is recommended that Cymlafax XR 225 be taken with food. Each capsule should be swallowed whole with fluid. Do not divide, crush, chew or place capsule in water.

Cymlafax XR 225 is contraindicated in:

• Patients with a known hypersensitivity to venlafaxine or to any of the ingredients listed in section 6.1.
• Patients concomitantly taking monoamine oxidase inhibitors (MAOIu2019s).
• Cymlafax XR 225 must not be initiated for at least 14 days after discontinuation of treatment with a MAOI. Cymlafax XR 225 must be discontinued for at least 7 days before starting treatment with any MAOI (see section 4.5). Severe adverse reactions have been reported when Cymlafax XR 225 therapy is initiated soon after discontinuation of a MAOI and when a MAOI is initiated soon after discontinuation of Cymlafax XR 225. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures and death (see section 4.5).
• Children under 18 years (see section 4.4).
• Pregnancy and lactation (see section 4.6).

Suicide/suicidal thoughts or clinical worsening: Patients with major depressive disorder, both adults and children, may experience worsening of their depression and or the emergence of suicidal ideation and behaviour, whether or not they are taking antidepressant medicines. This risk may persist until significant remission occurs. A casual role, however, for antidepressant medicine in inducing such behaviour has not been established. Patients being treated with Cymlafax XR 225 should, nevertheless, be observed closely for clinical worsening and suicidality, especially at the beginning of a course of therapy or at any time of dose changes, either increases or decreases.

Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and non-psychiatric disorders, the same precautions observed when treating patients with major depressive disorders should be observed when treating patients with other psychiatric and non-psychiatric disorders.

The following symptoms have been reported in patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric: anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness, impulsivity, akathisia, hypomania and mania). Although a causal link between the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing Cymlafax XR 225, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patientu2019s presenting symptoms. If the decision is made to discontinue treatment, Cymlafax XR 225 should be tapered (see section 4.2).

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement 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 antidepressant medicines in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients, and in particular those at high risk, should accompany medicine therapy, especially in early treatment and following dose changes. Patients (and caregivers of patients) should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restless), hypomania, mania, other unusual changes in behaviour, worsening of depression, and suicidal ideation, especially when initiating therapy or during any change in dose or dosage regimen. The risk of suicide attempt must be considered especially in depressed patients, and the smallest quantity of medicine, consistent with good patient management, should be provided to reduce the risk of overdose. Risk assessment for suicide should be performed regularly.

Paediatric population: Cymlafax XR 225 should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo.

Serotonin syndrome: Serotonin syndrome, a potentially life-threatening condition may occur with Cymlafax XR 225 treatment, particularly with concomitant use of other medicines that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, SNRIs, amphetamines, lithium, sibutramine, St. John's Wort [ Hypericum perforatum ], fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, pethidine, methadone and pentazocine), with medicines that impair metabolism of serotonin (such as MAOIs e.g. methylene blue), with serotonin precursors (such as tryptophan supplements) or with antipsychotics or other dopamine antagonists (see sections 4.3 and 4.5).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea). Serotonin syndrome in its most severe form, can resemble Neuroleptic Malignant Syndrome (NMS), which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs and mental status changes.

If concomitant treatment with Cymlafax XR 225 and other medicines that may affect the serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of Cymlafax XR 225 with serotonin precursors (such as tryptophan supplements) is not recommended.

Narrow-angle glaucoma: Mydriasis may occur in association with Cymlafax XR 225. It is recommended that patients with raised intraocular pressure or patients at risk for acute narrow-angle glaucoma (angle-closure glaucoma) be closely monitored.

Blood pressure: Dose-related increases in blood pressure have been frequently reported with venlafaxine. In some cases, severely elevated blood pressure requiring immediate treatment has been reported in post marketing experience. All patients should be carefully screened for high blood pressure and pre-existing hypertension should be controlled before initiation of treatment. Blood pressure should be reviewed periodically, after initiation of treatment and after dose increases.

Caution should be exercised in patients whose underlying conditions might be compromised by increases in blood pressure, e.g., those with impaired cardiac function.

Heart rate: Increases in heart rate can occur, particularly with higher doses. Caution should be exercised in patients whose underlying conditions might be compromised by increases in heart rate.

Cardiac disease and risk of dysrhythmia: Cymlafax XR 225 has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, it should be used with caution in these patients. In post marketing experience, cases of QTc prolongation, Torsade de Pointes (TdP), ventricular tachycardia, and fatal cardiac dysrhythmias have been reported with the use of venlafaxine, especially in overdose or in patients with other risk factors for QTc prolongation/TdP. The balance of risks and benefits should be considered before prescribing Cymlafax XR 225 to patients at high risk of serious cardiac dysrhythmias or QTc prolongation (see section 5.1).

Convulsions: Convulsions may occur with Cymlafax XR 225 therapy. Cymlafax XR 225 should be introduced with caution in patients with a history of convulsions and concerned patients should be closely monitored. Treatment should be discontinued in any patient who develops seizures.

Hyponatraemia: Cases of hyponatraemia and/or the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion may occur with Cymlafax XR 225. This has most frequently been reported in volume-depleted or dehydrated patients. Elderly patients, patients taking diuretics, and patients who are otherwise volume-depleted may be at greater risk for this event.

Abnormal bleeding: Medicines that inhibit serotonin uptake may lead to reduced platelet function. Bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to gastrointestinal and life-threatening haemorrhages. The risk of haemorrhage may be increased in patients taking Cymlafax XR 225. As with other serotonin-reuptake inhibitors, Cymlafax XR 225 should be used cautiously in patients predisposed to bleeding, including patients on anticoagulants and platelet inhibitors.

Postpartum haemorrhage: SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see sections 4.6 & 4.8).

Serum cholesterol: Clinically relevant increases in serum cholesterol were recorded in 5,3 % of venlafaxine treated patients and 0,0 % of placebo-treated patients treated for at least 3 months in placebo-controlled clinical trials. Measurement of serum cholesterol levels should be considered during long-term treatment.

Allergic phenomenon: Patients should be advised to notify their doctor if they develop a rash, hives, or a related allergic phenomenon.

Co-administration with weight loss medicines: The safety and efficacy of Cymlafax XR 225 therapy in combination with weight loss medicines, including phentermine, have not been established. Co-administration of Cymlafax XR 225 and weight loss medicines is not recommended. Cymlafax XR 225 is not indicated for weight loss alone or in combination with other products.

Mania/hypomania: Mania/hypomania may occur in a small proportion of patients with mood disorders who have received antidepressants, including Cymlafax XR 225. Cymlafax XR 225 should be used cautiously in patients with a history or family history of bipolar disorder.

Aggression: Aggression may occur in a small number of patients who have received antidepressants, including Cymlafax XR 225. This has been reported under initiation, dose changes and discontinuation of treatment. Cymlafax XR 225 should be used cautiously in patients with a history of aggression.

Discontinuation of treatment: Withdrawal symptoms, when treatment is discontinued, are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials, adverse events seen on treatment discontinuation (tapering and post-tapering) occurred in approximately 31 % of patients treated with venlafaxine and 17 % of patients taking placebo. The risk of withdrawal symptoms may be dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor and headache are the most frequently reported reactions. Generally, these symptoms are mild to moderate; however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been less frequent reports of such symptoms in patients who have inadvertently missed a dose. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be extended (2 to 3 months or more). It is therefore advised that Cymlafax XR 225 should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs (see section 4.2).

Sexual dysfunction: Serotonin-norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section 4.8). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SNRIs.

Akathisia/psychomotor restlessness: The use of venlafaxine has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Dry mouth: Dry mouth is reported in 10 % of patients treated with venlafaxine. This may increase the risk of caries, and patients should be advised upon the importance of dental hygiene.

Diabetes: In patients with diabetes, treatment with an SSRI or Cymlafax XR 225 may alter glycaemic control. Insulin and/or oral antidiabetic dosage may need to be adjusted.

Medicine-Laboratory test interactions: False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of Cymlafax XR 225 therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.

Monoamine Oxidase Inhibitors (MAOI): Cymlafax XR 225 must not be used in combination with irreversible non-selective MAOIs. Cymlafax XR 225 must not be initiated for at least 14 days after discontinuation of treatment with an irreversible non-selective MAOI. Cymlafax XR 225 must be discontinued for at least 7 days before starting treatment with an irreversible non-selective MAOI (see sections 4.3 and 4.4). Severe adverse reactions have been reported in patients who have recently been discontinued from an MAOI and started on Cymlafax XR 225 or have recently had Cymlafax XR 225 therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, and hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death.

Serotonin syndrome: Serotonin syndrome, a potentially life-threatening condition, may occur with Cymlafax XR 225 treatment, particularly with concomitant use of other medicines that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, SNRIs, amphetamines, lithium, sibutramine, St. John's Wort [ Hypericum perforatum ], fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, pethidine, methadone and pentazocine), with medicines that impair metabolism of serotonin (such as MAOIs e.g. methylene blue), with serotonin precursors (such as tryptophan supplements) or with antipsychotics or other dopamine antagonists (see sections 4.3 and 4.4).

If concomitant treatment with Cymlafax XR 225 and an SSRI, an SNRI or a serotonin receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of Cymlafax XR 225 with serotonin precursors (such as tryptophan supplements) is not recommended (see section 4.4).

CNS-active medicines: The risk of using Cymlafax XR 225 in combination with other CNS-active medicines has not been systematically evaluated. Consequently, caution is advised when Cymlafax XR 225 is taken in combination with other CNS-active medicines.

Ethanol: Venlafaxine has been shown not to increase the impairment of mental and motor skills caused by ethanol. However, Cymlafax XR 225 is a CNS-active medicine and patients should be advised to avoid alcohol consumption.

Medicines that prolong the QT interval: The risk of QTc prolongation and/or ventricular dysrhythmias (e.g., TdP) is increased with concomitant use of other medicines which prolong the QTc interval. Co-administration of such medicines should be avoided (see section 4.4).

Relevant classes include:

• class Ia and III anti-dysrhythmics (e.g. quinidine, amiodarone, sotalol, dofetilide)
• some antipsychotics (e.g. thioridazine)
• some macrolides (e.g. erythromycin)
• some antihistamines
• some quinolone antibiotics (e.g. moxifloxacin)

The above list is not exhaustive and other individual medicines known to significantly increase QT interval should be avoided.

Effect of other medicines on venlafaxine: Ketoconazole (CYP3A4 inhibitor) A pharmacokinetic study with ketoconazole in CYP2D6 extensive (EM) and poor metabolisers (PM) resulted in higher AUC of venlafaxine and O-desmethylvenlafaxine following administration of ketoconazole. Concomitant use of CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, voriconazole, posaconazole, ketoconazole, nelfinavir, ritonavir, saquinavir, telithromycin) and Cymlafax XR 225 may increase levels of venlafaxine and O-desmethylvenlafaxine. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and Cymlafax XR 225 concomitantly.

CYP2D6 and 3A4 inhibitors: The concomitant use of Cymlafax XR 225 with medicine treatment(s) that potentially inhibit both CYP2D6 and CYP3A4, the primary metabolizing enzymes for Cymlafax XR 225, has not been studied. However, this concomitant use would be expected to increase Cymlafax XR 225 plasma concentrations. Therefore, caution is advised when combining Cymlafax XR 225 with any medicine(s) that produce simultaneous inhibition of these two enzyme systems.

