MHM Magazine

Issue 2 | 2023 | MENTAL HEALTH MATTERS | 17 MHM Medication with a high risk for drug - drug interactions can have a negative impact on the successful treatment of MDD. 1 The simple metabolic properties of desvenlafaxine suggest a minimal likelihood of clinically significant CYP-mediated DDIs. 1 desvenlafaxine S5 EXSIRA50 mg and 100 mg extended–release tablets (Reg. nos.: 42/1.2/0935, 41/1.2/0427). Each tablet contains desvenlafaxine succinate equivalent to 50 mg and 100 mg desvenlafaxine respectively. LICENCE HOLDER: Pfizer Laboratories (Pty) Ltd. Reg. No. 1954/000781/07. 85 Bute Lane, Sandton, 2196, SouthAfrica.Tel. No.: 0860 PFIZER (734937). Please refer to detailed package insert for full prescribing information. References: 1. DeMaio et al. J Bioequiv Availab 2011, 3:7 Metabolism Studies of Desvenlafaxine To report an adverse event, please contact ZAF.AEReporting@pfizer.com. If you wish to contact Pfizer for any other purpose, please use contact details below. +2711 320 6000 or 0860 734 937 (SAOnly). Monday-Friday 09h00-17h00. S5EXSIRA , 50mgand 100mg extended-release tablets. QUALITATIVEANDQUANTITATIVE COMPOSITION: Each EXSIRA 50mg extended-release flm-coated tablet contains desvenlafaxine succinate equivalent to 50mg desvenlafaxine. Each EXSIRA 100mg extended-release flm-coated tablet contains desvenlafaxine succinate equiv- alent to 100 mg desvenlafaxine. Sugar free. PHARMACEUTICAL FORM: Extended-release tablets. EXSIRA 50 mg extended-release tablets are light pink, square (pyramid, one sided), flm coated tablets, debossed “W” over “50” on the flat side. EXSIRA 100mg extended-release tabletsare reddish-orange, square (pyramid,one sided), flm-coated tablets,debossed “W” over “100” on the flat side. CLINICAL PARTICULARS:Therapeutic Indications: Major depressive disorder EXSIRA tablets are indicated for the treatment of major depressive disorder (MDD). Posology andmethodof administration: Major depressive disorder.The recommended dose for EXSIRA is 50 mg once daily, with or without food, with a maximum dose of 100 mg per day. The dose increase should occur gradually and at an interval of not less than 7 days.Dis- continuing EXSIRA: Symptoms associated with discontinuation of EXSIRA, other SNRIs and SSRIs have been reported. Patients should bemonitored for these symptoms when discontin- uing treatment.A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon dis- continuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, themedical practitionermay continue decreasing the dose but at amore grad- ual rate. Switching patients from other antidepressants to EXSIRA: Discontinuation symptoms have been reportedwhen switching patients from other antidepressants, including venlafaxine, to EXSIRA. Tapering of the initial antidepressant may be necessary to minimise discontinua- tion symptoms. Specialpopulations: Use in patientswith renal impairment. The recommended starting dose in patients with severe renal impairment (24-hr CrCl < 30mL/min) or end-stage renal disease (ESRD) is 50mg every other day. Because of individual variability in clearance in these patients, individualisation of dosage may be desirable. Supplemental doses should not be given to patients after dialysis. Use in patients with hepatic impairment. No dosage ad- justment is necessary for patients with hepatic impairment. Use in elderly patients . No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of EXSIRA should be considered when determining dose. Paediatric populations: Safety and effcacy in patients less than 18 years of age has not been established. Method of administra- tion: For oral use. Contraindications: .•Hypersensitivity toEXSIRA, venlafaxine hydrochloride or to any excipients in the EXSIRA formulation.• EXSIRA is an inhibitor of both norepinephrine and serotonin reuptake. EXSIRAmust not be used in combination with amonoamine oxidase inhibitor (MAOI), orwithin at least 14 days of discontinuing treatmentwith anMAOI. Based on the half-life ofEXSIRA, at least 7 days should be allowed after stoppingEXSIRAbefore starting an MAOI. Severe adverse reactions have been reported when therapy is initiated with SSRI/ SNRI medicines such as EXSIRA soon after discontinuation of an MAOI and when an MAOI is initiated soon after discontinuation of SSRI/SNRImedicines. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with fea- tures resembling neuroleptic malignant syndrome, seizures and death.• Children less than 18 years of age, as safety and effcacy have not been established. • Pregnancy and lactation. Specialwarnings andprecautions foruse: SSRIs/SNRIsmay increase the risk ofpostpartum haemorrhage (see section 4.6 and 4.8). Clinical worsening of depressive symptoms, unusual changes in behaviour, and suicidality. Patients withmajor depressive disordermay experience worseningof theirdepressionand/or theemergenceof suicidal ideationandbehaviour,whether or not they are taking antidepressantmedicines.This riskmay persist until signifcant remission occurs.A causal role, however, for antidepressantmedicine in inducing such behaviour has not beenestablished.Patientsbeing treatedwithEXSIRAshould,nevertheless,beobserved closely for clinicalworsening 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 betweenmajordepressivedisorderandotherpsychiatricandnon-psychiatricdisorders, thesame precautionsobservedwhen treatingpatientswithmajordepressivedisordersshouldbeobserved when treating patientswith other psychiatric and non-psychiatric disorders.The following symp- consequences.Forpatientswhoexperiencea sustained increase inbloodpressurewhile receiv- ingEXSIRA,eitherdose reductionordiscontinuationshouldbeconsidered.Cautionshouldbeex- ercised in treatingpatientswithunderlying conditions thatmightbe compromisedby increases in bloodpressure.Posturalhypotension (seeUse inelderlypatients). Cardiovascular/cerebrovascu- lar. Caution is advised in administeringEXSIRA to patientswith cardiovascular, cerebrovascular, or lipidmetabolismdisorders. Increases inbloodpressureandheart ratewereobserved inclinical trialswithEXSIRA.EXSIRAhasnotbeenevaluatedsystematically inpatientswitha recenthisto- ryofmyocardial infarction,unstableheartdisease,uncontrolledhypertension,orcerebrovascular disease.Patientswith thesediagnoses,except for cerebrovasculardisease,wereexcluded from clinical trials. Serum lipids, Dose-related elevations in fasting serum total cholesterol, LDL (low density lipoprotein) cholesterol, and triglycerides were observed in clinical trials.Measurement of serum lipids should be considered during treatmentwithEXSIRA. Seizures, Cases of seizure were reported in pre-marketing clinical trialswithEXSIRA.EXSIRAhas not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were exclud- ed from pre-marketing clinical trials. EXSIRA should be prescribedwith caution in patientswith a seizure disorder. Discontinuation effects , Duringmarketing of SNRIs (Serotonin and Norepi- nephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors) such as EXSIRA, there have been spontaneous reports of adverse events occurring upon discontinu- ation of thesemedicines, particularly when abrupt, including the following: dysphoricmood, ir- ritability, agitation, dizziness, sensory disturbances (e.g. paraesthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures.While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.Patients should be monitored when discontinuing treatment with EXSIRA. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon dis- continuation of treatment, then resuming the previously prescribed dose may be considered. Abnormalbleeding, Medicines that inhibit serotoninuptake inplateletsmay lead toabnormalities of platelet aggregation.Aswith othermedicines that inhibit serotonin-reuptake, EXSIRA should be used cautiously in patients predisposed to bleeding. Hyponatraemia, Cases of hyponatrae- mia and/or the Syndrome of InappropriateAntidiuretic Hormone (SIADH) secretion have been described with SNRIs and SSRIs, including EXSIRA, usually in volume-depleted or dehydrat- ed patients, including elderly patients and patients taking diuretics. Interstitial lung disease and eosinophilic pneumonia. Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent medicine of EXSIRA) therapy have been reported. The possibili- ty of these adverse events should be considered in patients treated with EXSIRAwho present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo a prompt medicalevaluation,and discontinuation ofEXSIRAshould be considered. Specialpopulations. Use in elderly patients. No dosage adjustment is required solely on the basis of age; howev- er, possible reduced renal clearance of EXSIRA should be consideredwhen determining dose. Of the 7 785 patients in pre-marketing clinical trialswithEXSIRA, 5% of patientswere 65 years of age or older. No overall differences in safety or effcacywere observed between thesepa- tients and younger patients; however, in the short-term placebo-controlled trials, there was a higher incidence of systolic orthostatic hypotension in patients treated with EXSIRAwho were ≥ 65 years of age (8%) compared to patients < 65 years of age (0,9%). In addition, in both short-term and long-term placebo-controlled trials, there were increases in systolic blood pres- sure in patients ≥ 65 years of age compared to patients < 65 years of age treatedwithEXSIRA. Paediatric population. Safety and effcacy in childrenunder18 years of age hasnotbeen es- tablished (see sections 4.3 and 4.8). In clinical trials of SSRIs and SNRIs inmajor depressive disorder, there were increased reports of hostility and suicide-related adverse events such as suicidal ideation and self-harm. Interactionwith othermedicines and other forms of inter- action: Monoamine oxidase inhibitors (MAOI).Central nervous system (CNS)-activemedicines Serotonin syndrome,Ethanol, Potential forEXSIRA toaffectothermedicinesMedicinesmetabo- lised byCYP2D6,Medicinesmetabolised byCYP3A4,Medicinesmetabolised by a combination S5EXSIRA , 50mg and 100mgextended-release tablets. QUALITATIVEANDQUANTITATIVE COMPOSITION: Each EXSIRA 50mg extended-release flm-coated tablet contains desvenlafaxine succinate equivalent to 50mg desvenlafaxine. Each EXSIRA 100mg extended-release flm-coated tablet contains desvenlafaxine succinate equiv- alent to 100 mg desvenlafaxine. Sugar free. PHARMACEUTICAL FORM: Extended-release tablets. EXSIRA 50 mg extended-release tablets are light pink, square (pyramid, one sided), flm coated tablets, debossed “W” over “50” on