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Drug Details

Depefex 75mg & 150mg XL Capsules

• Presentation
  Prolonged-release capsules, hard. Depefex 75 mg XL Capsules are white opaque capsules containing white or whitish pellets. Depefex 150 mg XL Capsules are natural transparent capsules containing white or whitish pellets.
• Description
  Each prolonged release capsule contains 75 mg or 150 mg of venlafaxine as venlafaxine hydrochloride. Venlafaxine is chemically defined as (R/S)-1-[(2-dimethylamino)-1-(4-methoxy phenyl) ethyl] cyclohexanol hydrochloride. Depefex Capsules contain sucrose
• Indications
  

  Treatment of major depressive episodes.

  For prevention of recurrence of major depressive episodes.

• Adult Dosage
  

  Major depressive episodes

  The recommended starting dose for prolonged-release venlafaxine is 75mg given once daily. Patients not responding to the initial 75mg/day dose may benefit from dose increases up to a maximum dose of 375mg/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. 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.

  Use in 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.

  Use in children and adolescents under the age of 18 years

  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.

  The efficacy and safety of venlafaxine for other indications in children and adolescents under the age of 18 have not been established.

  Use in 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.

  Use in patients with renal impairment

  Although no change in dosage is necessary for patients with glomerular filtration rate (GFR) between 30-70ml/minute, caution is advised. For patients that require haemodialysis and in patients with severe renal impairment (GFR < 30ml/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. 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.

  For oral use.

  It is recommended that venlafaxine prolonged-release 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 venlafaxine prolonged-release capsules at the nearest equivalent daily dosage. For example, venlafaxine immediate-release tablets 37.5mg twice daily may be switched to venlafaxine prolonged-release capsules 75mg once daily. Individual dosage adjustments may be necessary.

  Venlafaxine prolonged-release capsules contain spheroids, which release the active substance slowly into the digestive tract. The insoluble portion of these spheroids is eliminated and may be seen in faeces.

• Contra Indications
  

   Hypersensitivity to the active substance or to any of the excipients.

  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.
   

• Special Precautions
  

  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 venlafaxine 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.

  Use in children and adolescents under 18 years of age

  Depefex 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, such as MAO-inhibitors, that may affect the serotonergic neurotransmitter systems.

  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).

  
  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 preexisting hypertension should be controlled before initation 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, fatal cardiac arrhythmias have been reported with the use of venlafaxine, especially in overdose. The balance of risks and benefits should be considered before prescribing venlafaxine to patients at high risk of serious cardiac arrhythmia.

  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. The risk of skin and mucous membrane bleeding, including gastrointestinal 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.

  Serum cholesterol

  Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled clinical trials. Measurement of serum cholesterol levels should be considered during long-term treatment.

  Co-administration with weight loss agents

  The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of venlafaxine and weight loss agents is not recommended. Venlafaxine is not indicated for weight loss alone or in combination with other products.

  Mania/hypomania

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

  Aggression

  Aggression may occur in a small number of patients who have received antidepressants, including venlafaxine. This has been reported under initiation, dose changes and discontinuation of treatment.

  As with other antidepressants, venlafaxine should be used cautiously in patients with a history of aggression.

  Discontinuation of treatment

  Withdrawal symptoms, when treatment is discontinued, are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials, adverse events seen on treatment discontinuation (tapering and post-tapering) occurred in approximately 31% of patients treated with venlafaxine and 17% of patients taking placebo.

  The risk of withdrawal symptoms may be dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor and headache are the most commonly reported reactions. Generally, these symptoms are mild to moderate; however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that venlafaxine should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs.

  Akathisia/psychomotor restlessness

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

  Dry mouth

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

• Interactions
  

  Monoamine Oxidase Inhibitors (MAOI)

  Irreversible non-selective MAOIs

  Venlafaxine must not be used in combination with irreversible non-selective MAOIs. Venlafaxine must not be initiated for at least 14 days after discontinuation of treatment with an irreversible nonselective MAOI. Venlafaxine must be discontinued for at least 7 days before starting treatment with an irreversible non-selective MAOI.