Effect of Cymlafax XR 225 on other medicines: Lithium: Serotonin syndrome may occur with the concomitant use of Cymlafax XR 225 and lithium (see section 4.4, serotonin syndrome). Diazepam: Venlafaxine has no effects on the pharmacokinetics and pharmacodynamics of diazepam and its active metabolite, desmethyldiazepam. Diazepam does not appear to affect the pharmacokinetics of either venlafaxine or O-desmethylvenlafaxine. It is unknown whether a pharmacokinetic and/or pharmacodynamic interaction with other benzodiazepines exists. Imipramine: Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. There was a dose-dependent increase of 2-OH-desipramine AUC by 2,5 to 4,5-fold when venlafaxine 75 mg to 150 mg daily was administered. Imipramine did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown. Caution should be exercised with co-administration of Cymlafax XR 225 and imipramine. Haloperidol: A pharmacokinetic study with haloperidol has shown a 42 % decrease in total oral clearance, a 70 % increase in AUC, an 88 % increase in C max, but no change in half-life for haloperidol. This should be taken into account in patients treated with haloperidol and Cymlafax XR 225 concomitantly. The clinical significance of this interaction is unknown. Cimetidine: At steady-state, cimetidine has been shown to inhibit first-pass metabolism of venlafaxine; however, cimetidine had no effect on the pharmacokinetics of O-desmethylvenlafaxine. The overall pharmacological activity of venlafaxine plus O-desmethylvenlafaxine is expected to increase only slightly in most patients. In the elderly and in patients with hepatic or renal dysfunction this interaction may be more pronounced. Risperidone: Venlafaxine increased the risperidone AUC by 50 % but did not significantly alter the pharmacokinetic profile of the total active moiety (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 medicines resulted in an increase of plasma concentrations of metoprolol by approximately 30 to 40 % without altering the plasma concentrations of its active metabolite, u03b1-hydroxymetoprolol. The clinical relevance of this finding in hypertensive patients is unknown. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. Caution should be exercised with co-administration of Cymlafax XR 225 and metoprolol. Indinavir: A pharmacokinetic study with indinavir has shown a 28 % decrease in AUC and a 36 % decrease in C max for indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown. Medicines metabolised by cytochrome P450 isoenzymes: In vivo studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP3A4b (alprazolam and carbamazepine), CYP1A2 (caffeine), and CYP2C9 (tolbutamide) or CYP2C19 (diazepam) in vivo. Oral contraceptives: In post-marketing experience unintended pregnancies have been reported in subjects taking oral contraceptives while on venlafaxine. There is no clear evidence these pregnancies were a result of medicine interaction with venlafaxine. No interaction study with hormonal contraceptives has been performed.

Cymlafax XR 225 must not be administered to pregnant or lactating women. Observational data indicate an increased risk (less than 2-fold) of postpartum haemorrhage following SSRIs/SNRIs exposure within the month prior to birth (see sections 4.4 & 4.8). Women of childbearing potential / Contraception in males and females: Patients should be advised to notify their doctor if they become pregnant or intend to become pregnant during treatment with Cymlafax XR 225. Pregnancy: Cymlafax XR 225 must not be administered to pregnant women. Safety during human pregnancy and lactation has not been established (see section 4.3). Some neonates exposed to venlafaxine late in the third trimester have developed complications requiring tube-feeding; respirator; support or extended hospitalisation. Such complications can arise immediately upon delivery. Breastfeeding: Venlafaxine and its active metabolite, O-desmethylvenlafaxine, are excreted in human milk. Therefore, mothers on treatment with Cymlafax XR 225 should not breastfeed (see section 4.3).

Cymlafax XR 225 causes dizziness and sedation; it may therefore impair judgment, thinking, and motor skills. Patients receiving Cymlafax XR 225 should therefore be cautioned about their ability to drive or operate hazardous machinery.

Summary of the safety profile: The most frequent observed adverse reactions reported in clinical studies were nausea, dry mouth, headache and sweating (including night sweats). The occurrence of many frequently observed adverse events is dose related.

Tabulated list of adverse reactions:

* ADR identified post-marketing

a Cases of suicidal ideation and suicidal behaviours have been reported during venlafaxine therapy or early after treatment discontinuation (see section 4.4).

b See section 4.4

c This event has been reported for the therapeutic class of SSRIs/SNRIs (see sections 4.4 & 4.6).

Description of selected adverse events: Discontinuation of treatment: Discontinuation of Cymlafax XR 225 (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, vertigo, headache and flu syndrome are the most commonly reported reactions. Generally, these events are mild to moderate and are self-limiting; however, in some patients, they may be severe and/or extended. It is therefore advised that when Cymlafax XR 225 treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

In post marketing experience, overdose with venlafaxine was reported predominantly in combination with alcohol and/or other medicines. The most commonly reported events in overdose include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, convulsion, and vomiting. Other reported events include electrocardiographic changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation (see section 5.1), ventricular tachycardia, bradycardia, hypotension, vertigo, and deaths.

Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine treated patients have a higher burden of suicide risk factors than SSRI patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristics of venlafaxine treated patients, is not clear. Prescriptions for Cymlafax XR 225 should be written for the smallest quantity of the medicine consistent with good patient management in order to reduce the risk of overdose.

Recommended treatment: General supportive and symptomatic measures are recommended; cardiac rhythm and vital signs must be monitored. When there is a risk of aspiration, induction of emesis is not recommended. Administration of activated charcoal may also limit absorption of the active substance. Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for Cymlafax XR 225 are known.