Exsira 50mg. 100mg Tablet

Major depressive disorder: EXSIRA tablets are indicated for the treatment of major depressive disorder (MDD).

The recommended dose for EXSIRA is 50 mg once daily, with or without food, with a maximum dose of 100 mg per day. The dose increase should occur gradually and at an interval of not less than 7 days.

Use in patients with renal impairment: The recommended starting dose in patients with severe renal impairment (24-hr CrCl < 30ml/min) or end-stage renal disease (ESRD) is 50 mg every other day. Because of individual variability in clearance in these patients, individualisation of dosage may be desirable. Supplemental doses should not be given to patients after dialysis.

Use in patients with hepatic impairment: No dosage adjustment is necessary for patients with hepatic impairment.

Paediatric use: Safety and efficacy in patients less than 18 years of age has not been established.

Use in elderly patients: No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of EXSIRA should be considered when determining dose.

Hypersensitivity to EXSIRA, venlafaxine hydrochloride or to any excipients in the EXSIRA formulation. EXSIRA is an inhibitor of both norepinephrine and serotonin reuptake. EXSIRA must not be used in combination with a monoamine oxidase inhibitor (MAOI), or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of EXSIRA, at least 7 days should be allowed after stopping EXSIRA before starting an MAOI. Severe adverse reactions have been reported when therapy is initiated with SSRI/SNRI medicines such as EXSIRA soon after discontinuation of an MAOI and when an MAOI is initiated soon after discontinuation of SSRI/SNRI medicines. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures and death. Children less than 18 years of age, as safety and efficacy have not been established.

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

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

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

Short-term trials did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond the age of 24 years; there was a reduction in the risk of suicidality with antidepressants compared to placebo in adults age 65 years and older. There have been reports of hostility, suicidal ideation and self-harm with use of SSRIs in children under the age of 18 years.

Paediatric use: Safety and efficacy in children under 18 years of age has not been established. In clinical trials of SSRIs and SNRIs in major depressive disorder, there were increased reports of hostility and suicide-related adverse events such as suicidal ideation and self-harm.

Mania/hypomania: In clinical trials, mania was reported for 0.03 % of patients treated with EXSIRA. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. EXSIRA should be used cautiously in patients with a history or family history of mania or hypomania.

Serotonin syndrome: The development of a potentially life-threatening serotonin syndrome may occur with EXSIRA treatment, particularly with concomitant use of other serotonergic medicines (including SSRIs, SNRIs and triptans) and with medicines that impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g. agitation, hallucinations, and coma), autonomic instability (e.g. tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g. nausea, vomiting, and diarrhoea). The concomitant use of EXSIRA with serotonin precursors (such as tryptophan supplements) is not recommended.

Narrow-angle glaucoma: Mydriasis has been reported in association with EXSIRA; therefore, patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored.

Ischaemic cardiac adverse events: In clinical trials, there were uncommon reports of ischaemic cardiac adverse events, including myocardial ischaemia, myocardial infarction, and coronary occlusion requiring revascularisation; these patients had multiple underlying cardiac risk factors. More patients experienced these events during EXSIRA treatment as compared to placebo.

Discontinuation symptoms: Adverse reactions reported in association with abrupt discontinuation, dose reduction or tapering of treatment in MDD clinical trials at a rate of u2265 2 % include: dizziness, withdrawal syndrome, nausea and headache. In general, discontinuation symptoms occurred more frequently with longer duration of therapy.

Monoamine oxidase inhibitors (MAOI): Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on antidepressants with pharmacological properties similar to EXSIRA (SNRIs or SSRIs), or who have recently had SNRI or SSRI therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures and death. Concomitant use of EXSIRA in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated.

Central nervous system (CNS)-active agents: The risk of using EXSIRA in combination with other CNS-active medicines has not been systematically evaluated. Consequently, caution is advised when EXSIRA is taken in combination with other CNS-active medicines.

Serotonin syndrome: Serotonin syndrome, a potentially life-threatening condition, may occur with EXSIRA treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, other SNRIs, lithium, sibutramine, tramadol, St. Johnu2019s Wort [Hypericum perforatum], pethidine), with medicines that impair metabolism of serotonin (such as MAOIs, including linezolid [an antibiotic which is a reversible non-selective MAOI]), or with serotonin precursors (such as tryptophan supplements). Serotonin syndrome symptoms may include mental status changes, autonomic instability, neuromuscular aberrations and/or gastrointestinal symptoms.

Ethanol: Patients should be advised to avoid alcohol consumption while taking EXSIRA.

Potential for other medicines to affect EXSIRA: Inhibitors of CYP3A4: CYP3A4 is involved in EXSIRA elimination. In a clinical trial, ketoconazole (200 mg twice daily) increased the area under the concentration vs. time curve (AUC) of EXSIRA (400 mg single dose) by approximately 43 %, a weak interaction and C max by about 8 %. Concomitant use of EXSIRA with potent inhibitors of CYP3A4 may result in higher exposure to EXSIRA.

Inhibitors of other CYP enzymes: Based on in vitro data, medicines that inhibit CYP isozymes 1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19, and 2E1 are not expected to have significant impact on the pharmacokinetic profile of EXSIRA.

Potential for EXSIRA to affect other medicines: Medicines metabolised by CYP2D6: Clinical trials have shown that EXSIRA is a weak inhibitor of CYP2D6 at a dose of 100 mg daily. When EXSIRA was administered at a dose of 100 mg daily in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased approximately 17 %. When 400 mg was administered, the AUC of desipramine increased approximately 90 %. When EXSIRA was administered at a dose of 100 mg daily in conjunction with a single 60 mg dose of codeine, a CYP2D6 substrate metabolised to morphine, the AUC of codeine was unchanged, the AUC of morphine decreased approximately 8 %. Concomitant use of EXSIRA with a medicine metabolised by CYP2D6 may result in increased concentrations of that medicine and decreased concentrations of its CYP2D6 metabolites.

Medicines metabolised by CYP3A4: In vitro, EXSIRA does not inhibit or induce the CYP3A4 isozymes. In a clinical trial, when EXSIRA was administered (at a dose of 400 mg daily) in conjunction with a single 4 mg dose of midazolam, a CYP3A4 substrate, the AUC of midazolam decreased by approximately 31 %. In a second study, EXSIRA 50 mg daily was co-administered with a single 4 mg dose of midazolam. The AUC and C max of midazolam decreased by approximately 29 % and 14 %, respectively. Concomitant use of EXSIRA with a medicine metabolised by CYP3A4 may result in lower exposures to that medicine.

Medicines metabolised by a combination of both CYP2D6 and CYP3A4 (tamoxifen and aripiprazole): Clinical studies have shown that EXSIRA (100 mg daily) does not have a clinically relevant effect on medicines metabolised by a combination of both CYP2D6 and CYP3A4 enzymes.

EXSIRA must not be administered to pregnant or lactating women. Safety during human pregnancy and lactation has not been established. If EXSIRA is used until, or shortly before birth, discontinuation effects in the newborn may occur. Complications, including the need for respiratory support, tube feeding or prolonged hospitalisation, have been reported in neonates exposed to SNRIs or SSRIs late in the third trimester. Such complications can arise immediately upon delivery. Patients should be advised to notify their doctor if they become pregnant or intend to become pregnant during therapy.

Lactation: EXSIRA (O-desmethylvenlafaxine) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from EXSIRA, a decision should be made whether or not to discontinue nursing or to discontinue EXSIRA, taking into account the importance of the medicine to the mother.

EXSIRA may impair judgement, thinking and motor skills. Therefore, patients should be cautioned about their ability to drive or operate hazardous machinery.

Adverse reactions are categorised by body system and listed in order of decreasing frequency using the following definitions: Expected frequency of adverse reactions is presented in CIOMS frequency categories: Very common: u2265 10 %, Common: u2265 1 % and < 10 %, Uncommon: u2265 0,1 % and < 1 %, Rare: u2265 0,01 % and < 0,1 %, Very rare: < 0,01 %.

System Organ Class Frequency Side effect

• Cardiac disorders Common Palpitations, tachycardia
• Ear and labyrinth disorders Common Tinnitus
• Eye disorders Common Blurred vision, mydriasis
• Gastrointestinal disorders Very common Nausea, dry mouth, constipation
• Common Diarrhoea, vomiting
• General disorders and administration site conditions Common Fatigue, chills, asthenia, feeling jittery, irritability
• Immune system disorders Uncommon Hypersensitivity
• Investigations Common Increased weight, increased blood pressure, decreased weight
• Uncommon Increased blood cholesterol, increased blood triglycerides, abnormal liver function test, increased blood prolactin
• Metabolism and nutritional disorders Common Decreased appetite
• Rare Hyponatraemia
• Musculoskeletal, connective tissue Common Musculoskeletal stiffness and bone disorders
• Nervous system disorders Very common Dizziness, headache
• Common Somnolence, tremor, paraesthesia, dysgeusia, disturbance in attention, vertigo
• Uncommon Syncope
• Rare Convulsion, dystonia
• Psychiatric disorders Very common Insomnia
• Common Anxiety, abnormal dreams, nervousness, decreased libido, anorgasmia
• Uncommon Withdrawal syndrome, abnormal orgasm, depersonalisation
• Rare Hypomania, hallucinations
• Renal and urinary disorders Uncommon Urinary hesitation, proteinuria, urinary retention
• Reproductive system and breast disorders Common Erectile dysfunction*, delayed ejaculation*, ejaculation failure*
• Uncommon Ejaculation disorder*, sexual dysfunction
• Respiratory, thoracic and mediastinal disorders Common Yawning
• Uncommon Epistaxis
• Skin and subcutaneous tissue disorders Very common Hyperhidrosis
• Common Rash
• Uncommon Alopecia
• Rare Photosensitivity reaction, angioedema
• Not known Stevens-Johnson syndrome**
• Vascular disorders Common Hot flush
• Uncommon Orthostatic hypotension (see WARNINGS AND SPECIAL PRECAUTIONS), peripheral coldness

*Frequency is calculated based on men only

**Adverse reaction identified during post-approval use

There is limited clinical experience with EXSIRA overdosage in humans. No specific antidotes for EXSIRA are known. Induction of emesis is not recommended. Because of the moderate volume of distribution of this medicine, forced diuresis, dialysis, haemoperfusion, and exchange transfusion are unlikely to be of benefit. Treatment should consist of those general measures employed in the management of overdosage with any SSRI/SNRI. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered.