- Approval Id
- 8d8e9d6513aeaa61
- Drug Approval Emc Name
- Venlafaxine 150mg prolonged release capsules
- Drug Name
- Venlafaxine 150mg prolonged release capsules
- Company Address
- Morningside House, Unit C Harcourt Way, Meridian Business Park, Leicester, LE19 1WP
- Company Website
- http://www.morningsidehealthcare.com
- Company Telephone
- +44 (0)116 204 5950
- Company Medical Info Direct Line
- +44 (0)116 478 0322
- Company Medical Info Email
- [email protected]
- Company Customer Care Direct Line
- +44 (0)116 204 5950
- Company Stock Availability
- +44 (0)1509 217 705
- Atc Code
- N06AX16
- Legal Category
- Prescription only medicine
- Authorisation Holder
- 7. Marketing authorisation holder Morningside Healthcare Ltd Unit C, Harcourt Way Leicester, LE19 1WP, UK
- Authorisation Number
- 8. Marketing authorisation number(s) PL 20117/0068
- Authorisation Date
- 9. Date of first authorisation/renewal of the authorisation 22/05/2008
- Instruction Authorisation Holder
- 7. Marketing authorisation holder Morningside Healthcare Ltd Unit C, Harcourt Way Leicester, LE19 1WP, UK
- Instruction Authorisation Number
- 8. Marketing authorisation number(s) PL 20117/0068
- Instruction Authorisation Date
- 9. Date of first authorisation/renewal of the authorisation 22/05/2008
- Instruction Composition
- 2. Qualitative and quantitative composition Each capsule contains venlafaxine hydrochloride equivalent to 150mg of venlafaxine One prolonged release capsule contains 0.3968 mg of Sunset yellow, see section 4.4 For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- 3. Pharmaceutical form Prolonged release capsules, hard. The capsules are dark orange / dark orange size '0' hard gelatin capsules having thick and thin radial circular band on the body in white ink and thick and thin radial circular band on the cap in white ink. The capsule is filled with 12 white to off-white round biconvex film coated mini tablets of 12.5mg.
- Instruction Clinical Particulars
- 4. Clinical particulars 4.1 Therapeutic indications The treatment of major depressive disorder For prevention of recurrence of major depressive episodes. Treatment of generalised anxiety disorder. Treatment of social anxiety disorder. Treatment of panic disorder, with or without agoraphobia. 4.2 Posology and method of administration Posology Major depressive episodes The recommended starting dose for prolonged-release venlafaxine is 75 mg given once daily. Patients not responding to the initial 75 mg/day dose may benefit from dose increases up to a maximum dose of 375 mg/day. Dosage increases can be made at intervals of 2 weeks or more. If clinically warranted due to symptom severity, dose increases can be made at more frequent intervals, but not less than 4 days. Because of the risk of dose-related adverse effects, dose increments should be made only after a clinical evaluation (see section 4.4). The lowest effective dose should be maintained. Patients should be treated for a sufficient period of time, usually several months or longer. Treatment should be reassessed regularly on a case-by-case basis. Longer-term treatment may also be appropriate for prevention of recurrence of major depressive episodes (MDE). In most of the cases, the recommended dose in prevention of recurrence of MDE is the same as the one used during the current episode. Antidepressive medicinal products should continue for at least six months following remission. Generalised anxiety disorder The recommended starting dose for prolonged-release venlafaxine is 75 mg given once daily. Patients not responding to the initial 75 mg/day dose may benefit from dose increases up to a maximum dose of 225 mg/day. Dosage increases can be made at intervals of 2 weeks or more. Because of the risk of dose-related adverse effects, dose increments should be made only after a clinical evaluation (see section 4.4). The lowest effective dose should be maintained. Patients should be treated for a sufficient period of time, usually several months or longer. Treatment should be reassessed regularly, on a case-by-case basis. Social anxiety disorder The recommended dose for prolonged-release venlafaxine is 75 mg given once daily. There is no evidence that higher doses confer any additional benefit. However, in individual patients not responding to the initial 75 mg/day, increases up to a maximum dose of 225 mg/day may be considered. Dosage increases can be made at intervals of 2 weeks or more. Because of the risk of dose-related adverse effects, dose increments should be made only after a clinical evaluation (see section 4.4). The lowest effective dose should be maintained. Patients should be treated for a sufficient period of time, usually several months or longer. Treatment should be reassessed regularly, on a case-by-case basis. Panic disorder It is recommended that a dose of 37.5 mg/day of prolonged-release venlafaxine be used for 7 days. Dosage should then be increased to 75 mg/day. Patients not responding to the 75 mg/day dose may benefit from dose increases up to a maximum dose of 225 mg/day. Dosage increases can be made at intervals of 2 weeks or more. Because of the risk of dose-related adverse effects, dose increments should be made only after a clinical evaluation (see section 4.4). The lowest effective dose should be maintained. Patients should be treated for a sufficient period of time, usually several months or longer. Treatment should be reassessed regularly, on a case-by-case basis. Elderly patients No specific dose adjustments of venlafaxine are considered necessary based on patient age alone. However, caution should be exercised in treating the elderly (e.g., due to the possibility of renal impairment, the potential for changes in neurotransmitter sensitivity and affinity occurring with aging). The lowest effective dose should always be used, and patients should be carefully monitored when an increase in the dose is required. Paediatric population Venlafaxine is not recommended for use in children and adolescents. Controlled clinical studies in children and adolescents with major depressive disorder failed to demonstrate efficacy and do not support the use of venlafaxine in these patients (see sections 4.4 and 4.8). The efficacy and safety of venlafaxine for other indications in children and adolescents under the age of 18 have not been established. Patients with hepatic impairment In patients with mild and moderate hepatic impairment, in general a 50% dose reduction should be considered. However, due to inter-individual variability in clearance, individualisation of dosage may be desirable. There are limited data in patients with severe hepatic impairment. Caution is advised, and a dose reduction by more than 50% should be considered. The potential benefit should be weighed against the risk in the treatment of patients with severe hepatic impairment. Patients with renal impairment Although no change in dosage is necessary for patients with glomerular filtration rate (GFR) between 30-70 ml/minute, caution is advised. For patients that require haemodialysis and in patients with severe renal impairment (GFR < 30 ml/min), the dose should be reduced by 50%. Because of inter-individual variability in clearance in these patients, individualisation of dosage may be desirable. Withdrawal symptoms seen on discontinuation of venlafaxine Abrupt discontinuation should be avoided. When stopping treatment with venlafaxine, the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see sections 4.4 and 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate. Method of administration For oral use. It is recommended that Vensir XL/Venlafaxine Morningside Prolonged Release Hard Capsules be taken with food, at approximately the same time each day. Capsules must be swallowed whole with fluid and not divided, crushed, chewed, or dissolved. Patients treated with venlafaxine immediate-release tablets may be switched to Vensir XL/Venlafaxine Morningside Prolonged Release Hard Capsules at the nearest equivalent daily dosage. For example, venlafaxine immediate-release tablets 37.5 mg twice daily may be switched to Vensir XL/Venlafaxine Morningside Prolonged Release Hard Capsules 75 mg once daily. Individual dosage adjustments may be necessary. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concomitant treatment with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serotonin syndrome with symptoms such as agitation, tremor and hyperthermia. Venlafaxine must not be initiated for at least 14 days after discontinuation of treatment with an irreversible MAOI. Venlafaxine must be discontinued for at least 7 days before starting treatment with an irreversible MAOI (see sections 4.4 and 4.5). 4.4 Special warnings and precautions for use Suicide/suicidal thoughts or clinical worsening Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Other psychiatric conditions for which Vensir XL/Venlafaxine Morningside Prolonged Release Hard Capsules is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders. 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 drugs 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 drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present Paediatric PopulationVensir XL/Venlafaxine Morningside Prolonged Release Hard Capsules 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. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking. Serotonin syndrome As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with venlafaxine treatment, particularly with concomitant use of other agents 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, buprenorphine, dextromethorphan, tapentadol, pethidine, methadone and pentazocine), with medicinal agents 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 NMS, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs and mental status changes. If concomitant treatment with venlafaxine and other agents 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 venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended. Narrow-angle glaucoma Mydriasis may occur in association with venlafaxine. 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 commonly reported with venlafaxine. In some cases, severely elevated blood pressure requiring immediate treatment has been reported in postmarketing 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 arrhythmia Venlafaxine 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 postmarketing experience, cases of QTc prolongation, Torsades de Pointes (TdP), ventricular tachycardia, and fatal cardiac arrhythmias 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 venlafaxine to patients at high risk of serious cardiac arrhythmia or QTc prolongation. Convulsions Convulsions may occur with venlafaxine therapy. As with all antidepressants, venlafaxine 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 venlafaxine. 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 Medicinal products that inhibit serotonin uptake may lead to reduced platelet function. Bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hepatoma, epistaxis, and petechiae to gastrointestinal and life-threatening haemorrhages. The risk of haemorrhage may be increased in patients taking venlafaxine. As with other serotonin-reuptake inhibitors, venlafaxine should be used cautiously in patients predisposed to bleeding, including patients on anticoagulants and platelet inhibitors. 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
- Instruction Pharmacology
- 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic Group: Other antidepressants ATC code: N06A X16 Vensir XL/Venlafaxine Morningside Prolonged Release Hard Capsules is a structurally novel antidepressant which is chemically unrelated to tricyclic, tetracyclic, or other available antidepressant agents. It is a racemate with two active enantiomers. Mechanism of action The mechanism of Vensir XL/Venlafaxine Morningside Prolonged Release Hard Capsules's antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the central nervous system. Preclinical studies have shown that venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV), are inhibitor of serotonin and noradrenaline reuptake. Venlafaxine also weakly inhibits dopamine uptake. Venlafaxine and its active metabolite reduce β-adrenergic responsiveness after both acute (single dose) and chronic administration. Venlafaxine ODV are very similar with respect to their overall action on neurotransmitter re-uptake and receptor binding. Venlafaxine has virtually no affinity for rat brain muscarinic, cholinergic, H1-histaminergic or α1-adrenergic receptors in vitro. Pharmacological activity at these receptors may be related to various side effects seen with other antidepressant medicinal products, such as anticholinergic, sedative and cardiovascular side effects. Venlafaxine does not possess monoamine oxidase (MAO) inhibitory activity. In vitro studies revealed that venlafaxine has virtually no affinity for opiate or benzodiazepine sensitive receptors. Clinical efficacy and safety Major depressive episodes The efficacy of venlafaxine immediate-release as a treatment for major depressive episodes was demonstrated in five randomised, double-blind, placebo-controlled, short-term trials ranging from 4 to 6 weeks duration, for doses up to 375 mg/day. The efficacy of venlafaxine prolonged-release as a treatment for major depressive episodes was established in two placebo-controlled, short-term studies for 8 and 12 weeks duration, which included a dose range of 75 to 225 mg/day. In one longer-term study, adult outpatients who had responded during an 8-week open trial on venlafaxine prolonged-release (75, 150, or 225 mg) were randomised to continuation of their same venlafaxine prolonged-release dose or to placebo, for up to 26 weeks of observation for relapse. In a second longer-term study, the efficacy of venlafaxine in prevention of recurrent depressive episodes for a 12-month period was established in a placebo-controlled double-blind clinical trial in adult outpatients with recurrent major depressive episodes who had responded to venlafaxine treatment (100 to 200 mg/day, on a twice daily schedule) on the last episode of depression. Generalised anxiety disorder The efficacy of venlafaxine prolonged-release capsules as a treatment for generalised anxiety disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies (75 to 225 mg/day), one 6-month, placebo-controlled, fixed-dose study (75 to 225 mg/day), and one 6-month, placebo-controlled, flexible-dose study (37.5, 75, and 150 mg/day) in adult outpatients. While there was also evidence for superiority over placebo for the 37.5 mg/day dose, this dose was not as consistently effective as the higher doses. Social anxiety disorder The efficacy of venlafaxine prolonged-release capsules as a treatment for social anxiety disorder was established in four double-blind, parallel-group, 12-week, multi-center, placebo-controlled, flexible-dose studies and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study in adult outpatients. Patients received doses in a range of 75 to 225 mg/day. There was no evidence for any greater effectiveness of the 150 to 225 mg/day group compared to the 75 mg/day group in the 6-month study. Panic disorder The efficacy of venlafaxine prolonged-release capsules as a treatment for panic disorder was established in two double-blind, 12-week, multi-center, placebo-controlled studies in adult outpatients with panic disorder, with or without agoraphobia. The initial dose in panic disorder studies was 37.5 mg/day for 7 days. Patients then received fixed doses of 75 or 150 mg/day in one study and 75 or 225 mg/day in the other study. Efficacy was also established in one long-term double-blind, placebo-controlled, parallel-group study of the long-term safety, efficacy, and prevention of relapse in adult outpatients who responded to open-label treatment. Patients continued to receive the same dose of venlafaxine prolonged-release that they had taken at the end of the open-label phase (75, 150, or 225 mg). Cardiac electrophysiology In a dedicated thorough QTc study in healthy subjects, venlafaxine did not prolong the QT interval to any clinically relevant extent at a supra-therapeutic dose of 450 mg/day (given as 225 mg twice daily). However, postmarketing cases of QTc prolongation/TdP and ventricular arrhythmia have been reported, especially in overdose or in patients with other risk factors for QTc prolongation/TdP (see sections 4.4, 4.8 and 4.9). 5.2 Pharmacokinetic properties Venlafaxine is extensively metabolised, primarily to the active metabolite, O-desmethylvenlafaxine (ODV). Mean ± SD plasma half-lives of venlafaxine and ODV are 5±2 hours and 11±2 hours, respectively. Steady-state concentrations of venlafaxine and ODV are attained within 3 days of oral multiple-dose therapy. Venlafaxine and ODV exhibit linear kinetics over the dose range of 75 mg to 450 mg/day. Absorption At least 92% of venlafaxine is absorbed following single oral doses of immediate-release venlafaxine. Absolute bioavailability is 40% to 45% due to presystemic metabolism. After immediate-release venlafaxine administration, the peak plasma concentrations of venlafaxine and ODV occur in 2 and 3 hours, respectively. Following the administration of venlafaxine prolonged-release capsules, peak plasma concentrations of venlafaxine and ODV are attained within 5.5 hours and 9 hours, respectively. When equal daily doses of venlafaxine are administered as either an immediate-release tablet or prolonged-release capsule, the prolonged-release capsule provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet. Food does not affect the bioavailability of venlafaxine and ODV. Distribution Venlafaxine and ODV are minimally bound at therapeutic concentrations to human plasma proteins (27% and 30%, respectively). The volume of distribution for venlafaxine at steady-state is 4.4±1.6 L/kg following intravenous administration. Biotransformation Venlafaxine undergoes extensive hepatic metabolism. In vitro and in vivo studies indicate that venlafaxine is biotransformed to its major active metabolite, ODV, by CYP2D
- Instruction Pharmaceutical Particulars
- 6. Pharmaceutical particulars 6.1 List of excipients • Microcrystalline cellulose • Copovidone • Ethyl cellulose • Magnesium stearate • Povidone • Colloidal Silicon Dioxide • Talc Capsule shell components • Gelatin • Titanium dioxide (E171) • Brilliant blue FCF (E133) • Allura red (E129) • Sunset yellow FCF (E110) Printing ink • Shellac • Propylene glycol • Sodium hydroxide • Povidone • Titanium dioxide (E171) 6.2 Incompatibilities Not Applicable 6.3 Shelf life 3 years 6.4 Special precautions for storage Do not store above 25°C Store in the original container to protect from moisture 6.5 Nature and contents of container PVC/ACLAR* film and Aluminium lidding foil. PVC/PVdC film and Aluminium foil. Blister packs of 10, 14, 15 20, 28, 30, 56, 60 and 100 capsules. Not all pack sizes may be marketed 6.6 Special precautions for disposal and other handling No special requirements
- Instruction Content
- ## Composition
2. Qualitative and quantitative composition Each capsule contains venlafaxine hydrochloride equivalent to 150mg of venlafaxine One prolonged release capsule contains 0.3968 mg of Sunset yellow, see section 4.4 For the full list of excipients, see section 6.1.
## Pharmaceutical Form
3. Pharmaceutical form Prolonged release capsules, hard. The capsules are dark orange / dark orange size '0' hard gelatin capsules having thick and thin radial circular band on the body in white ink and thick and thin radial circular band on the cap in white ink. The capsule is filled with 12 white to off-white round biconvex film coated mini tablets of 12.5mg.
## Clinical Particulars
4. Clinical particulars 4.1 Therapeutic indications The treatment of major depressive disorder For prevention of recurrence of major depressive episodes. Treatment of generalised anxiety disorder. Treatment of social anxiety disorder. Treatment of panic disorder, with or without agoraphobia. 4.2 Posology and method of administration Posology Major depressive episodes The recommended starting dose for prolonged-release venlafaxine is 75 mg given once daily. Patients not responding to the initial 75 mg/day dose may benefit from dose increases up to a maximum dose of 375 mg/day. Dosage increases can be made at intervals of 2 weeks or more. If clinically warranted due to symptom severity, dose increases can be made at more frequent intervals, but not less than 4 days. Because of the risk of dose-related adverse effects, dose increments should be made only after a clinical evaluation (see section 4.4). The lowest effective dose should be maintained. Patients should be treated for a sufficient period of time, usually several months or longer. Treatment should be reassessed regularly on a case-by-case basis. Longer-term treatment may also be appropriate for prevention of recurrence of major depressive episodes (MDE). In most of the cases, the recommended dose in prevention of recurrence of MDE is the same as the one used during the current episode. Antidepressive medicinal products should continue for at least six months following remission. Generalised anxiety disorder The recommended starting dose for prolonged-release venlafaxine is 75 mg given once daily. Patients not responding to the initial 75 mg/day dose may benefit from dose increases up to a maximum dose of 225 mg/day. Dosage increases can be made at intervals of 2 weeks or more. Because of the risk of dose-related adverse effects, dose increments should be made only after a clinical evaluation (see section 4.4). The lowest effective dose should be maintained. Patients should be treated for a sufficient period of time, usually several months or longer. Treatment should be reassessed regularly, on a case-by-case basis. Social anxiety disorder The recommended dose for prolonged-release venlafaxine is 75 mg given once daily. There is no evidence that higher doses confer any additional benefit. However, in individual patients not responding to the initial 75 mg/day, increases up to a maximum dose of 225 mg/day may be considered. Dosage increases can be made at intervals of 2 weeks or more. Because of the risk of dose-related adverse effects, dose increments should be made only after a clinical evaluation (see section 4.4). The lowest effective dose should be maintained. Patients should be treated for a sufficient period of time, usually several months or longer. Treatment should be reassessed regularly, on a case-by-case basis. Panic disorder It is recommended that a dose of 37.5 mg/day of prolonged-release venlafaxine be used for 7 days. Dosage should then be increased to 75 mg/day. Patients not responding to the 75 mg/day dose may benefit from dose increases up to a maximum dose of 225 mg/day. Dosage increases can be made at intervals of 2 weeks or more. Because of the risk of dose-related adverse effects, dose increments should be made only after a clinical evaluation (see section 4.4). The lowest effective dose should be maintained. Patients should be treated for a sufficient period of time, usually several months or longer. Treatment should be reassessed regularly, on a case-by-case basis. Elderly patients No specific dose adjustments of venlafaxine are considered necessary based on patient age alone. However, caution should be exercised in treating the elderly (e.g., due to the possibility of renal impairment, the potential for changes in neurotransmitter sensitivity and affinity occurring with aging). The lowest effective dose should always be used, and patients should be carefully monitored when an increase in the dose is required. Paediatric population Venlafaxine