Mylan Venlafaxine Xl 75 mg, 150 mg Capsule

MYLAN VENLAFAXINE XL is indicated for the treatment of depression, including depression with associated anxiety. MYLAN VENLAFAXINE XL is indicated for the prevention of relapses of an episode of depression in patients responding to an initial 6 to 8 weeks treatment. In patients responding to 6 months of relapse prevention, MYLAN VENLAFAXINE XL may be used to prevent recurrence. Safety and efficacy beyond one year have not been demonstrated in clinical studies.

Posology

• The usual recommended dose for MYLAN VENLAFAXINE XL is 75 mg given once daily.
• If after several weeks further clinical improvement is required, the dose may be increased to 150 mg, given once daily.
• If needed, the dose can be further increased up to 225 mg given once daily.
• Dose increments should be made at intervals of approximately 2 weeks or more, but not less than 4 days.
• It is recommended that MYLAN VENLAFAXINE XL be taken with food.
• Each capsule should be swallowed whole with fluid.
• Do not divide, crush, chew or place capsule in water.
• MYLAN VENLAFAXINE XL should be administered once daily, at approximately the same time either morning or in the evening. The extended-release formulation allows venlafaxine to be released slowly into the digestive tract.

Special populations

• Elderly population: No specific dosage adjustments of MYLAN VENLAFAXINE XL are recommended based on the patient's age.
• Patients with renal impairment: Patients with renal impairment should receive lower doses of MYLAN VENLAFAXINE XL. The total daily dose of MYLAN VENLAFAXINE XL should be reduced by 25 u2013 50 % for patients with renal impairment with a glomerular filtration rate (GFR) of 10 u2013 70 mL/min. The total daily dose of MYLAN VENLAFAXINE XL should be reduced by 50 % in haemodialysis patients. Because of individual variability in clearance in these patients, individualisation of dosage may be desirable.
• Patients with hepatic impairment: The total daily dose of MYLAN VENLAFAXINE XL should be reduced by 50 % in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been studied; therefore, caution should be used if considering treating these patients with MYLAN VENLAFAXINE XL and a further reduction should be considered. Since there is a variability in clearance between hepatically impaired patients, individualisation of dosing, including further dose reductions (u02c3 50 %), may be desirable in some patients. Because of individual variability in clearance in these patients, individualisation of dosage may be desirable.
• Paediatric population: Not for use for children under the age of 18 years (see section 4.3).
• Maintenance, continuation and extended treatment: The need for long-term therapy with MYLAN VENLAFAXINE XL must be periodically reassessed. Whether the dose of antidepressant needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.
• Discontinuing MYLAN VENLAFAXINE XL: Dose tapering with an immediate release venlafaxine formulation is recommended when discontinuing MYLAN VENLAFAXINE XL therapy. Tapering over at least a two-week period is recommended if MYLAN VENLAFAXINE XL has been used for more than 6 weeks (see section 4.4 and 4.8). The period required for tapering may depend on the dose, duration of therapy and the individual patient. Patients should be advised to consult their doctor before abruptly discontinuing MYLAN VENLAFAXINE XL (see section 4.4 and 4.8).

Method of administration

• For oral use.

• Hypersensitivity to the active substance MYLAN venlafaxine XL or any excipients in the formulation.
• Children under the age of 18 years (see section 4.4 and 4.8).
• Pregnancy and lactation (see section 4.6).
• Concomitant use in patients taking monoamine oxidase inhibitors (MAOls) (see section 4.4).

Monoamine oxidase inhibitor (MAOI): Severe adverse reactions have been reported when MYLAN VENLAFAXINE XL therapy is initiated soon after discontinuation of a monoamine oxidase inhibitor (MAOI) and when an MAOI is initiated soon after discontinuation of MYLAN VENLAFAXINE XL. Reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures and death. MYLAN VENLAFAXINE XL must not be initiated for at least 14 days after discontinuing treatment with a monoamine oxidase inhibitor (MAOI). Allow at least 7 days after stopping MYLAN VENLAFAXINE XL before starting a MAOI (see section 4.5 and 4.3).

Convulsions: MYLAN VENLAFAXINE XL should be introduced with care in patients with a history of seizures and should be discontinued in any patient developing a seizure.

Overdose: Patients should be advised not to use alcohol, considering its central nervous system (CNS)-effects and potential of clinical worsening of psychiatric conditions, and the potential for adverse interactions with MYLAN VENLAFAXINE XL including CNS depressant effects (see section 4.5). Overdose with MYLAN VENLAFAXINE XL has been reported predominantly in combination with alcohol and/or other medicines, including cases with fatal outcome (see section 4.9). Prescriptions for MYLAN VENLAFAXINE XL should be written for the smallest quantity consistent with good patient management, in order to reduce the risk of overdose (see section 4.9).

Suicide/suicidal thoughts or clinical worsening: The risk of suicide must be considered in all depressed patients. Prescriptions for MYLAN VENLAFAXINE XL should be written for the smallest quantity of capsules consistent with good patient management in order to reduce the possibility of overdose. Patients with major depressive disorder, both adults and children, may experience worsening of their depression and or the emergence of suicidal ideation and behaviour, whether or not they are taking antidepressant medicines. The 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 MYLAN VENLAFAXINE XL should, nevertheless, be observed closely for clinical worsening of symptoms 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 MYLAN VENLAFAXINE XL, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Serotonin syndrome: Serotonin syndrome, a potentially life-threatening condition, may occur with MYLAN VENLAFAXINE XL treatment, particularly with concomitant use of other medicines that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, SNRIs, tricyclic antidepressants, amphetamines, lithium, sibutramine, St. Johnu2019s Wort (Hypericum perforatum), opioids (e.g. buprenorphine, fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, pethidine, methadone and pentazocine), with medicines 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).

Narrow-angle glaucoma: Mydriasis may occur in association with MYLAN VENLAFAXINE XL. It is recommended that patients with raised intra-ocular pressure or patients at risk for acute narrow angle glaucoma (angle closure glaucoma) be closely monitored.

Mania/hypomania: Activation of mania/hypomania has been reported. MYLAN VENLAFAXINE XL should be used with caution in patients with a history of mania or family history of bipolar disorder.

Aggression: Aggression may occur in a small proportion of patients who have received MYLAN VENLAFAXINE XL treatment, dose reduction or discontinuation. MYLAN VENLAFAXINE XL should be used cautiously in patients with a history of aggression.

Hyponatraemia: Hyponatraemia and/or the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion may occur with MYLAN VENLAFAXINE XL, usually 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. If the decision is made to discontinue treatment, the dosage of MYLAN VENLAFAXINE XL should be tapered (see section 4.4 and 4.2).

Allergic reactions: Patients should be advised to notify their doctor if they develop a rash, urticaria, or a related allergic phenomenon (see section 4.8).

Co-administration with weight loss medicines: Treatment-associated anorexia has frequently been reported with venlafaxine. Dose-related weight loss has also been noted. Significant weight loss, especially in underweight depressed patients, may be an undesirable effect of venlafaxine treatment. Weight gain has been experienced less frequently. MYLAN VENLAFAXINE XL is not indicated for weight loss, alone or in combination with other medicines.

Serum cholesterol: Measurement of serum cholesterol levels should be considered during long-term treatment.

Abnormal bleeding: Medicines that inhibit serotonin uptake may lead to abnormalities of platelet aggregation. The risk of skin and mucous membrane bleeding including gastrointestinal haemorrhage, may be increased. SSRIs/SNRIs such as MYLAN VENLAFAXINE XL may increase the risk of postpartum haemorrhage (see sections 4.6 and 4.8). MYLAN VENLAFAXINE XL should be used cautiously in patients predisposed to bleeding, including patients on anti-coagulants and platelet inhibitors. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants or other medicines known to affect platelet function may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of medicines that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Inform patients about the risk of bleeding associated with the concomitant use of MYLAN VENLAFAXINE XL and nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or other medicines that affect coagulation. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing MYLAN VENLAFAXINE XL.

General: Clinical experience with MYLAN VENLAFAXINE XL in patients with concomitant systemic illnesses is limited. Caution is advised in administering MYLAN VENLAFAXINE XL to patients with diseases or conditions that could affect haemodynamic responses or metabolism.

Cardiac disease and risk of arrhythmia: MYLAN VENLAFAXINE XL has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. The mean heart rate may be increased during treatment. As increases in heart rate were observed, caution should be exercised in patients whose underlying medical conditions might be compromised by increases in heart rate (e.g. patients with hyperthyroidism, heart failure, or recent myocardial infarction). Treatment with MYLAN VENLAFAXINE XL has been associated with an increase in blood pressure in some patients. The presence of treated hypertension or elevated blood pressure at baseline does not seem to predispose patients to further increases during MYLAN VENLAFAXINE XL therapy. Blood pressure monitoring may be advisable. Either dose reduction or discontinuation should be considered for patients who experience a sustained increase in blood pressure while receiving MYLAN VENLAFAXINE XL. QTc prolongation, Torsade de Pointes (TdP), ventricular tachycardia and fatal cardiac dysrhythmias have been reported with the use of MYLAN VENLAFAXINE XL, 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 MYLAN VENLAFAXINE XL to patients at high risk of serious cardiac dysrhythmia or QTc prolongation.

Hepatic and renal impairment: MYLAN VENLAFAXINE XL should not be used in patients with moderate to severe renal impairment or cirrhosis of the liver as this dosage form is not suitable for these patients.

Discontinuing MYLAN VENLAFAXINE XL treatment: Abrupt discontinuation of MYLAN VENLAFAXINE XL can lead to withdrawal effects. Symptoms of withdrawal include dizziness, sensory disturbances (including paraesthesia and electric shock sensations), sleep disturbances (including insomnia and abnormal dreams), agitation, anxiety, nausea, vomiting, tremor, sweating, headache, diarrhoea, palpitations and emotional instability.

Monoamine oxidase inhibitors: Severe adverse reactions have been reported in patients who have recently discontinued taking MAOl's and started on MYLAN VENLAFAXINE XL or have recently had MYLAN VENLAFAXINE XL discontinued prior to initiation of an MAOI (see section 4.3). These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness and hyperthermia with features resembling neuroleptic malignant syndrome, seizure and death.

CNS active medicines: Based on the known mechanism of action of MYLAN VENLAFAXINE XL and the potential for serotonin syndrome, caution is advised when MYLAN VENLAFAXINE XL is co-administered with other medicines that may affect serotogenic neurotransmitter system, such as triptans, selective serotonin re-uptake inhibitors, lithium, sibutramine, tramadol, St John's Wort (Hypericum perforatum).

Serotonin syndrome: Serotonin syndrome, a potentially life-threatening condition which may occur with MYLAN VENLAFAXINE XL treatment, particularly with concomitant use of other medicines that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, other SNRIs, tricyclic antidepressants, amphetamines, lithium, sibutramine, tramadol, or St. Johnu2019s Wort (Hypericum perforatum), opioids (e.g. buprenorphine), with medicines which impair metabolism of serotonin (such as MAOIs, including linezolid (an antibiotic), selegiline (for Parkinsonu2019s disease), (see section 4.3), or with serotonin precursors (such as tryptophan supplements). Serotonin syndrome symptoms may include mental status changes, autonomic instability, neuromuscular aberrations and/or gastrointestinal symptoms (see sections 4.3 and 4.4). If concomitant treatment of MYLAN VENLAFAXINE XL with an SSRI, an SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of MYLAN VENLAFAXINE XL with serotonin precursors (such as tryptophan supplements) is not recommended (see section 4.4).

Indinavir: Pharmacokinetic studies showed a 28 % decrease in AUC and a 36 % decrease in Cmax for indinavir. Indinavir does not affect the pharmacokinetics of MYLAN VENLAFAXINE XL and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown.

Warfarin: Potentiation of anticoagulant effects may occur in patients taking warfarin following addition of MYLAN VENLAFAXINE XL.

Alcohol: Patients should be advised not to use alcohol, considering its CNS-effects and potential of clinical worsening of psychiatric conditions, and the potential for adverse interactions with venlafaxine including CNS depressant effects.

Haloperidol: Haloperidol may have a 42 % decrease in total clearance after oral administration, with a 70 % increase in AUC, an 88 % increase in Cmax but without any change in half-life. This should be taken into account in patients treated with haloperidol and MYLAN VENLAFAXINE XL concomitantly.

Cimetidine: Cimetidine inhibits the first-pass metabolism of MYLAN VENLAFAXINE XL but has no apparent effect on the formation or elimination of O-desmethylvenlafaxine, which is present in a much greater quantity in the systemic circulation. Consequently, the overall pharmacological activity of MYLAN VENLAFAXINE XL plus O-desmethylvenlafaxine is expected to increase only slightly. No dosage adjustments seem necessary when MYLAN VENLAFAXINE XL is co-administered with cimetidine. However, for elderly patients or patients with hepatic dysfunction concomitantly taking MYLAN VENLAFAXINE XL and cimetidine, the extent of interaction is not known and potentially could be more pronounced. For such patients, clinical monitoring is indicated.

Metoprolol: MYLAN VENLAFAXINE XL appeared to reduce the blood pressure lowering effect of metoprolol. Caution should be exercised with co-administration of MYLAN VENLAFAXINE XL and metoprolol.

Risperidone: MYLAN VENLAFAXINE XL may increase the risperidone AUC by 32 % but does not significantly alter the pharmacokinetics profile of the total active moiety (risperidone plus 9-hydroxyrisperidone).

Diazepam: Diazepam does not appear to affect the pharmacokinetics of MYLAN VENLAFAXINE XL or O-desmethylvenlafaxine. MYLAN VENLAFAXINE XL has no effects on the pharmacokinetics and pharmacodynamics of diazepam and its active metabolite, desmethyldiazepam.

Lithium: The steady state pharmacokinetics of MYLAN VENLAFAXINE XL and O-desmethylvenlafaxine are not affected when lithium is co-administered. MYLAN VENLAFAXINE XL also has no effects on the pharmacokinetics of lithium.

Medicines highly bound to plasma proteins: MYLAN VENLAFAXINE XL is not highly bound to plasma proteins (27 % bound); therefore, administration of MYLAN VENLAFAXINE XL to a patient taking another medicine that is highly protein bound is not expected to cause increased free concentration of the other medicine.

Medicines metabolised by cytochrome P450 iso-enzymes: MYLAN VENLAFAXINE XL is a relatively weak inhibitor of CYP2D6. MYLAN VENLAFAXINE XL does not inhibit CYP3A4, CYP1A2 and CYP2C9 in vitro.

Women of childbearing potential/ Contraception in males and females: Patients should be advised to notify their doctor if they become pregnant or intend to become pregnant during therapy.

Pregnancy: Safety during pregnancy and lactation has not been established (see section 4.3). Some neonates exposed to MYLAN VENLAFAXINE XL late in the third trimester have developed complications requiring tube-feeding, respiratory support or prolonged hospitalisation. Such complications can arise immediately upon delivery. Observational data indicate an increased risk (less than 2-fold) of postpartum haemorrhage following SSRI/SNRI such as MYLAN VENLAFAXINE XL exposure within the month prior to birth (see sections 4.4 and 4.8).

Breastfeeding: MYLAN VENLAFAXINE XL and O-desmethylvenlafaxine are excreted in human milk; therefore, women on treatment with MYLAN VENLAFAXINE XL should not breastfeed their infants.

MYLAN VENLAFAXINE XL may impair judgement, thinking or motor skills and patients should be cautioned about operating hazardous machinery, including driving, until they are reasonably certain that MYLAN VENLAFAXINE XL does not affect them adversely.

Summary of the safety profile: In children reports of hostility, suicidal ideation and self-harm. The most commonly observed adverse events associated with the use of MYLAN VENLAFAXINE XL are nervous system complaints, including headache, dizziness, dry mouth, insomnia, nervousness and somnolence; gastro-intestinal complaints, including anorexia, constipation and nausea; abnormal ejaculation/orgasm, sweating and asthenia. The occurrence of many frequently observed adverse events is dose related. Adverse events generally decrease in intensity and frequency with continued therapy, and generally do not lead to cessation of treatment.