  Reversible, selective MAO-A inhibitor (moclobemide)

  Due to the risk of serotonin syndrome, the combination of venlafaxine with a reversible and selective MAOI, such as moclobemide, is not recommended. Following treatment with a reversible MAO-inhibitor, a shorter withdrawal period than 14 days may be used before initiation of venlafaxine treatment. It is recommended that venlafaxine should be discontinued for at least 7 days before starting treatment with a reversible MAOI.

  Reversible, non-selective MAOI (linezolid)

  The antibiotic linezolid is a weak reversible and non-selective MAOI and should not be given to patients treated with venlafaxine.

  Severe adverse reactions have been reported in patients who have recently been discontinued from an MAOI and started on venlafaxine, or have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, and hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death.

  Serotonin syndrome

  As with other serotonergic agents, serotonin syndrome may occur with venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, SNRIs, lithium, sibutramine, tramadol, or St. John's Wort [Hypericum perforatum]), with medicinal agents which impair metabolism of serotonin (including MAOIs), or with serotonin precursors (such as tryptophan supplements).

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

  CNS-active substances

  The risk of using venlafaxine in combination with other CNS-active substances has not been systematically evaluated. Consequently, caution is advised when venlafaxine is taken in combination with other CNS-active substances.

  Ethanol

  Venlafaxine has been shown not to increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS-active substances, patients should be advised to avoid alcohol consumption.

  Effect of other medicinal products on venlafaxine

  Ketoconazole (CYP3A4 inhibitor)

  A pharmacokinetic study with ketoconazole in CYP2D6 extensive (EM) and poor metabolisers (PM) resulted in higher AUC of venlafaxine (70% and 21% in CYP2D6 PM and EM subjects, respectively) and O-desmethylvenlafaxine (33% and 23% in CYP2D6 PM and EM subjects, respectively) following administration of ketoconazole. Concomitant use of CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, voriconazole, posaconazole, ketoconazole, nelfinavir, ritonavir, saquinavir, telithromycin) and venlafaxine may increase levels of venlafaxine and O-desmethylvenlafaxine. Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly.

  Effect of venlafaxine on other medicinal products

  Lithium

  Serotonin syndrome may occur with the concomitant use of venlafaxine and lithium (see Serotonin syndrome).

  Diazepam

  Venlafaxine has no effects on the pharmacokinetics and pharmacodynamics of diazepam and its active metabolite, desmethyldiazepam. Diazepam does not appear to affect the pharmacokinetics of either venlafaxine or O-desmethylvenlafaxine. It is unknown whether a pharmacokinetic and/or pharmacodynamic interaction with other benzodiazepines exists.

  Imipramine

  Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. There was a dose-dependent increase of 2-OH-desipramine AUC by 2.5 to 4.5-fold when venlafaxine 75 mg to 150 mg daily was administered. Imipramine did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown. Caution should be exercised with co-administration of venlafaxine and imipramine.

  Haloperidol

  A pharmacokinetic study with haloperidol has shown a 42% decrease in total oral clearance, a 70% increase in AUC, an 88% increase in Cmax, but no change in half-life for haloperidol. This should be taken into account in patients treated with haloperidol and venlafaxine concomitantly. The clinical significance of this interaction is unknown.

  Risperidone

  Venlafaxine increased the risperidone AUC by 50%, but did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9 hydroxyrisperidone). The clinical significance of this interaction is unknown.

  Metoprolol

  Concomitant administration of venlafaxine and metoprolol to healthy volunteers in a pharmacokinetic interaction study for both medicinal products resulted in an increase of plasma concentrations of metoprolol by approximately 30-40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. The clinical relevance of this finding in hypertensive patients is unknown. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite,O-desmethylvenlafaxine. Caution should be exercised with co-administration of venlafaxine and metoprolol.

  Indinavir

  A pharmacokinetic study with indinavir has shown a 28% decrease in AUC and a 36% decrease in Cmax for indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown.

• Adverse Drug Reactions
  

  The most commonly (>1/10) reported adverse reactions in clinical studies were nausea, dry mouth, headache and sweating (including night sweats).

  Adverse reactions are listed below by system organ class and frequency.

  Frequencies are defined as: very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000), not known (cannot be estimated from the available data).

   

  Body System	Very Common	Common	Uncommon	Rare	Not Known
  Haematological / Lymphatic			Ecchymosis, Gastrointestinal haemorrhage		Mucous membrane bleeding, Prolonged bleeding time, Thrombocytopaenia , Blood dyscrasias, (including agranulocytosis, aplastic anaemia, neutropaenia and pancytopaenia)
  Metabolic/ Nutritional		Serum cholesterol increased, Weight loss	Weight gain		Abnormal liver function tests, Hyponatraemia, Hepatitis, Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), Prolactin increased
  Nervous	Dry mouth (10.0%), Headache (30.3%)*	Abnormal dreams, Decreased libido, Dizziness, Increased muscle tonus (hypertonia), Insomnia, Nervousness, Paresthesia, Sedation, Tremor, Confusion, Depersonalisation	Apathy, Hallucinations, Myoclonus, Agitation, Impaired coordination and balance	Akathisia/ Psychomotor restlessness, Convulsion, Manic reaction	Neuroleptic Malignant Syndrome (NMS), Serotonergic syndrome, Delirium, Extrapyramidal reactions (including dystonia and dyskinaesia), Tardive dyskinaesia, Suicidal ideation and behaviours**
  Special Senses		Abnormality of accommodation, Mydriasis, Visual disturbance,	Altered taste sensation, Tinnitus		Angle-closure glaucoma
  Cardiovascular		Hypertension, Vasodilatation (mostly hot flashes/flushes), Palpitations	Postural hypotension, Syncope, Tachycardia		Hypotension, QT prolongation, Ventricular fibrillation, Ventricular tachycardia (including torsade de pointes)
  Respiratory		Yawning			Pulmonary eosinophilia
  Digestive	Nausea (20.0%)	Appetite decreased (anorexia), Constipation, Vomiting	Bruxism, Diarrhoea		Pancreatitis
  Skin	Sweating (includin g night sweats) [12.2%]		Rash, Alopecia		Erythema multiforme, Toxic epidermal necrolysis, Stevens- Johnson syndrome, Pruritus, Urticaria
  Musculoskeletal					Rhabdomyolysis
  Urogenital		Abnormal ejaculation/orgasm (males), Anorgasmia, Erectile dysfunction (impotence), Urination impaired (mostly hesitancy), Menstrual disorders associated with increased bleeding or increased irregular bleeding (e.g., menorrhagia, metrorrhagia), Pollakiuria	Abnormal orgasm (females), Urinary retention
  Body as a Whole		Asthenia (fatigue), Chills	Photosensitivity reaction		Anaphylaxis

  *In pooled clinical trials, the incidence of headache was 30.3% with venlafaxine versus 31.3% with placebo.

  **Cases of suicidal ideation and suicidal behaviours have been reported during venlafaxine therapy or early after treatment discontinuation.

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

   

  Paediatric patients

  In general, the adverse reaction profile of venlafaxine (in placebo-controlled clinical trials) in children and adolescents (ages 6 to 17) was similar to that seen for adults. As with adults, decreased appetite, weight loss, increased blood pressure, and increased serum cholesterol were observed.

  In paediatric clinical trials the adverse reaction suicidal ideation was observed. There were also increased reports of hostility and, especially in major depressive disorder, self-harm.

  Particularly, the following adverse reactions were observed in paediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia.