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Drug Details

Winfex XL 75mg

• Generic Name
  venlafaxine hydrochloride
• Presentation
  Prolonged Release capsules Winfex XL 75mg Capsules are opaque flesh capsules containing two 37.5mg tablets.
• Description
  Each prolonged release capsule contains venlafaxine hydrochloride equivalent to 75mg of venlafaxine.
• Indications
  Major depressive disorder Winfex XL is indicated for the treatment of moderate to severe major depressive disorder including depression accompanied by anxiety. All patients should be evaluated for the risk of suicidality and monitored for clinical worsening. Following an initial response Winfex XL is indicated for the prevention of relapses of the initial episode of depression or for the prevention of the recurrence of new episodes.
• Adult Dosage
  

  Treatment with Winfex XL should not be started until 14 days after discontinuing a monoamine oxidase inhibitor (MAOI).

  Do not crush, chew, or place the capsule in water.

  Depression:

  The recommended dose is 75mg per day given once daily. Most patients respond to this dose. It is recommended that Winfex XL be taken with food.

  If, after an adequate trial and evaluation, further clinical improvement is required, the dose may be increased to 150mg per day given once daily. There may be an increased risk of side effects at higher doses and dose increments should be made only after a clinical evaluation and after at least 3-4 weeks of therapy. The lowest effective dose should be maintained.

  In more severely depressed or hospitalised patients, and under close supervision of a physician, the daily dose may then be increased to the maximum recommended dose of 225mg given once daily. In those more severely depressed or hospitalised patients who require daily doses of 300mg or more, treatment should be initiated under specialist supervision including shared care arrangements. The maximum recommended dose is 375mg per day.

  The dose should then be gradually reduced, to the minimum effective dose consistent with patient response and tolerance. A limited number of capsules should be provided to reduce the risk from overdose .

  Usually, the dosage for prevention of relapse or for prevention of recurrence of a new episode is similar to that used during the index episode. Patients should be re-assessed regularly in order to evaluate the benefit of long-term therapy.

  Depressed patients who are currently being treated with Venlafaxine Tablets may be switched to Winfex XL. For example, a patient receiving Venlafaxine Tablets 37.5mg b.d. would receive Winfex XL 75mg o.d. When switching, individual dosage adjustments may be necessary.

  Patients at increased risk for suicide:

  Patients with increased risk factors for suicide should be carefully evaluated for the presence or worsening of suicide-related behaviour and a limited number of capsules should be provided to reduce the risk from overdose. A maximum of two weeks supply should be considered in these patients at initiation of treatment, during any dosage adjustment and until improvement occurs.

  Patients with Renal or Hepatic Impairment:

  For patients with mild renal impairment (GFR>30ml/minute) or mild hepatic impairment (PT <14 seconds), no change in dosage is necessary.

  For patients with moderate renal impairment (GFR 10-30ml/minute) or moderate hepatic impairment (PT 14-18 seconds), the dose should be reduced by 50%. This dose may be given once daily due to the longer half-lives of venlafaxine and O-desmethylvenlafaxine (ODV) in these patients.

  Insufficient data are available to support the use of Winfex XL in patients with severe renal impairment (GFR <10ml/minute) or severe hepatic impairment (PT>18 seconds).

  Maintenance/Continuation/Extended Treatment:

  The physician should periodically re-evaluate the usefulness of long-term treatment with Winfex XL for the individual patient. It is generally agreed that acute episodes of major depression require several months or longer of sustained therapy. Winfex XL has been shown to be efficacious during long-term (up to 12 months) treatment.

  In clinical trials venlafaxine was demonstrated to be effective for preventing relapse, or recurrence of new episodes, in patients responding to venlafaxine treatment during the index episode.

  Withdrawal symptoms seen on discontinuation of venlafaxine

  Abrupt discontinuation should be avoided. Following treatment with daily doses of venlafaxine greater than 75mg for more than one week, it is recommended that when discontinuing treatment the dose should be gradually reduced over at least a further week. If high doses have been used for more than 6 weeks tapering over at least a 2 week period is recommended. 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.

• Child Dosage
  

  Controlled clinical studies in children and adolescents with Major Depressive Disorder failed to demonstrate efficacy and do not support the use of Winfex XL in these patients.

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

• Elderly Dosage
  

  No adjustment in the usual dosage is recommended for elderly patients. However, as with any therapy, caution should be exercised in treating the elderly (e.g. due to the possibility of renal impairment. See also dosage recommendations for renal impairment). The lowest effective dose should always be used and patients should be carefully monitored when an increase in the dose is required.

• Contra Indications
  

  1. Known hypersensitivity to venlafaxine or any other component of the product.

  2. Concomitant use of venlafaxine with monoamine oxidase inhibitors.

  3. Winfex XL should not be used in children and adolescents under the age of 18 years with Major Depressive Disorder.

  4. Venlafaxine should not be used in patients with an identified very high risk of a serious cardiac ventricular arrhythmia (e.g. those with a significant left ventricular dysfunction, NYHA Class III/IV) or uncontrolled hypertension.

• 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

  Venlafaxine 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, hallycinations, 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 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, 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 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. 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.

   

  Diabetes

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

• Interactions
  

  MAOIs: Adverse reactions, some serious, have been reported when venlafaxine therapy is initiated soon after discontinuation of an MAOI, and when an MAOI is initiated soon after discontinuation of venlafaxine. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, and hyperthermia with features resembling neuroleptic malignant syndrome, seizures and death. Do not use Winfex XL in combination with a MAOI, or within at least 14 days of discontinuing MAOI treatment. Allow at least 7 days after stopping Winfex XL before starting an MAOI.

  Serotonergic drugs: Based on the known mechanism of action of venlafaxine and the potential for serotonergic syndrome, caution is advised when venlafaxine is co-administered with drugs that may affect the serotonergic neurotransmitter systems (such as triptans, SSRIs or lithium). 

  Lithium: Reports have been received of an interaction between lithium and venlafaxine leading to increased lithium levels.

  Imipramine/desipramine: The metabolism of imipramine and its metabolite 2-OH-imipramine were unaffected by venlafaxine although the total renal clearance of 2-hydroxydesipramine was reduced and desipramine AUC and C_max were increased by approximately 35%.

  Haloperidol: In a pharmacokinetic study co-administration of venlafaxine with a single 2mg oral dose of haloperidol resulted in a 42% decrease in renal clearance, a 70% increase in AUC and an 88% increase in C_max for haloperidol.The elimination half-life remained unchanged.

  Diazepam: The pharmacokinetic profiles of venlafaxine and ODV were not significantly altered by the administration of diazepam. Venlafaxine has no effect on the pharmacokinetic profile of diazepam or on the psychomotor or psychometric effects induced by diazepam.

  Clozapine: Increased levels of clozapine, that were temporally associated with adverse events, including seizures, have been reported following the addition of venlafaxine.

  Alcohol: Venlafaxine has been shown not to increase the impairment of mental or motor skills caused by ethanol. However, as with all CNS-active drugs, patients should be advised to avoid alcohol consumption while taking Winfex XL.

  ECT: There is little clinical experience of the concurrent use of venlafaxine with ECT. As prolonged seizure activity has been reported with concomitant SSRI antidepressants, caution is advised.

  Drugs metabolised by Cytochrome P450 isoenzymes: The major elimination pathways for venlafaxine are through CYP2D6 and CYP3A4. Venlafaxine is primarily metabolised to its active metabolite, ODV, by the cytochrome P450 enzyme CYP2D6. Although CYP3A4 is a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, there is potential for a clinically significant drug interaction between inhibitors of CYP3A4 mediated metabolism and venlafaxine as this could result in increased venlafaxine plasma levels in poor CYP2D6 metabolisers. Therefore, potent CYP3A4 inhibitors (e.g. ketoconazole, erythromycin) or drug combinations that inhibit both CYP3A4 and CYP2D6 should only be co-administered with venlafaxine if strictly indicated.

  Effects of venlafaxine on the metabolism of other drugs metabolised by cytochrome P450: Studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP1A2, CYP2C9 or CYP3A4. This was confirmed by in vivo studies with the following drugs: alprazolam (CYP3A4), caffeine (CYP1A2), carbamazepine (CYP3A4) and diazepam (CYP3A4 and CYP2C19).

  Cimetidine:Cimetidine inhibited the first-pass metabolism of venlafaxine but had no significant effect on the formation or elimination of ODV, which is present in much greater quantities in the systemic circulation. No dosage adjustment therefore seems necessary when Winfex XL is co-administered with cimetidine. For elderly patients, or patients with hepatic dysfunction the interaction could potentially be more pronounced, and for such patients clinical monitoring is indicated when Winfex XL is administered with cimetidine.

  Warfarin: Potentiation of anticoagulant effects including increases in PT or INR have been reported in patients taking warfarin following the addition of venlafaxine.

  Indinavir: A pharmacokinetic study with indinavir has shown a 28% decrease in AUC and a 36% decrease in C_max for indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this interaction is not known.

• 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, Thrombocytopenia, Blood dyscrasias, (including agranulocytosis, aplastic anaemia, neutropenia and pancytopenia)
  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, Paraesthesia, 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 dyskinesia), Tardive dyskinesia, Suicidal ideation and behaviours**, Vertigo, Aggression
  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 (including 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	Urinary incontinence
  Body as a Whole		Asthenia (figure), Chills	Angioedema, 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 of 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 the 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.