is not recommended for use in children and adolescents. Controlled clinical studies in children and adolescents with major depressive disorder failed to demonstrate efficacy and do not support the use of venlafaxine in these patients (see sections 4.4 and 4.8). The efficacy and safety of venlafaxine for other indications in children and adolescents under the age of 18 have not been established. Patients with hepatic impairment In patients with mild and moderate hepatic impairment, in general a 50% dose reduction should be considered. However, due to inter-individual variability in clearance, individualisation of dosage may be desirable. There are limited data in patients with severe hepatic impairment. Caution is advised, and a dose reduction by more than 50% should be considered. The potential benefit should be weighed against the risk in the treatment of patients with severe hepatic impairment. Patients with renal impairment Although no change in dosage is necessary for patients with glomerular filtration rate (GFR) between 30-70 ml/minute, caution is advised. For patients that require haemodialysis and in patients with severe renal impairment (GFR < 30 ml/min), the dose should be reduced by 50%. Because of inter-individual variability in clearance in these patients, individualisation of dosage may be desirable. Withdrawal symptoms seen on discontinuation of venlafaxine Abrupt discontinuation should be avoided. When stopping treatment with venlafaxine, the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see sections 4.4 and 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate. Method of administration For oral use. It is recommended that Vensir XL/Venlafaxine Morningside Prolonged Release Hard Capsules be taken with food, at approximately the same time each day. Capsules must be swallowed whole with fluid and not divided, crushed, chewed, or dissolved. Patients treated with venlafaxine immediate-release tablets may be switched to Vensir XL/Venlafaxine Morningside Prolonged Release Hard Capsules at the nearest equivalent daily dosage. For example, venlafaxine immediate-release tablets 37.5 mg twice daily may be switched to Vensir XL/Venlafaxine Morningside Prolonged Release Hard Capsules 75 mg once daily. Individual dosage adjustments may be necessary. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concomitant treatment with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serotonin syndrome with symptoms such as agitation, tremor and hyperthermia. Venlafaxine must not be initiated for at least 14 days after discontinuation of treatment with an irreversible MAOI. Venlafaxine must be discontinued for at least 7 days before starting treatment with an irreversible MAOI (see sections 4.4 and 4.5). 4.4 Special warnings and precautions for use Suicide/suicidal thoughts or clinical worsening Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Other psychiatric conditions for which Vensir XL/Venlafaxine Morningside Prolonged Release Hard Capsules is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders. 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 drugs 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 drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present Paediatric PopulationVensir XL/Venlafaxine Morningside Prolonged Release Hard Capsules 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. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking. Serotonin syndrome As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with venlafaxine treatment, particularly with concomitant use of other agents 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, buprenorphine, dextromethorphan, tapentadol, pethidine, methadone and pentazocine), with medicinal agents 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 NMS, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs and mental status changes. If concomitant treatment with venlafaxine and other agents 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 venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended. Narrow-angle glaucoma Mydriasis may occur in association with venlafaxine. 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 commonly reported with venlafaxine. In some cases, severely elevated blood pressure requiring immediate treatment has been reported in postmarketing 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 arrhythmia Venlafaxine 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 postmarketing experience, cases of QTc prolongation, Torsades de Pointes (TdP), ventricular tachycardia, and fatal cardiac arrhythmias 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 venlafaxine to patients at high risk of serious cardiac arrhythmia or QTc prolongation. Convulsions Convulsions may occur with venlafaxine therapy. As with all antidepressants, venlafaxine 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 venlafaxine. 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 Medicinal products that inhibit serotonin uptake may lead to reduced platelet function. Bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hepatoma, epistaxis, and petechiae to gastrointestinal and life-threatening haemorrhages. The risk of haemorrhage may be increased in patients taking venlafaxine. As with other serotonin-reuptake inhibitors, venlafaxine should be used cautiously in patients predisposed to bleeding, including patients on anticoagulants and platelet inhibitors. 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
## Pharmacological Properties
5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic Group: Other antidepressants ATC code: N06A X16 Vensir XL/Venlafaxine Morningside Prolonged Release Hard Capsules is a structurally novel antidepressant which is chemically unrelated to tricyclic, tetracyclic, or other available antidepressant agents. It is a racemate with two active enantiomers. Mechanism of action The mechanism of Vensir XL/Venlafaxine Morningside Prolonged Release Hard Capsules's antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the central nervous system. Preclinical studies have shown that venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV), are inhibitor of serotonin and noradrenaline reuptake. Venlafaxine also weakly inhibits dopamine uptake. Venlafaxine and its active metabolite reduce β-adrenergic responsiveness after both acute (single dose) and chronic administration. Venlafaxine ODV are very similar with respect to their overall action on neurotransmitter re-uptake and receptor binding. Venlafaxine has virtually no affinity for rat brain muscarinic, cholinergic, H1-histaminergic or α1-adrenergic receptors in vitro. Pharmacological activity at these receptors may be related to various side effects seen with other antidepressant medicinal products, such as anticholinergic, sedative and cardiovascular side effects. Venlafaxine does not possess monoamine oxidase (MAO) inhibitory activity. In vitro studies revealed that venlafaxine has virtually no affinity for opiate or benzodiazepine sensitive receptors. Clinical efficacy and safety Major depressive episodes The efficacy of venlafaxine immediate-release as a treatment for major depressive episodes was demonstrated in five randomised, double-blind, placebo-controlled, short-term trials ranging from 4 to 6 weeks duration, for doses up to 375 mg/day. The efficacy of venlafaxine prolonged-release as a treatment for major depressive episodes was established in two placebo-controlled, short-term studies for 8 and 12 weeks duration, which included a dose range of 75 to 225 mg/day. In one longer-term study, adult outpatients who had responded during an 8-week open trial on venlafaxine prolonged-release (75, 150, or 225 mg) were randomised to continuation of their same venlafaxine prolonged-release dose or to placebo, for up to 26 weeks of observation for relapse. In a second longer-term study, the efficacy of venlafaxine in prevention of recurrent depressive episodes for a 12-month period was established in a placebo-controlled double-blind clinical trial in adult outpatients with recurrent major depressive episodes who had responded to venlafaxine treatment (100 to 200 mg/day, on a twice daily schedule) on the last episode of depression. Generalised anxiety disorder The efficacy of venlafaxine prolonged-release capsules as a treatment for generalised anxiety disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies (75 to 225 mg/day), one 6-month, placebo-controlled, fixed-dose study (75 to 225 mg/day), and one 6-month, placebo-controlled, flexible-dose study (37.5, 75, and 150 mg/day) in adult outpatients. While there was also evidence for superiority over placebo for the 37.5 mg/day dose, this dose was not as consistently effective as the higher doses. Social anxiety disorder The efficacy of venlafaxine prolonged-release capsules as a treatment for social anxiety disorder was established in four double-blind, parallel-group, 12-week, multi-center, placebo-controlled, flexible-dose studies and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study in adult outpatients. Patients received doses in a range of 75 to 225 mg/day. There was no evidence for any greater effectiveness of the 150 to 225 mg/day group compared to the 75 mg/day group in the 6-month study. Panic disorder The efficacy of venlafaxine prolonged-release capsules as a treatment for panic disorder was established in two double-blind, 12-week, multi-center, placebo-controlled studies in adult outpatients with panic disorder, with or without agoraphobia. The initial dose in panic disorder studies was 37.5 mg/day for 7 days. Patients then received fixed doses of 75 or 150 mg/day in one study and 75 or 225 mg/day in the other study. Efficacy was also established in one long-term double-blind, placebo-controlled, parallel-group study of the long-term safety, efficacy, and prevention of relapse in adult outpatients who responded to open-label treatment. Patients continued to receive the same dose of venlafaxine prolonged-release that they had taken at the end of the open-label phase (75, 150, or 225 mg). Cardiac electrophysiology In a dedicated thorough QTc study in healthy subjects, venlafaxine did not prolong the QT interval to any clinically relevant extent at a supra-therapeutic dose of 450 mg/day (given as 225 mg twice daily). However, postmarketing cases of QTc prolongation/TdP and ventricular arrhythmia have been reported, especially in overdose or in patients with other risk factors for QTc prolongation/TdP (see sections 4.4, 4.8 and 4.9). 5.2 Pharmacokinetic properties Venlafaxine is extensively metabolised, primarily to the active metabolite, O-desmethylvenlafaxine (ODV). Mean ± SD plasma half-lives of venlafaxine and ODV are 5±2 hours and 11±2 hours, respectively. Steady-state concentrations of venlafaxine and ODV are attained within 3 days of oral multiple-dose therapy. Venlafaxine and ODV exhibit linear kinetics over the dose range of 75 mg to 450 mg/day. Absorption At least 92% of venlafaxine is absorbed following single oral doses of immediate-release venlafaxine. Absolute bioavailability is 40% to 45% due to presystemic metabolism. After immediate-release venlafaxine administration, the peak plasma concentrations of venlafaxine and ODV occur in 2 and 3 hours, respectively. Following the administration of venlafaxine prolonged-release capsules, peak plasma concentrations of venlafaxine and ODV are attained within 5.5 hours and 9 hours, respectively. When equal daily doses of venlafaxine are administered as either an immediate-release tablet or prolonged-release capsule, the prolonged-release capsule provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet. Food does not affect the bioavailability of venlafaxine and ODV. Distribution Venlafaxine and ODV are minimally bound at therapeutic concentrations to human plasma proteins (27% and 30%, respectively). The volume of distribution for venlafaxine at steady-state is 4.4±1.6 L/kg following intravenous administration. Biotransformation Venlafaxine undergoes extensive hepatic metabolism. In vitro and in vivo studies indicate that venlafaxine is biotransformed to its major active metabolite, ODV, by CYP2D
## Pharmaceutical Particulars
6. Pharmaceutical particulars 6.1 List of excipients • Microcrystalline cellulose • Copovidone • Ethyl cellulose • Magnesium stearate • Povidone • Colloidal Silicon Dioxide • Talc Capsule shell components • Gelatin • Titanium dioxide (E171) • Brilliant blue FCF (E133) • Allura red (E129) • Sunset yellow FCF (E110) Printing ink • Shellac • Propylene glycol • Sodium hydroxide • Povidone • Titanium dioxide (E171) 6.2 Incompatibilities Not Applicable 6.3 Shelf life 3 years 6.4 Special precautions for storage Do not store above 25°C Store in the original container to protect from moisture 6.5 Nature and contents of container PVC/ACLAR* film and Aluminium lidding foil. PVC/PVdC film and Aluminium foil. Blister packs of 10, 14, 15 20, 28, 30, 56, 60 and 100 capsules. Not all pack sizes may be marketed 6.6 Special precautions for disposal and other handling No special requirements
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