the flat side. EXSIRA 100mg extended-release tabletsare reddish-orange, square (pyramid,one sided), flm-coated tablets,debossed “W” over “100” on the flat side. CLINICAL PARTICULARS:Therapeutic Indications: Major depressive disorder EXSIRA tablets are indicated for the treatment of major depressive disorder (MDD). Posology andmethodof administration: Major depressive disorder.The recommended dose for EXSIRA is 50 mg once daily, with or without food, with a maximum dose of 100 mg per day. The dose increase should occur gradually and at an interval of not less than 7 days.Dis- continuing EXSIRA: Symptoms associated with discontinuation of EXSIRA, other SNRIs and SSRIs have been reported. Patients should bemonitored for these symptoms when discontin- uing treatment.A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon dis- continuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, themedical practitionermay continue decreasing the dose but at amore grad- ual rate. Switching patients from other antidepressants to EXSIRA: Discontinuation symptoms have been reportedwhen switching patients from other antidepressants, including venlafaxine, to EXSIRA. Tapering of the initial antidepressant may be necessary to minimise discontinua- tion symptoms. Specialpopulations: Use in patientswith renal impairment. The recommended starting dose in patients with severe renal impairment (24-hr CrCl < 30mL/min) or end-stage renal disease (ESRD) is 50mg every other day. Because of individual variability in clearance in these patients, individualisation of dosage may be desirable. Supplemental doses should not be given to patients after dialysis. Use in patients with hepatic impairment. No dosage ad- justment is necessary for patients with hepatic impairment. Use in elderly patients . No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of EXSIRA should be considered when determining dose. Paediatric populations: Safety and effcacy in patients less than 18 years of age has not been established. Method of administra- tion: For oral use. Contraindications: .•Hypersensitivity toEXSIRA, venlafaxine hydrochloride or to any excipients in the EXSIRA formulation.• EXSIRA is an inhibitor of both norepinephrine and serotonin reuptake. EXSIRAmust not be used in combination with amonoamine oxidase inhibitor (MAOI), orwithin at least 14 days of discontinuing treatmentwith anMAOI. Based on the half-life ofEXSIRA, at least 7 days should be allowed after stoppingEXSIRAbefore starting an MAOI. Severe adverse reactions have been reported when therapy is initiated with SSRI/ SNRI medicines such as EXSIRA soon after discontinuation of an MAOI and when an MAOI is initiated soon after discontinuation of SSRI/SNRImedicines. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with fea- tures resembling neuroleptic malignant syndrome, seizures and death.• Children less than 18 years of age, as safety and effcacy have not been established. • Pregnancy and lactation. Specialwarnings andprecautions foruse: SSRIs/SNRIsmay increase the risk of postpartum haemorrhage (see section 4.6 and 4.8). Clinical worsening of depressive symptoms, unusual changes in behaviour, and suicidality. Patients withmajor depressive disordermay experience worseningof theirdepressionand/or theemergenceof suicidal ideationandbehaviour,whether or not they are taking antidepressantmedicines.This riskmay persist until signifcant remission occurs.A causal role, however, for antidepressantmedicine in inducing such behaviour has not beenestablished.Patientsbeing treatedwithEXSIRAshould,nevertheless,beobserved closely for clinicalworsening 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 betweenmajordepressivedisorderandotherpsychiatricandnon-psychiatricdisorders, thesame precautionsobservedwhen treatingpatientswithmajordepressivedisordersshouldbeobserved when treating patientswith other psychiatric and non-psychiatric disorders.The following symp- toms have been reported in patients being treated with antidepressants for major depressive disorder aswell as for other indications, both psychiatric and non-psychiatric: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, andmania.Althougha causal linkbetween theemergenceof suicidal impulseshasnotbeenes- tablished, consideration should be given to changing the therapeutic regimen, including possibly discontinuingEXSIRA in patients forwhom such symptoms are severe, abrupt in onset, orwere not part of the patient’s presenting symptoms. If the decision ismade to discontinue treatment, EXSIRA should be tapered. Short-term trials did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond the age of 24 years; therewas a re- duction in the riskof suicidalitywithantidepressants compared toplacebo inadultsage65 years and older.There have been reports of hostility, suicidal ideation and self-harmwith use ofSSRIs in children under the age of18 years. Mania/hypomania. In clinical trials,maniawas reported for 0,03%ofpatients treatedwithEXSIRA.Activationofmania/hypomaniahasalsobeen reported in a smallproportionofpatientswithmajoraffectivedisorderwhowere treatedwithothermarketed antidepressants. EXSIRA should be used cautiously in patients with a history or family history ofmania or hypomania. Serotonin syndrome. The development of a potentially life-threatening serotonin syndromemayoccurwithEXSIRA treatment,particularlywith concomitantuseofoth r serotonergic medicines (including SSRIs, SNRIs and triptans) and with medicines that impair metabolism of serotonin (includingMAOIs).Serotonin syndrome symptoms ay includemental status changes (e.g. agitation, hallucinations, and coma), autonomic instability (e.g. tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, inco- ordination) and/or gastrointestinal symptoms (e.g. nausea, vomiting, and diarrhoea).The con- comitant use ofEXSIRAwith serotonin precursors (such as tryptophan supplements) is not rec- ommended. Narrow-angle glaucoma. Mydriasis has been reported in association with EXSIRA; therefore,patientswith raised intraocularpressureor thoseat riskofacute narrow-angleglauco- ma (angle-closure glaucoma) should bemonitored. Ischaemic cardiac adverse events. In clinical trials, there were uncommon reports of ischaemic cardiac adverse events, includingmyocardi- al ischaemia, myocardial infarction, and coronary occlusion requiring revascularisation; these patients had multiple underlying cardiac risk factors. More patients experienced these events duringEXSIRA treatmentas compared toplacebo. Discontinuation symptoms. Adverse reactions reported in association with abrupt discontinuation, dose reduction or tapering of treatment in MDD clinical trials at a rate of ≥2% include: dizziness,withdrawal syndrome, nausea and head- ache. In general, discontinuation symptoms occurred more frequently with longer duration of therapy. Adverse reactions leading to discontinuation of therapy. The most common adverse reaction leading todiscontinuation inat least2%of theEXSIRA-treatedpatients in theshort-term trials, up to 12weeks,was nausea (2%); in the long-term studies, up to 11months, no events lead todiscontinuation inat least2%of thepatientsandata rategreater thanplacebo in thedou- ble-blindphase. Adverse reactions reportedwithotherSNRIs .Althoughgastrointestinalbleeding is not considered an adverse reaction for EXSIRA, it is an adverse reaction for other SN Is andmay also occurwithEXSIRA. Effects on activities requiring concentration and performance. Interference with cognitive andmotor performance. The results of a clinical trial that assessed the effects of EXSIRA on behavioural performance of healthy individuals revealed no clinically signifcant impairment of psychomotor, cognitive, or complex behaviour performance.However, sinceanyCNS-activemedicinemay impair judgement, thinking,ormotorskills,patientsshouldbe cautionedaboutoperatinghazardousmachinery, includingautomobiles,until theyare reasonably certain that EXSIRA therapy does not adversely affect their ability to engage in such activities. consequences.Forpatientswhoexperiencea sustained increase inbloodpressurewhile receiv- ingEXSIRA,eitherdose reductionordiscontinuationshouldbeconsidered.Cautionshouldbeex- ercised in treatingpatientswithunderlying conditions thatmightbe compromisedby increases in bloodpressure.Posturalhypotension (seeUse inelderlypatients). Cardiovascular/cerebrovascu- lar. Caution is advised in administeringEXSIRA to patientswith cardiovascular, cerebrovascular, or lipidmetabolismdisorders. Increases inbloodpressureandheart ratewereobserved inclinical trialswithEXSIRA.EXSIRAhasnotbeenevaluatedsystematically inpatientswitha recenthisto- ryofmyocardial infarction,unstableheartdisease,uncontrolledhypertension,orcerebrovascular disease.Patientswith thesediagnoses,except for cerebrovasculardisease,wereexcluded from clinical trials. Serum lipids, Dose-related elevations in fasting serum total cholesterol, LDL (low density lipoprotein) cholesterol, and triglycerides were observed in clinical trials.Measurement of serum lipids should be considered during treatmentwithEXSIRA. Seizures, Cases of seizure were reported in pre-marketing clinical trialswithEXSIRA.EXSIRAhas not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were exclud- ed from pre-marketing clinical trials. EXSIRA should be prescribedwith caution in patientswith a seizure disorder. Discontinuation effects , Duringmarketing of SNRIs (Serotonin and Norepi- nephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors) such as EXSIRA, there have been spontaneous reports of adverse events occurring upon discontinu- ation of thesemedicines, particularly when abrupt, including the following: dysphoricmood, ir- ritability, agitation, dizziness, sensory disturbances (e.g. paraesthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures.While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.Patients should be monitored when discontinuing treatment with EXSIRA. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon dis- continuation of treatment, then resuming the previously prescribed dose may be considered. Abnormalbleeding, Medicines that inhibit serotoninuptake inplateletsmay lead toabnormalities of platelet aggregation.Aswith othermedicines that inhibit serotonin-reuptake, EXSIRA should be used cautiously in patients predisposed to bleeding. Hyponatraemia, Cases of hyponatrae- mia and/or the Syndrome of InappropriateAntidiuretic Hormone (SIADH) secretion have been described with SNRIs and SSRIs, including EXSIRA, usually in volume-depleted or dehydrat- ed patients, including elderly patients and patients taking diuretics. Interstitial lung disease and eosinophilic pneumonia. Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent medicine of EXSIRA) therapy have been reported. The possibili- ty of these adverse events should be considered in patients treated with EXSIRAwho present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation ofEXSIRAshould be considered. Specialpopulations. Use in elderly patients. No dosage adjustment is required solely on the basis of age; howev- er, possible reduced renal clearance of EXSIRA should be consideredwhen determining dose. Of the 7 785 patients in pre-marketing clinical trialswithEXSIRA, 5% of patientswere 65 years of age or older. No overall differences in safety or effcacywere observed between these pa- tients and younger patients; however, in the short-term placebo-controlled trials, there was a higher incidence of systolic orthostatic hypotension in patients treated with EXSIRAwho were ≥ 65 years of age (8%) compared to patients < 65 years of age (0,9%). In addition, in both short-term and long-term placebo-controlled trials, there were increases in systolic blood pres- sure in patients ≥ 65 years of age compared to patients < 65 years of age treatedwithEXSIRA. Paediatric population. Safety and effcacy in childrenunder 18 yearsof agehas not been es- tablished (see sections 4.3 and 4.8). In clinical trials of SSRIs and SNRIs inmajor depressive disorder, there were increased reports of hostility and suicide-related adverse events such as suicidal ideation and self-harm. Interactionwith othermedicines and other forms of inter- action: Monoamine oxidase inhibitors (MAOI).Central nervous system (CNS)-activemedicines Serotonin syndrome,Ethanol, Potential forEXSIRA toaffectothermedicinesMedicinesmetabo- lised byCYP2D6,Medicinesmetabolised byCYP3A4,Medicinesmetabolised by a combination of bothCYP2D6 andCYP3A4,Medicinesmetabolized byCYP1A2, 2A6, 2C8, 2C9 and 2C19, P-glycoprotein transporter, Laboratory test interactions, Electroconvulsive therapy, Fertility, pregnancy and lactation: EXSIRAmust not be administered to pregnant or lactating women. Safetyduringhumanpregnancyand lactationhasnotbeenestablished.Observationaldata indi- cate an increased risk (less than 2-fold) of postpartum haemorrhage followingSSRI/SNRI expo- surewithin themonth prior to birth. Undesirable effects: Metabolism and nutritionaldisorders: Common:Decreasedappetite.Psychiatricdisorders:Verycommon: Insomnia.Common:Anxiety, abnormal dreams, nervousness, decreased libido, anorgasmia.Nervous systemdisorders: Very common: Dizziness, headache. Common: Somnolence, tremor, paraesthesia, dysgeusia, disturbance inattention,vertigo. Eyedisorders:Common:Blurred vision,mydriasis.Earand lab- yrinth disorders:Common:Tinnitus.Cardiac disorders:Common:Palpitations, tachycardia.Vas- cular disorders:Common:Hot flush.Respiratory, thoracic andmediastinaldisorders:Common: Yawning.Gastrointestinal disorders:Very common:Nausea, drymouth, constipation.Common: Diarrhoea, vomiting. Skin and subcutaneous tissue disorders: Very common: Hyperhidrosis. Common: Rash. Musculoskeletal, connective tissue and bone disorders: Common: Musculo- skeletal stiffness. Reproductive system and breast disorders: Common: Erectile dysfunction*, delayed ejaculation*, ejaculation failure*. (*Frequency is calculated based on men only).Not known:Postpartum haemorrage***. (***This event has been reported for the therapeutic class of SSRIs/SNRIs). General disorders and administration: Common: Fatigue, chills, asthenia, feeling jittery, irritability. Investigations: Common: Increased weight, increased blood pressure, decreased weight. Overdose: There is limited clinical experience with EXSIRA overdosage in humans.No specifc antidotes forEXSIRA are known. Induction ofemesis is not recommended. Because of themoderate volume of distribution of thismedicine, forced diuresis, dialysis, hae- moperfusion, and exchange transfusion are unlikely to be of beneft.Treatment should consist of those generalmeasures employed in themanagement of overdosage with any SSRI/SNRI. Ensureanadequateairway,oxygenation,and ventilation.Monitor cardiac rhythmand vital signs. General supportive and symptomatic measures are also recommended.Gastric lavage with a large-bore orogastric tubewith appropriate airway protection, if needed,may be indicated if per- formed soon after ingestion or in symptomaticpatients.Activated charcoal should be administered. PHARMACOLOGICALPROPERTIES: Pharmacological classifcation:A1.2 Psychoanaleptics (antidepressants) PHARMACEUTICAL PARTICULARS: List of excipients: EXSIRA50mgextended-release tabletsTablet core:Hypromellose,Magnesium stearate,Micro- crystalline cellulose,Talc.Film-coating:Macrogol/PEG 3350,Polyvinyl alcohol (part hydrolysed), Red ironoxide, Talc,Titaniumdioxide,Yellow ironoxide.EXSIRA100mgextended-release tab- lets:Tablet core:Hypromellose,Magnesium stearate,Microcrystalline cellulose,Talc. Film-coat- ing:Macrogol/PEG 3350, Polyvinyl alcohol (part hydrolysed),Red iron oxide, Talc, Titanium di- oxide, Yellow iron oxide, FD&C Yellow #6/Sunset Yellow FCF Aluminium Lake. Shelf life : 24 months, Special precautions for storage: Store at or below 25 °C. Keepwell closed.Do not remove blister card from the carton until required for use. Nature and contents of container: EXSIRA (desvenlafaxine succinate)extended-release tabletsareavailableas follows:Acarton containing one ormore clearplastic/aluminium foil blister strips containing7, 14or 28 tablets each. HOLDEROFCERTIFICATEOFREGISTRATION: Pfzer Laboratories (Pty)Ltd, 85Bute Lane, Sandton, 2196,SouthAfrica ,Tel:+27(0)11 3206000 / 0860 734 937 (toll freeSouthAfrica). REGISTRATIONNUMBER(S): EXSIRA50mg: 42/1.2/0935,EXSIRA100mg: 41/1.2/0427. S5EXSIRA , 50mg and 100mg extended-release tablets. QUALITATIVEANDQUANTITATIVE COMPOSITION: Each EXSIRA 50mg extended-release flm-coated tablet contains desvenlafaxine succinate equivalent to 50mg desvenlafaxine. Each EXSIRA 100mg extended-release flm-coated tablet contains desvenlafaxine succinate equiv- alent to 100 mg desvenlafaxine. Sugar free. PHARMACEUTICAL FORM: Extended-release tablets. EXSIRA 50 mg extended-release tablets are light pink, square (pyramid, one sided), flm coated tablets, debossed “W” over “50” on the flat side. EXSIRA 100mg extended-release tabletsare reddish-orange, square (pyramid,one sided), flm-coated tablets,debossed “W” over “100” on the flat side. CLINICAL PARTICULARS:Therapeutic Indications: Major depressive disorder EXSIRA tablets are indicated for the treatment of major depressive disorder (MDD). Posology andmethodof administration: Major depressive disorder.The recommended dose for EXSIRA is 50 mg once daily, with or without food, with a maximum dose of 100 mg per day. The dose increase should occur gradually and at an interval of not less than 7 days.Dis- continuing EXSIRA: Symptoms associated with discontinuation of EXSIRA, other SNRIs and SSRIs have been reported. Patients should bemonitored for these symptoms when discontin- uing treatment.A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon dis- continuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, themedical practitionermay continue decreasing the dose but at amore grad- ual rate. Switching patients from other antidepressants to EXSIRA: Discontinuation symptoms have been reportedwhen switching patients from other antidepressants, including venlafaxine, to EXSIRA. Tapering of the initial antidepressant may be necessary to minimise discontinua- tion symptoms. Specialpopulations: Use in patientswith renal impairment. The recommended starting dose in patients with severe renal impairment (24-hr CrCl < 30mL/min) or end-stage renal disease (ESRD) is 50mg every other day. Because of individual variability in clearance in these patients, individualisation of dosage may be desirable. Supplemental doses should not be given to patients after dialysis. Use in patients with hepatic impairment. No dosage ad- justment is necessary for patients with hepatic impairment. Use in elderly patients . No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of EXSIRA should be considered when determining dose. Paediatric populations: Safety and effcacy in patients less than 18 years of age has not been established. Method of administra- tion: For oral use. Contraindications: .•Hypersensitivity toEXSIRA, venlafaxine hydrochloride or to any excipients in the EXSIRA formulation.• EXSIRA is an inhibitor of both norepinephrine and serotonin reuptake. EXSIRAmust not be used in combination with amonoamine oxidase inhibitor (MAOI), orwithin at least 14 days of discontinuing treatmentwith anMAOI. Based on the half-life ofEXSIRA, at least 7 days should be allowed after stoppingEXSIRAbefore starting an MAOI. Severe adverse reactions have been reported when therapy is initiated with SSRI/ SNRI medicines such as EXSIRA soon after discontinuation of an MAOI and when an MAOI is initiated soon after discontinuation of SSRI/SNRImedicines. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with fea- tures resembling neuroleptic malignant syndrome, seizures and death.• Children less than 18 years of age, as safety and effcacy have not been established. • Pregnancy and lactation. Specialwarnings andprecautions foruse: SSRIs/SNRIsmay increase the risk of postpartum haemorrhage (see section 4.6 and 4.8). Clinical worsening of depressive symptoms, unusual changes in behaviour, and suicidality. Patients withmajor depressive disordermay experience worseningof theirdepressionand/or theemergenceof suicidal ideationandbehaviour,whether or not they are taking antidepressantmedicines.This riskmay persist until signifcant remission o curs.A causalr le, however, f r antid pr ssantmedicine in inducing such behaviour has not beenestablish d.Patientsbeing treatedwithEXSIRA l ,nevertheless,beobserved closely for linicalworse ing and uicidality, specially a the beginnng of a course of therapy o t any time ofdo e changes, eit er increases or decreas s.Bec use of the possibility of co-morbidity betweenmajordepressivedisorderandotherpsychiatricandnon-psychiatri disorders, the ame precautionso serve when treatingpatientswithmajord pressiv disorderssh uldb observed when treating patientswith ot erpsychiatric nd non-p ychi tric disorders.The following symp- toms have been repored in patients being treat d with antidepressant f r majo depre sive disorder aswell a for ot r indication , both sychiatic and non-psychi tric: anxi ty, agitation, panic ttack , inso na, irritability, hostility, aggres ivene s, impulsiviy, akathisia, hypomania, andmania.Althougha cau al linkbetween theemergenceof suicidalimpulseshasnotbeenes- tabli hed, considerationshould be given to changing the therapeutic regimen, including po sbly discontinuingEXSIRA in patie ts forwhom such symptoms are severe, abrupt in onse, orwere not part of the ti t’s presenting sympt ms. If the decisionismade t discontinue treatment, EXSIRA should be tapered. Shot-term trials did not show an increase in the risk of suicidality with antid pressants compared to placebo inadults beyond the age of 24 yeas; therewas a r - duction in th riskof suicidalitywithantidepressants compared toplac bo inadultsage65 years and older.T ha b re rts of hostility, suicidal id ation and elf-hamwith use ofSSRIs in children under the ageof 18 years. Mania/hypomania. In clinical trials,maniawas reported for 0,03%ofpatents treatedwithEXSIRA.Activatio ofmania/hypomaniahasalsobeen reported in a smallproportionofpatie tswithmajoraffectivedisorderwh were treatedwithothermarketed antidepressants. EXSIRA should b used c utiously in patients with a history or family history ofmaniaor hypom nia. Serotonin syndrome. The development of a potentially life-threatening serotonin syndromemayoccurwithEXSIRA treatment,particul rlywith concomitantuseofother serotonergic medicines (including SSRIs, SNRIs and triptans) and with medicines that impar metabolism of serotonin (includi gMAOIs).S rotonin syndrome symptomsm includemental status ch ng s (e. . agitation, hallucnation , and coma), autonomic instability (e.g.t chycardia, labile blood pressure, and hyperthermia), neuromuscular aberati s ( .g. hyperreflexia, inco- ordination) nd/or gastroint sinal symptoms (e.g. nausea, vomiting, and diarrhoea).The con- comit t use ofEXSIRAwith serotonin precursors (such as tryptophan suppl m nts) is notrec- ommend . Narrow-angle glaucoma. Mydriasis has been reported in association with EXSIRA; th refore,patie tswth raised intr ocularpressureor thoseat riskofacute narrow-angleglauco- m (angle-closureglaucoma) should bemonitored. Ischaemic cardiac advers eve ts. In clinical trials,there were uncommo reports ofischaemic cardiac adverse eve ts, inclu ingmyocardi- al ischaemia, myocardial infarction, and coronary occlusio requiring revascularisation; th se patients had multiple u derlying cardiac risk factors. More patients experienced these events duringEXSIRA treatmenta ompared toplacebo. Di c ntinuation ymptoms. Adverse reac ns reported in association with abrupt discontinuation, dose reduction ortapering of treatment in MDD clincal tials ata rateof ≥ 2% include: dizziness,withdrawal syndrome, naus a and head- ache. In general, disco tinuation symptoms occurred more frequently with lo ger duration of therapy. Adverse reactions leading to discontinuation of therapy. The most commo adv rse reaction leading todisconti uation inat least2%of theEXSIRA-treatedpati nts n theshort-term trials, up to 12w eks,was nausea (2%); in the long-term studies, up to 11months, no events lead todiscontinuation inat least2%of thepatientsandata rategr ater thanplacebo n thedou- ble-blindphase. Adverse reactions reportedwithotherSNRIs .Althoughgastrointestnalbleeding is not considered an adverse reacti n for EXSIRA, it i an adve e reaction for other SNRIs andmay also ccurwithEXSIRA. Eff cts on activities requiring concentration and performa c . Interference with cognitive andmotor performance. The result of aclinicaltrial that assessed the effects of EXSIRA on behavioural perormanceof healthy individuals revealed no clini ally signifc nt impairmentof psychomotor, cognitive, or complex behaviour performance.H wever, sinceanyCNS- ctiv me icinemay impair judgem t, thi king,ormoorskills,patientsshouldb cauti nedabout peratinghazard usmachinery, includingaut mobiles,until theyare r asonably certain that EXSIRA therapy does not adversely affect their abilityto engage in such activities. Abuse and dependence. hysical and psychological ependence. Although EXSIRA has not been systematically tudi d in preclinical or cl ical trals for its p te tia for abuse, no indica- tion of drug-seeking behaviour was seen i the clinical trials. C -adminisration of medicines containing venlafaxine and/or EXSIRA. EXSIRA is he major activ metabolite of venl fax- ine, a medicine used to trea major depressive, generalis d anxiety, social anxiety and panic disorders. EXSIRA should n t be use concomitantly with products containing venlafaxine hydrochlorideo oth r producs containingEXSIRA. Incr ases in blood pressurewere bserved in somepatients in clinical trial , particul rlywth higher do es.Pre-existing hypertension should be contr lled before treatmentwithEXSIRA .Patients receivingEXSIRAshould ave regular monitoring ofbloodpressure.Cases of elevated bl odpressure requirng immediate treatment have been reportedwithEXSIRA.Sust ined blood pre sure increases could have adverse consequences.Forpatientswhoexperiencea sustained increase inbloodpressurewhile receiv- ingEXSIRA,eitherdose reductionordiscontinuationshouldbeconsidered.Cautionshouldbeex- ercised in treatingpatientswithunderlying conditions thatmightbe compromisedby increases in bloodpressure.Posturalhypotension (seeUse inelderlypatients). Cardiovascular/cerebrovascu- lar. Caution is advised in administeringEXSIRA to patientswith cardiovascular, cerebrovascular, or lipidmetabolismdisorders. Increases inbloodpressureandheart ratewereobserved inclinical trialswithEXSIRA.EXSIRAhasnotbeenevaluatedsystematically inpatientswitha recenthisto- ryofmyocardial infarction,unstableheartdisease,uncontrolledhypertension,orcerebrovascular disease.Patientswith thesediagnoses,except for cerebrovasculardisease,wereexcluded from clinical trials. Serum lipids, Dose-related elevations in fasting serum total cholesterol, LDL (low density lipoprotein) cholesterol, and triglycerides were observed in clinical trials.Measurement of serum lipids should be considered during treatmentwithEXSIRA. Seizures, Cases of seizure were reported in pre-marketing clinical trialswithEXSIRA.EXSIRAhas not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were exclud- ed from pre-marketing clinical trials. EXSIRA should be prescribedwith caution in patientswith a seizure disorder. Discontinuation effects , Duringmarketing of SNRIs (Serotonin and Norepi- nephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors) such as EXSIRA, there have been spontaneous reports of adverse events occurring upon discontinu- ation of thesemedicines, particularly when abrupt, including the following: dysphoricmood, ir- ritability, agitation, dizziness, sensory disturbances (e.g. paraesthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures.While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.Patients should be monitored when discontinuing treatment with EXSIRA. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon dis- continuation of treatment, then resuming the previously prescribed dose may be considered. Abnormalbleeding, Medicines that inhibit serotoninuptake inplateletsmay lead toabnormalities of platelet aggregation.Aswith othermedicines that inhibit serotonin-reuptake, EXSIRA should be used cautiously in patients predisposed to bleeding. Hyponatraemia, Cases of hyponatrae- mia and/or the Syndrome of InappropriateAntidiuretic Hormone (SIADH) secretion have been described with SNRIs and SSRIs, including EXSIRA, usually in volume-depleted or dehydrat- ed patients, including elderly patients and patients taking diuretics. Interstitial lung disease and eosinophilic pneumonia. Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent medicine of EXSIRA) therapy have been reported. The possibili- ty of these adverse events should be considered in patients treated with EXSIRAwho present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation ofEXSIRAshouldbe considered. Specialpopulations. Use in elderly patients. No dosage adjustment is required solely on the basis of age; howev- er, possible reduced renal clearance of EXSIRA should be consideredwhen determining dose. Of the 7 785 patients in pre-marketing clinical trialswithEXSIRA, 5% of patientswere 65 years of age or older. No overall differences in safety or effcacywere observedbetween these pa- tients and younger patients; however, in the short-term placebo-controlled trials, there was a higher incidence of systolic orthostatic hypotension in patients treated with EXSIRAwho were ≥ 65 years of age (8%) compared to patients < 65 years of age (0,9%). In addition, in both short-term and long-term placebo-controlled trials, there were increases in systolic blood pres- sure in patients ≥ 65 years of age compared to patients < 65 years of age treatedwithEXSIRA. Paediatric population. Safety and effcacy in children under18 years of age has not been es- tablished (see sections 4.3 and 4.8). In clinical trials of SSRIs and SNRIs inmajor depressive disorder, there were increased reports of hostility and suicide-related adverse events such as suicidal ideation and self-harm. Interactionwith othermedicines and other forms of inter- action: Monoamine oxidase inhibitors (MAOI).Central nervous system (CNS)-activemedicines Serotonin syndrome,Ethanol, Potential forEXSIRA toaffectothermedicinesMedicinesmetabo- lised byCYP2D6,Medicinesmetabolised byCYP3A4,Medicinesmetabolised by a combination of bothCYP2D6 andCYP3A4,Medicinesmetabolized byCYP1A2, 2A6, 2C8, 2C9 and 2C19, P-glycoprotein transporter, Laboratory test interactions, Electroconvulsive therapy, Fertility, pregnancy and lactation: EXSIRAmust not be administered to pregnant or lactating women. Safetyduringhumanpregnancyand lactationhasnotbeenestablished.Observationaldata indi- cate an increased risk (less than 2-fold) of postpartum haemorrhage followingSSRI/SNRI expo- surewithin themonth prior to birth. Undesirable effects: Metabolism and nutritional disorders: Common:Decreasedappetite.Psychiatricdisorders:Verycommon: Insomnia.Common:Anxiety, abnormaldreams, nervousness, decreased libido, anorgasmia.Nervous systemdisorders: Very common: Dizziness, headache. Common: Somnolence, tremor, paraesthesia, dysgeusia, disturbance inattention,vertigo. Eyedisorders:Common:Blurred vision,mydriasis.Earand lab- yrinth disorders:Common:Tinnitus.Cardiac disorders:Common:Palpitations, tachycardia.Vas- cular disorders:Common:Hot flush.Respiratory, thoracic andmediastinaldisorders:Common: Yawning.Gastrointestinal disorders:Very common:Nausea, drymouth, constipation.Common: Diarrhoea, vomiting. Skin and subcutaneous tissue disorders: Very common: Hyperhidrosis. Common: Rash. Musculoskeletal, connective tissue and bone disorders: Common: Musculo- skeletal stiffness. Reproductive system and breast disorders: Common: Erectile dysfunction*, delayed ejaculation*, ejaculation failure*. (*Frequency is calculated based on men only).Not known:Postpartum haemorrage***. (***This event has been reported for the therapeutic class of SSRIs/SNRIs). General disorders and administration: Common: Fatigue, chills, asthenia, feeling jittery, irritability. Investigations: Common: Increased weight, increased blood pressure, decreased weight. Overdose: There is limited clinical experience with EXSIRA overdosage in humans.No specifc antidotes forEXSIRAare known. Induction ofemesis is not recommended. Because of themoderate volume of distribution of thismedicine, forced diuresis, dialysis, hae- moperfusion, and exchange transfusion are unlikely to be of beneft.Treatment should consist of those generalmeasures employed in themanagement of overdosage with any SSRI/SNRI. Ensureanadequateairway,oxygenation,and ventilation.Monitor cardiac rhythmand vital signs. General supportive and symptomatic measures are also recommended.Gastric lavage with a large-bore orogastric tubewith appropriate airway protection, if needed,may be indicated if per- formed soon after ingestionor in symptomatic patients.Activated charcoal should be administered. PHARMACOLOGICALPROPERTIES: Pharmacological classifcation:A1.2 Psychoanaleptics (antidepressants) PHARMACEUTICAL PARTICULARS: List of excipients: EXSIRA50mgextended-release tabletsTablet core:Hypromellose,Magnesium stearate,Micro- crystalline cellulose,Talc.Film-coating:Macrogol/PEG 3350,Polyvinyl alcohol (part hydrolysed), Red ironoxide, Talc,Titaniumdioxide,Yellow ironoxide.EXSIRA100mgextended-release tab- lets:Tablet core:Hypromellose,Magnesium stearate,Microcrystalline cellulose,Talc. Film-coat- ing:Macrogol/PEG 3350, Polyvinyl alcohol (part hydrolysed),Red iron oxide, Talc, Titanium di- oxide, Yellow iron oxide, FD&C Yellow #6/Sunset Yellow FCF Aluminium Lake. Shelf life : 24 months, Special precautions for storage: Store at or below 25 °C. Keepwell closed.Do not remove blister card from the carton until required for use. Nature and contents of container: EXSIRA (desvenlafaxine succinate)extended-release tabletsareavailableas follows:Acarton containing one ormore clear plastic/aluminium foil blister strips containing 7, 14 or 28 tablets each. HOLDEROFCERTIFICATEOFREGISTRATION: Pfzer Laboratories (Pty) Ltd, 85Bute Lane, Sandton, 2196,SouthAfrica,Tel:+27(0)11320 6000 /0860 734 937 (toll freeSouthAfrica). REGISTRATIONNUMBER(S): EXSIRA50mg: 42/1.2/0935,EXSIRA100mg: 41/1.2/0427. REFERENCE: ApprovedProfessional Information date ofpublication (14March 2021). PLEASEREFERTODETAILEDPROFESSIONAL INFORMATIONFORCOMPLETE PRESCRIBING INFORMATION. S5EXSIRA , 50mg and 100mg extended-releasetablets. QUALITATIVEANDQUANTITATIVE COMPOSITION: Each EXSIRA 50 g extended-rel ase flm-coated t blet contains desv lafaxine succi ate equivalent to 50mg desvenlafaxine. Each EXSIRA 100mg exended-release flm-coated tablet contains desvenlafaxine succinate equiv- alent to 100 mg desvenlafaxine. Sugar free. PHARMACEUTICAL FORM: Extended-relea e tablets. EXSIRA 50 mg extended-release tablets are light pink, square (pyr mid, one sided), flm coated tablets, debossed “W” over“50” on the flat side. EXSIRA 100mg exte ded-rel as tabletsar reddish-orange, square (pyramid,one ided), flm-coated tablets,d bos d “W” over “100” on he flat side. CLINICAL PARTICULARS:Therapeutic Indications: Major depressive disorder EXSIRA tablets are indicated for the treatment of major depressive disorder (MDD). Posology andmethodof administration: Major depressive dis rder.The recomm nded dose f r EXSIRA is 50 mg once daily, with r without food, with a aximum dos of 100 mg per day. The dose increase should occu gradually and at an intervalof not les than 7 days.Dis- c ntinuing EXSIRA: Symptoms a sociated with di conti ati n of EXSIRA, oth r SNRIs and SSRIs have been report d. Patiens should bemo itored forthes symptom when discontin- uing tr atment.A grad al reducti n in the dose rather thanabrupt cessation is r commended whenever possible. If intol rabl symptoms occur following ecreas i the dose or upon dis- continu tion of treatment, then resumi g the pr viously pre cribed dos may be considered. Subsequently, th medical practitionermay continue decreasing the dose but at am re grad- ual rate. Switching p tients fr oth r antidepressants to EXSIRA: Disc ntinuation symptoms hav b en reportedwhen switchin p tients from other antidepr ssa ts, including venlafaxin , to EXSIRA. Tapering of the initial antidepr ssant may be nece sary to inimise discontinu - tionsymptoms. Specialpop lations: Use in patientswith renal impairment. The recommend d starting dose in patients with s v re renal impairment (24-hr CCl < 30mL/min) or end- tage ren l disease (ESRD) is 50mg every other day. Because of individual variability in clearance in these pati ts, individualis tion of dosage may be desirable. S pplemental do es should not be given to patients after dialysis. Use n patientswith hep tic impairment. No dosag ad- ju tme t is necessary for patients with hepatic mpairment. Use in lderly patient . No dosage adjustment s required sol ly on the basis ofage; however, possibl reduced renal clearance of EXSIRA h uld be consid red wh n determining dose. Paediatric population : Safety and effcacy in pati nts less than18 years of age h s not be n stablished. Method of administra- tion: For oral use. Contraindications: .•Hypersensitivity toEXSIRA, venlafaxine hydrochloride or to any exci ients i the EXSIRA f mulation.• EXSIRA is an inhibitor of both n repinephrin and serotoni reuptake. EXSIRAmust not be used in combination withamonoamine oxidas inhibit r (MAOI), rwithin at least 14 days of disconinuing treatmentwith anMAOI. B ed on th half-life ofEXSIRA, at least 7 days shouldbe allowed after stoppingEXSIRAbefore starting consequences.Forpatientswhoexperience sustained increase inbloodpressurewhile receiv- ingEXSIRA,eitherdose reductionordiscontinuatio sho ldbeconsidered.Cautionshouldbeex- ercised in treatingpatientswithunderlying c nditions thatmightbe compromisedby increases in bloodpressure.Posturalhypotension (seeUse inelderlypatients). Cardiovascular/cerebrovascu- lar. Caution is advised in administeringEXSIRA to patientswith cardiovascular, cerebrovas ular, or lipidmetabolismdisorders. Increases inbloodpressureandheart ratewereobserved inclinical trialswithEXSIRA.EXSIRAh snotbeenevaluatedsystematically inpatientswit a recenthisto- ryofmyocardial infarction,unstableheartdisease,uncontrolledhypertension,orcerebrovascular disease.Patientswith thesedia noses,except for cerebrovasculardiseas ,w reexcluded from clinical trials. Serum lipids, Dose-related elevations in fasting serum total cholesterol, LDL (low density lipoprotein) holesterol, and triglycerides were observed in clinical trials.Measur ment of ser m lipids shoul be considered during treatmentwithEXSIRA. Seizures, Cases of seizur were reported in pre-marketing clinical trialswithEXSIRA.EXSIRAhas not been ystematically evaluated in patients with a seizure isorder. P tients with a history of seizures were exclud- ed from pre-marketing clinical trials. EXSIRA should be prescribedwith aution in patientswith a seizure disorder. Discontinuation effects , Duringmarketing of SNRIs (Serotonin nd Norepi- nephrine Reuptake Inhi itors), nd SSRIs (Selective Ser tonin Reuptake Inhibitors) such as EXSIRA, there have been spontaneous reports of adverse events occurring upon discontinu- ation of thesemedicines, particularly when abrupt, including the following: dysphoricmood, ir- ritability, agitation, dizzin ss, sensory disturbances (e.g. paraesthesias such as electri shock sensations), anxiety, confusion, headache, l thargy, emotional lability, insomnia, hypomania, tinnitus, and seizur s.While these events re enerally self-limiting, there have been reports of serious discontinu tion symptoms.Patients should be monitored when discontinuing tr tment with EXSIRA. A gradual reduction in the do e rath r than abrupt c ssation is recommended whenever possible. If intolerable s mptoms occur following a decrease in the dose or upon dis- c ntinuation of treatment, then resuming the previously prescribed dose m y be considered. Abnormalbleeding, Medicines that inhibit s rotoninuptake inplateletsmay lead toabnormalities of platelet aggregation.Aswith othermedicines that inhibit serotonin-reuptake, EXSIRA should be used cautiously in patients predisposed to bleeding. Hyponatraemia, Cases of hyponatrae- mia and/or the Syndrome of InappropriateAntidiuretic Hormone (SIADH) secretion have bee described with SNRIs and SSRIs, including EXSIRA, usually in volume-depleted or dehydrat- ed patients, including elderly patients and patients taking diuretics. Interstitial lung disease and eosinophilic pneumonia. Interstitial lung disease and eosinophilic pneumonia associat d with venlafaxine (the parent m dicine of EXSIRA) th erapy have been reported. The possibili- ty of these adverse events should be considered in patients treated with EXSIRAwho present S5EXSIRA , 50mg nd 100mg exe ded-relea e tablets. QUALITATIVEANDQUANTITATIVE COMPOSITION: Each EXSIRA 50m extended-rel ase flm-coaed t blet cont insdesvenlafaxine uccinat equivalent to 50mg desvenlafaxine. Each EXSIRA100mg extended-release flm-coat d tablet contains desvenlafax e succinate equiv- ale t to 100 mg desvenlafaxine. Sugar free. PHARMACEUTICAL FORM: Extend d- lease tablets. EXSIRA 50 mg extended-rele se ablets ar light pnk, square (pyr mid, one sided), flm c ated tablets, debossed “W” ver “50”on the fla side. EXSIRA100mg exended-releas tabletsare eddish-orange, squar (p ramid,one ide ), flm-coat d tabl ts,debossed “W” ver “100” on the flat side. CLINICAL PARTICULARS:Therapeutic Indicati n : Major depressiv disorde EXSIRA tablets re indic ed for the treatment of major d pressve dis rder (MDD). Posology andm thodof adminisration: Major depressvedisorder.The recommended dose f EXSIRAis 50 mg once daily, with or with ut food, with a aximum dose of 100 mg per day. The d se increase shouldoccur gradually and at an interval of not less than 7 days.Dis- c ntinuing EXSIRA: Symptoms as ociate wth discontinuati n of EXSIRA, other SNRIs and SSRIs have be reported. Patients should bemonitored for these symptoms whe discontin- uingtreatment.A grad al reduction in thedose rather th abrupt cessation is recommended whenev r possibl . If intolerabl symptomsoccur following ecr as i the dose or upon dis- continuation of tr atm nt, then resumi g the pr viously prescribed ose may be consider d. Subsequently, th m dical practitione may continue decreasing he do but at amore grad- ual rate. Switching patients fr m oth r antidepressants to EXSIRA: Discontinuaton symptoms have b en r portedwhenswitchin patients fromoth r antidepressants, includng venlafaxine, to EXSIRA. Tapering of the initi l antidepr ssant may be neces ary to inimis discontinua- tion symptoms. Sp cialpopulation : Use in paients it renal impairment. The r commend d sartin d se in patients with severe r nal impairme t (24- r CrCl < 30mL/min) or end-stage ren l disease (ESRD) is 50mg every otherday. Becauseof individual variability in cleaance in these patients, individua s tion of dosage may be desirable. Supplemental do es should not be given t patients after dialysis. Us in patients with hepatic impairment. No osag ad- justme is nec ssary fo patients with hepatic impairm nt. Us elderly paten . Nod sag adj stment is requiredsol ly on the basis of age; however, possible r duced renal cl arance of EXSIRA hould be considered when determining dose. Pa diatri popul tio s: Safety and effcacy i pati nt less han 18 years of age has notbe n stablished. Method of administra- tion: For oral use. Contraindications: .•Hyper ensitivitytoEXSIRA, venlafaxin hydr chloride or to any exci ients i th EXSIRA fomulation.• EXSIRA is an inhibitor ofb th norepinephrin and serotonin reuptake. EXSIRAmust notbe used incombination withamonoamn oxi ase inhibit r (MAOI), rwithi at le st 14 d ys of discontinuing treatmentwith an AOI.B ed on th h lf-life ofEXSIRA, at lea t 7 days should be llowed after stoppingEXSIRAbefore sarting an MAOI. Sev r adverse reactions hav been report d when th rapy is initiated with SSRI/ SNRI medicines such as EXSIRA soon ft r dscontinuation of an MAOI and when an MAOI is i itiated soon afterdiscontinuationof SSRI/SNRImedicine . These re ctions have included tremor, myoclo us, dia horesis, n use , vomiting, flushing, dizziness, hyperthermia with fea- tur s res mbli g neuroleptic malignant syndr me, seizure and d ath.• Ch dren less than 18 years of age, as safety and effcacy hav not b en established. • Preg ancy and actation. Specialwarnings and recautions foruse: SS Is/SNRIsmay increase the risk fpostpartum haemorh ge (see secton 4.6 and 4.8). Clinical worsening of depres ive symptom , unusual changes in behaviour, and suici ality. Patients withmajor depressive disord rm y experience wor eningof theird ionand/ortheemergenceofsuicidal id ationandb h vou,whether or not th y ae taking antidepressantmedicines.This i kmay p rsist unil signifcant r mission o rs.A causal r le, however, for antid pr ssantmedicinein inducing such behaviour has not beenestablish d.Patientsbeng tr atedwithEXSIRA l ,nevertheless,beobserved closely for linicalworse ng and uicidality, especially at the begnning ofa course of therap or t any time of d se changes, eit er incre ses or decr ase .Bec use of the possibility of c -morbidity betw nmajordepressive isord randotherpsychiatricandnon-psychiatri disord rs, thesame precautionso serve wh n tre ngp tientswithmajordepressivedisorder sh uldb observed when treating paientswith ther psychiatric nd non-p ychiatric disor ers.T e following symp- toms have been reported in patients being treat d with antidepressants for major depre sive disorder aswellas for other indications, both sychiatric and non-psychi tic: anxiety, agitation, panic ttack , inso nia, iritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and ia.Althoughacau al linkbetween the merge ceof suicidal i pul e hasnotbeenes- tabli hed, c nsid rati n should be given to changing the therapeuticregimen, including po ibly disc ntinuingEXSIRA in patie s forwhom such symptoms are severe, abrupt in onset, orwere not part ofth pati nt’s presenting sympt ms.If the d cision ismade t discontinue treatment, EXSIRA shoul be tapered. Short-t rm trials did not sh w an increase in the riskof sucidality with antid pressants compared to pl cebo in adults b yond th age of 24 years; therewas a re- duction in the riskof suicidalitywithantidepr ssants compared toplacebo in dultsage65 years and older.T r n reports of ho tility, suicidal ideation and elf-harmwith us ofSSRIs in children un er the ag of 18 years. Mania/hypomania. In clinical trials,maniaw s reported for 0,03%ofpati nts tre tedwithEXSIRA.Activatio ofmania/hypomaniahasalsobeen reported in a smallproportionofpati ntswithm joraffectivedisord rwhowere treatedwithoth rmarketed antidepressants. EXSIRA should be used c utiously in patients with a hist ry or famil history ofmana or hypom nia. Serotonin syndrome. The development of a potentially lif -th atening serotonin syndromemayoccurwithEXSIRA treatmen,particul rlywith concomitantuseofother serotonergic medicines (including SSRIs, SNRIs and triptans) and with me icines tha impair metabolism f seotonin (includi gMAOIs).Serotonin syndrome symptoms ay includ mental status ch nges (e. . agit tion, hallucination , and coma), autonomic instability(e.g. tachycardia, labile blood pressue, and hyperthermia), n uromuscular aberrati s (e.g. hyperreflexia, inco- ordination) nd/or gastroint stinal symptoms (e.g. nausea, vomiting, and diarrhoea).The con- comita t use ofEXSIRAwithserotonin pr cursors (such as tryptoph n supplements) isnot rec- ommende . Narrow-angle gla coma. Mydria is has been reported in association with EXSIRA; therefore,patie tswith raised intraocularpressureor thoseat riskofacute narrow-angleglauco- ma (angle-closure glaucoma) should bemonitored. Ischaemic cardiac advers eve ts. In clinical trials, therewere uncommon r eports of ischaemic card iac adverse ev nts, inclu ingmyocardi- al ischa mia, myocardial infarction, and coronary occlusion requiring revascularisation; these consequenc s.Forpatie tswhoexperience sustained increase inbloodpres urewhile receiv- ingEXSIRA,eiherdose re uctionordiscontinuatio shouldbeconsidered.Cau onshouldbeex- ercised in treatingpatientswithunderlying c nditions thatmightbe compr isedby increases in bloodpressure.Post ralhypotension (seeUse inelderlypatients). Cardiovascular/cerebrovascu- lar. Caution is advised in admnisteringEXSIRA to patientswith cardiovascular, erebrovas ular, or lipidmetabolismdisorders. Increases inbloodpressureandheart ratewer observ d incinical trialswithEXSIRA.EXSIRAhasnotbeenevaluatedsy tematically inpatientswi a recenthisto- ryofmyocardial infarction,unstableheartdisease,uncontrolledhypertension,orcerebrovascular dis ase.Patientswith hesediagnoses,except for cerebrovasculardiseas ,w reexcluded from clinical trials. Serumlipids, Dose-related elevations in fasting s rum total cholesterol, LDL (low density lipoprotein) cholesterol, and triglycerides wereobservedinclinicaltrials.Measur ment of serum lipids shoul be considered during treatmentwithEXSIRA. Seizures, Cases of eizur were reportedin pr -marketing clinical trialswithEXSIRA.EXSIRAhas not bee ystematically evaluated in patients with a seizure isord r. P tients with a history of seizures were exclud- ed frompre-marketing clinical trials. EXSIRA should be prescrbedwith aution in patientswith a s izure disorder. Discontinuation effects , Duringmarketing of SNRIs (Serotonin nd Norepi- nephrine Reupt ke Inhi itors), nd SSRIs (Selective Ser tonin Reuptake Inhibitors) such as EXSIRA, there have been spontaneous reports of adverse events occurring pon discontinu- ation of thesemedicines, particularly when abrupt, including the following: dysph ricmood, ir- ritability, agitation, dizzn ss, sensory disturbances (e.g. paraesthesias such as electri shock sensations), anxiey, confusion, headache, thargy, emotional lability, insomnia, hypomania, tinnitus, and seizur s.While these events are enerally self-limiting, there have been report of serious discontinu tion symptoms.Patients should be monitored when discontinuing tr tment with EXSIRA. A gradual r duction in the dose rath r than abrupt c ssation is recommended whenever possible. If intolerable s mpt ms occurfollowing a decrease in the dose or upon dis- c ntinuation of treatment then resuming the previousy prescribed dose may be considered. Abnormalbleeding, Medicines that inhibit s rotoninuptake inplateletsmay lead toabnormalities of platelet aggegation.Aswith othermedicines that inhibitserotonin-reuptak , EXSIRA should be used cautiously in patients predisposed to bleeding. Hyponatraemia, Cases of hyponatrae- mia and/or the Syndrome of InappropriateAnidiuretic Hormone (SIADH) ecretion have bee described with SNRIs and SSRIs, including EXSIRA, usually in volume-depleted or dehydrat- ed patients, including elderly patients and patients taking diuretics. Interstitial lung disease and eosinophilic pneumonia. Interstitial lung disease and eosinophilic pneumonia associ ted with venlafaxine (the parent m dicine of EXSIRA) therapy have been reported. The possibili- ty of these adverse events should be considered in patients treated with EXSIRAwho present with progressive dyspn a, c ugh, r chest disc mfor. Such patientsshould undergo a prompt medical evaluation, and discontinuation ofEXSIRAshould be considered. Specialpopulations. Use in elderly patients. No dosage adjustment is required solely on the basis of age; howev- er, possible reduced renal clearance of EXSIRA should be consideredwhen determining dose. Of the 7 785 patients in pre-marketing clinical trialswithEXSIRA, 5% of patientswere 65 years of age or older. No overall differences in safety or effcacywere observedbetween these pa- tients and younger patients; however, in the short-term placebo-controlled trials, there was a higher incidence of systolic orthostatic hypotension in patients treated with EXSIRAwho were ≥ 65 years of age (8%) compared to patients < 65 years of age (0,9%). In addition, in both short-term and long-term placebo-controlled trials, there were increases in systolic blood pres- sure in patients ≥ 65 years of age compared to patients < 65 years of age treatedwithEXSIRA. Paediatric population. Safety and effcacy in children under 18 years of age has not beenes- tablished (see sections 4.3 and 4.8). In clinical trials of SSRIs and SNRIs inmajor depressive disorder, there were increased reports of hostility and suicide-related adverse events such as suicidal ideation and self-harm. Interactionwith othermedicines and other forms of inter- action: Monoamine oxidase inhibitors (MAOI).Central nervous system (CNS)-activemedicines Serotonin syndrome,Ethanol, Potential forEXSIRA toaffectothermedicinesMedicinesmetabo- lised byCYP2D6,Medicinesmetabolised byCYP3A4,Medicinesmetabolised by a combination of bothCYP2D6 andCYP3A4,Medicinesmetabolized byCYP1A2, 2A6, 2C8, 2C9 and 2C19, P-glycoprotein transporter, Laboratory test interactions, Electroconvulsive therapy, Fertility, pregnancy and lactation: EXSIRAmust not be administered to pregnant or lactating women. Safetyduringhumanpregnancyand lactationhasnotbeenestablished.Observationaldata indi- cate an increased risk (less than 2-fold) of postpartum haemorrhage followingSSRI/SNRI expo- surewithin themonth prior to birth. Undesirable effects: Metabolism and nutritional disorders: Common:Decreasedappetite.Psychiatricdisorders:Verycommon: Insomnia.Common:Anxiety, abnormaldreams, nervousness, decreased libido, anorgasmia.Nervous system disorders: Very common: Dizziness, headache. Common: Somnolence, tremor, paraesthesia, dysgeusia, disturbance inattention,vertigo. Eyedisorders:Common:Blurred vision,mydriasis.Earand lab- yrinth disorders:Common:Tinnitus.Cardiac disorders:Common:Palpitations, tachycardia.Vas- cular disorders:Common:Hot flush.Respiratory, thoracic andmediastinal disorders:Common: Yawning.Gastrointestinal disorders:Very common:Nausea, drymouth, constipation.Common: Diarrhoea, vomiting. Skin and subcutaneous tissue disorders: Very common: Hyperhidrosis. Common: Rash. Musculoskeletal, connective tissue and bone disorders: Common: Musculo- skeletal stiffness. Reproductive system and breast disorders: Common: Erectile dysfunction*, delayed ejaculation*, ejaculation failure*. (*Frequency is calculated based on men only).Not known:Postpartum haemorrage***. (***This event has been reported for the therapeutic class of SSRIs/SNRIs). General disorders and administration: Common: Fatigue, chills, asthenia, feeling jittery, irritability. Investigations: Common: Increased weight, increased blood pressure, decreased weight. Overdose: There is limited clinical experience with EXSIRA overdosage in humans.No specifc antidotes forEXSIRA are known. Inductionof emesis isnot recommended. Because of themoderate volume of distribution of thismedicine, forced diuresis, dialysis, hae- moperfusion, and exchange transfusion are unlikely to be of beneft.Treatment should consist of those generalmeasures employed in themanagement of overdosage with any SSRI/SNRI. Ensureanadequateairway,oxygenation,and ventilation.Monitor cardiac rhythmand vital signs. General supportive and symptomatic measures are also recommended.Gastric lavage with a large-bore orogastric tubewith appropriate airway protection, if needed,may be indicated if per- S5EXSIRA , 50mg and 100mg extended-release tablets. QUALITATIVEANDQUANTITATIVE COMPOSITION: Each EXSIRA 50mg extended-release flm-coated tablet contains desvenlafaxine succinate equivalent to 50mg desvenlafaxine. Each EXSIRA 100mg extended-release flm-coated tablet contains desvenlafaxine succinate equiv- alent to 100 mg desvenlafaxine. Sugar free. PHARMACEUTICAL FORM: Extended-release tablets. EXSIRA 50 mg extended-release tablets are light pink, square (pyramid, one sided), flm coated tablets, debossed “W” over “50” on the flat side. EXSIRA 100mg extended-release tabletsare reddish-orange, square (pyramid,one sided), flm-coated tablets,debossed “W” over “100” on the flat side. CLINICAL PARTICULARS:Therapeutic Indications: Major depressive disorder EXSIRA tablets are indicated for the treatment of major depressive disorder (MDD). Posology andmethodof administration: Major depressive disorder.The recommended dose for EXSIRA is 50 mg once daily, with or without food, with a maximum dose of 100 mg per day. The dose increase should occur gradually and at an interval of not less than 7 days.Dis- continuing EXSIRA: Symptoms associated with discontinuation of EXSIRA, other SNRIs and SSRIs have been reported. Patients should bemonitored for these symptoms when discontin- uing treatment.A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon dis- continuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, themedical practitionermay continue decreasing the dose but at amore grad- ual rate. Switching patients from other antidepressants to EXSIRA: Discontinuation symptoms have been reportedwhen switching patients from other antidepressants, including venlafaxine, to EXSIRA. Tapering of the initial antidepressant may be necessary to minimise discontinua- tion symptoms. Specialpopulations: Use in patientswith renal impairment. The recommended starting dose in patients with severe renal impairment (24-hr CrCl < 30mL/min) or end-stage renal disease (ESRD) is 50mg every other day. Because of individual variability in clearance in these patients, individualisation of dosage may be desirable. Supplemental doses should not be given to patients after dialysis. Use in patients with hepatic impairment. No dosage ad- justment is necessary for patients with hepatic impairment. Use in elderly patients . No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of EXSIRA should be considered when determining dose. Paediatric populations: Safety and effcacy in patients less than 18 years of age has not been established. Method of administra- tion: For oral use. Contraindications: .•Hypersensitivity toEXSIRA, venlafaxine hydrochloride or to any excipients in the EXSIRA formulation.• EXSIRA is an inhibitor of both norepinephrine and serotonin reuptake. EXSIRAmust not be used in combination with amonoamine oxidase inhibitor (MAOI), orwithin at least 14 days of discontinuing treatmentwith anMAOI. Based on the half-life ofEXSIRA, at least 7 days should be allowed after stoppingEXSIRAbefore starting an MAOI. Severe adverse reactions have been reported when therapy is initiated with SSRI/ SNRI medicines such as EXSIRA soon after discontinuation of an MAOI and when an MAOI is initiated soon after discontinuation of SSRI/SNRImedicines. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with fea- tures resembling neuroleptic malignant syndrome, seizures and death.• Children less than 18 years of age, as safety and effcacy have not been established. • Pregnancy and lactation. Specialwarnings andprecautions foruse: SSRIs/SNRIsmay increase the risk of postpartum haemorrhage (see section 4.6 and 4.8). Clinical worsening of depressive symptoms, unusual changes in behaviour, and suicidality. Patients with ajor depressive disordermay experience worseningof theirdepressionand/or theemergenceof suicidal ideationandbehaviour,whether or not they are taking antidepressantmedicines.This riskmay persist until signifcant remission occurs.A causal role, however, for antidepressantmedicine in inducing such behaviour has not beenestablished.Patientsbeing treatedwithEXSIRAshould,nevertheless,beobserved closely for clinicalworsening 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 betweenmajordepressivedisorderandotherpsychiatricandnon-psychiatricdisorders, thesame precautionsobservedwhen treatingpatientswithmajordepressivedisordersshouldbeobserved when treating patientswith other psychiatric and non-psychiatric disorders.The following symp- toms have been reported in patients being treated with antidepressants for major depressive disorder aswell as for other indications, both psychiatric and non-psychiatric: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, andmania.Althougha causal linkbetween theemergenceof suicidal impulseshasnotbeenes- tablished, consideration should be given to changing the therapeutic regimen, including possibly discontinuingEXSIRA in patients forwhom such symptoms are severe, abrupt in onset, orwere not part of the patient’s presenting symptoms. If the decision ismade to discontinue treatment, EXSIRA should be tapered. Short-term trials did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond the age of 24 years; therewas a re- duction in the riskof suicidalitywithantidepressants compared toplacebo inadultsage65 years and older.There have been reports of hostility, suicidal ideation and self-harmwith use ofSSRIs in children under the age of 18 years. Mania/hypomania. In clinical trials,maniawas reported for 0,03%ofpatients treatedwithEXSIRA.Activationofmania/hypomaniahasalsobeen reported in a smallproportionofpatientswithmajoraffectivedisorderwhowere treatedwithothermarketed antidepressants. EXSIRA should be used cautiously in patients with a history or family history ofmania or hypomania. Serotonin syndrome. The development of a potentially life-threatening serotonin syndromemayoccurwithEXSIRA treatment,particularlywith concomitantuseofother serotonergic medicines (including SSRIs, SNRIs and triptans) and with medicines that impair metabolism of serotonin (includingMAOIs).Serotonin syndrome symptomsmay includemental status changes (e.g. agitation, hallucinations, and coma), autonomic instability (e.g. tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, inco- ordination) and/or gastrointestinal symptoms (e.g. nausea, vomiting, and diarrhoea).The con- comitant use ofEXSIRAwith serotonin precursors (such as tryptophan supplements) is not rec- ommended. Narrow-angle glaucoma. Mydriasis has been reported in association with EXSIRA; therefore,patientswith raised intraocularpressureor thoseat riskofacute narrow-angleglauco- ma (angle-closure glaucoma) should bemonitored. Ischaemic cardiac adverse events. In clinical trials, there were uncommon reports of ischaemic cardiac adverse events, includingmyocardi- al ischaemia, myocardial infarction, and coronary occlusion requiring revascularisation; these patients had multiple underlying cardiac risk factors. More patients experienced these events duringEXSIRA treatmentas compared toplacebo. Discontinuation symptoms. Adverse reactions reported in association with abrupt discontinuation, dose reduction or tapering of treatment in MDD clinical trials at a rate of ≥ 2% include: dizziness,withdrawal syndrome, nausea and head- ache. In general, discontinuation symptoms occurred more frequently with longer duration of therapy. Adverse reactions leading to discontinuation of therapy. The most common adverse reaction leading todiscontinuation inat least2%of theEXSIRA-treatedpatients in theshort-term trials, up to 12weeks,was nausea (2%); in the long-term studies, up to 11months, no events lead todiscontinuation inat least2%of thepatientsandata rategreater thanplacebo in thedou- ble-blindphase. Adverse reactions reportedwithotherSNRIs .Althoughgastrointestinalbleeding is not considered an adverse reaction for EXSIRA, it is an adverse reaction for other SN Is andmay also occurwithEXSIRA. Effects on activities requiring concentration and performance. Interference with cognitive andmotor performance. The results of a clinical trial that assessed the effects of EXSIRA on behavioural performance of healthy individuals revealed no clinically signifcant impairment of psychomotor, cog itive, or complex behaviour performance.Howev r, sinceanyCNS-activemedicinemay impair judgement, thinking,ormotorskills,patientsshouldbe cautionedaboutoperatinghazardousmachinery, includingautomobiles,until theyare reasonably certain that EXSIRA therapy does not adversely affect their ability to engage in such activities. Abuse and dependence. Physical and psychological dependence. Although EXSIRA has not been systematically studied in preclinical or clinical trials for its potential for abuse, no indica- tion of drug-seeking behaviour was seen in the clinical trials. Co-administration of medicines containing venlafaxine and/or EXSIRA. EXSIRA is the major active metabolite of venlafax- ine, a medicine used to treat major depressive, generalised anxiety, social anxiety and panic disorders. EXSIRA should not be used concomitantly with products containing venlafaxine hydrochloride orother products containingEXSIRA. Increases inblood pressurewere observed in some patients in clinical trials, particularlywithhigher doses.Pre-existing hypertension should be controlled before treatmentwithEXSIRA .Patients receivingEXSIRAshould have regular monitoring of blood pressure.Cases of elevated blood pressure requiring immediate treatment have been reportedwithEXSIRA.Sustained blood pressure increases could have adverse consequences.Forpatientswhoexperiencea sustained increase inbloodpressurewhile receiv- ingEXSIRA,eitherdose reductionordiscontinuationshouldbeconsidered.Cautionshouldbeex- ercised in treatingpatientswithunderlying conditions thatmightbe compromisedby increases in bloodpressure.Posturalhypotension (seeUse inelderlypatients). Cardiovascular/cerebrovascu- lar. Caution is advised in administeringEXSIRA to patientswith cardiovascular, cerebrovascular, or lipidmetabolismdisorders. Increases inbloodpressureandheart ratewereobserved inclinical trialswithEXSIRA.EXSIRAhasnotbeenevaluatedsystematically inpatientswitha recenthisto- ryofmyocardial infarction,unstableheartdisease,uncontrolledhypertension,orcerebrovascular disease.Patientswith thesediagnoses,except for cerebrovasculardisease,wereexcluded from clinical trials. Serum lipids, Dose-related elevations in fasting serum total cholesterol, LDL (low density lipoprotein) cholesterol, and triglycerides were observed in clinical trials.Measurement of serum lipids should be considered during treatmentwithEXSIRA. Seizures, Cases of seizure were reported in pre-marketing clinical trialswithEXSIRA.EXSIRAhas not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were exclud- ed from pre-marketing clinical trials. EXSIRA should be prescribedwith caution in patientswith a seizure disorder. Discontinuation effects , Duringmarketing of SNRIs (Serotonin and Norepi- nephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors) such as EXSIRA, there have been spontaneous reports of adverse events occurring upon discontinu- ation of thesemedicines, particularly when abrupt, including the following: dysphoricmood, ir- ritability, agitation, dizziness, sensory disturbances (e.g. paraesthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures.While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.Patients should be monitored when discontinuing treatment with EXSIRA. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon dis- continuation of treatment, then resuming the previously prescribed dose may be considered. Abnormalbleeding, Medicines that inhibit serotoninuptake inplateletsmay lead toabnormalities of platelet aggregation.Aswith othermedicines that inhibit serotonin-reuptake, EXSIRA should be used cautiously in patients predisposed to bleeding. Hyponatraemia, Cases of hyponatrae- mia and/or the Syndrome of InappropriateAntidiuretic Hormone (SIADH) secretion have been described with SNRIs and SSRIs, including EXSIRA, usually in volume-depleted or dehydrat- ed patients, including elderly patients and patients taking diuretics. Interstitial lung disease and eosinophilic pneumonia. Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent medicine of EXSIRA) therapy have been reported. The possibili- ty of these adverse events should be considered in patients treated with EXSIRAwho present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo a prompt medical evaluation,and discontinuation ofEXSIRAshouldbe considered. Specialpopulations. Use in elderly patients. No dosage adjustment is required solely on the basis of age; howev- er, possible reduced renal clearance of EXSIRA should be consideredwhen determining dose. Of the 7 785 patients in pre-marketing clinical trialswithEXSIRA, 5% of patientswere 65 years of age or older. No overall differences in safety or effcacywere observed between these pa- tients and younger patients; however, in the short-term placebo-controlled trials, there was a higher incidence of systolic orthostatic hypotension in patients treated with EXSIRAwho were ≥ 65 years of age (8%) compared to patients < 65 years of age (0,9%). In addition, in both short-term and long-term placebo-controlled trials, there were increases in systolic blood pres- sure in patients ≥ 65 years of age compared to patients < 65 years of age treatedwithEXSIRA. Paediatric population. Safety and effcacy in children under 18 years of age has not been es- tablished (see sections 4.3 and 4.8). In clinical trials of SSRIs and SNRIs inmajor depressive disorder, there were increased reports of hostility and suicide-related adverse events such as suicidal ideation and self-harm. Interactionwith othermedicines and other forms of inter- action: Monoamine oxidase inhibitors (MAOI).Central nervous system (CNS)-activemedicines Serotonin syndrome,Ethanol, Potential forEXSIRA toaffectothermedicinesMedicinesmetabo- lised byCYP2D6,Medicinesmetabolised byCYP3A4,Medicinesmetabolised by a combination of bothCYP2D6 andCYP3A4,Medicinesmetabolized byCYP1A2, 2A6, 2C8, 2C9 and 2C19, P-glycoprotein transporter, Laboratory test interactions, Electroconvulsive therapy, Fertility, pregnancy and lactation: EXSIRAmust not be administered to pregnant or lactating women. Safetyduringhumanpregnancyand lactationhasnotbeenestablished.Observationaldata indi- cate an increased risk (less than 2-fold) of postpartum haemorrhage followingSSRI/SNRI expo- surewithin themonth prior to birth. Undesirable effects: Metabolism and nutritional disorders: Common:Decreasedappetite.Psychiatricdisorders:Verycommon: Insomnia.Common:Anxiety, abnormaldreams, nervousness, decreased libido,anorgasmia.Nervous system disorders: Very common: Dizziness, headache. Common: Somnolence, tremor, paraesthesia, dysgeusia, disturbance inattention,vertigo. Eyedisorders:Common:Blurred vision,mydriasis.Earand lab- yrinth disorders:Common:Tinnitus.Cardiac disorders:Common:Palpitations, tachycardia.Vas- cular disorders:Common:Hot flush.Respiratory, thoracic andmediastinaldisorders:Common: Yawning.Gastrointestinal disorders:Very common:Nausea, drymouth, constipation.Common: Diarrhoea, vomiting. Skin and subcutaneous tissue disorders: Very common: Hyperhidrosis. Common: Rash. Musculoskeletal, connective tissue and bone disorders: Common: Musculo- skeletal stiffness. Reproductive system and breast disorders: Common: Erectile dysfunction*, delayed ejaculation*, ejaculation failure*. (*Frequency is calculated based on men only).Not known:Postpartum haemorrage***. (***This event has been reported for the therapeutic class of SSRIs/SNRIs). General disorders and administration: Common: Fatigue, chills, asthenia, feeling jittery, irritability. Investigations: Common: Increased weight, increased blood pressure, decreased weight. Overdose: There is limited clinical experience with EXSIRA overdosage in humans.No specifc antidotes forEXSIRA are known. Induction ofemesis is not recommended. Because of themoderate volume of distribution of thismedicine, forced diuresis, dialysis, hae- moperfusion, and exchange transfusion are unlikely to be of beneft.Treatment should consist of those generalmeasures employed in themanagement of overdosage with any SSRI/SNRI. Ensureanadequateairway,oxygenation,and ventilation.Monitor cardiac rhythmand vital signs. General supportive and symptomatic measures are also recommended.Gastric lavage with a large-bore orogastric tubewith appropriate airway protection, if needed,may be indicated if per- formed soon after ingestion or in symptomaticpatients.Activated charcoal should be administered. PHARMACOLOGICALPROPERTIES: Pharmacological classifcation:A1.2 Psychoanaleptics (antidepressants) PHARMACEUTICAL PARTICULARS: List of excipients: EXSIRA50mgextended-release tabletsTablet core:Hypromellose,Magnesium stearate,Micro- crystalline cellulose,Talc.Film-coating:Macrogol/PEG 3350,Polyvinyl alcohol (part hydrolysed), Red ironoxide, Talc,Titaniumdioxide,Yellow ironoxide.EXSIRA100mgextended-release tab- lets:Tablet core:Hypromellose,Magnesium stearate,Microcrystalline cellulose,Talc. Film-coat- ing:Macrogol/PEG 3350, Polyvinyl alcohol (part hydrolysed),Red iron oxide, Talc, Titanium di- oxide, Yellow iron oxide, FD&C Yellow #6/Sunset Yellow FCF Aluminium Lake. Shelf life : 24 months, Special precautions for storage: Store at or below 25 °C. Keepwell closed.Do not remove blister card from the carton until required for use. Nature and contents of container: EXSIRA (desvenlafaxine succinate)extended-release tabletsareavailableas follows:Acarton containing oneormore clear plastic/aluminium foil blister strips containing 7, 14 or 28 tablets each. HOLDEROFCERTIFICATEOFREGISTRATION: Pfzer Laboratories (Pty) Ltd, 85Bute Lane, Sandton, 2196,SouthAfrica,Tel:+27(0)11320 6000 / 0860734 937 (toll freeSouthAfrica). REGISTRATIONNUMBER(S): EXSIRA50mg: 42/1.2/0935,EXSIRA100mg: 41/1.2/0427. REFERENCE: ApprovedProfessional Information date of publication (14March 2021). PLEASEREFERTODETAILEDPROFESSIONAL INFORMATIONFORCOMPLETE PRESCRIBING INFORMATION. PP-EXS-ZAF-0145 Abbreviations: MDD: Major depressive disorder, DDIs: Drug-Drug Interactions