Tabulated list of adverse reactions

MedDRA system organ class Frequency Adverse reactions Blood and lymphatic system disorders Less frequent Ecchymosis, mucous membrane bleeding, prolonged bleeding time, thrombocytopenia, blood dyscrasias including agranulocytosis, aplastic anaemia, neutropenia and pancytopenia Immune system disorders Less frequent Anaphylaxis Metabolism and nutrition disorders Frequent Weight loss, changes in serum cholesterol Less frequent Weight gain, abnormal liver function tests, hyponatraemia, increased prolactin, Syndrome of Inappropriate Antidiuretic Hormone Secretion (SAIDH) Psychiatric disorders Frequent Insomnia, abnormal dreams, nervousness Less frequent Apathy, hallucinations, mania, hypomania, derealisation Frequency not known Suicidal ideation and suicidal behaviour, aggression (see section 4.4) Nervous system disorders Frequent Dizziness, hypertonia, paraesthesia, tremor, sedation, headache Less frequent Agitation, myoclonus, akathisia, convulsions, manic reaction, neuroleptic malignant syndrome (NMS), serotonergic syndrome, delirium, extrapyramidal reactions, tardive dyskinesia Frequency unknown Amnesia, anxiety, confusion, depersonalisation, depression, emotional lability, hyperaesthesia, somnolence, abnormal thinking, trismus, twitching, aggression, migraine Eye disorders Frequent Abnormal vision, abnormality of accommodation, mydriasis, visual impairment Less frequent Angle closure glaucoma Ear and labyrinth disorders Less frequent Tinnitus Frequency not known Vertigo Cardiac disorders Frequent Chest pain Less frequent Tachycardia, oedema, QT prolongation, ventricular fibrillation, ventricular tachycardia (including Torsades de Pointes) Frequency unknown Palpitations Vascular disorders Frequent Hypertension, vasodilation Less frequent Postural hypotension Respiratory, thoracic and mediastinal disorders Frequent Yawning Less frequent Pulmonary eosinophilia Frequency unknown Pharyngitis, rhinitis, dyspnoea, bronchitis Gastrointestinal disorders Frequent Nausea, vomiting, constipation, decreased appetite, dry mouth, abdominal pain Less frequent Diarrhoea, hepatitis, pancreatitis, bruxism, taste perversion Frequency unknown Dyspepsia, eructation, flatulence, anorexia and increased appetite (weight) Skin and subcutaneous tissue disorders Frequent Sweating, photosensitivity reaction Less frequent Rash, alopecia, erythema multiforme, Stevens-Johnson syndrome, urticaria, pruritus Musculoskeletal and connective tissue disorders Frequent Arthralgia, neck pain, back pain Less frequent Rhabdomyolysis Frequency unknown Myalgia Renal and urinary disorders Frequent Impaired urination Less frequent Urinary retention, urinary frequency Reproductive system and breast disorders Frequent Decreased libido, impotence, abnormal ejaculation/orgasm (see section 4.4), anorgasmia Less frequent Menorrhagia General disorders and administration site conditions Frequent Asthenia, chills, fatigue

Description of selected adverse reactions

Paediatric population (see section 4.3) As with adults, decreased appetite, weight loss, increased blood pressure, and increased serum cholesterol were observed. Particularly, the following adverse reactions were observed: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8). Somnolence was the most commonly reported symptom. Generalised convulsions may occur. In post-marketing experience, overdose with MYLAN VENLAFAXINE XL was reported predominantly in combination with alcohol and/or other medicines, including cases with fatal outcome. The most commonly reported events in overdose include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, convulsion, and vomiting. Other reported events include electrocardiographic changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation, ventricular tachycardia, bradycardia, hypotension, vertigo, and deaths. Severe poisoning symptoms may occur in adults after intake of approximately 3 grams of venlafaxine as contained in MYLAN VENLAFAXINE XL. Published retrospective studies report that MYLAN VENLAFAXINE XL overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant medicines, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that MYLAN VENLAFAXINE XL-treated patients have a higher burden of suicide risk factors than SSRI patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of MYLAN VENLAFAXINE XL in overdosage, as opposed to some characteristics of MYLAN VENLAFAXINE XL-treated patients, is not clear. Treatment should be symptomatic and supportive. Severe poisoning may require complex emergency treatment and monitoring. Therefore, in event of suspected overdose involving MYLAN VENLAFAXINE XL, prompt contact with (e.g. national poison information center or hospital emergency) is recommended. General supportive and symptomatic measures are recommended; cardiac rhythm and vital signs must be monitored. When there is a risk of aspiration, induction of emesis is not recommended. Administration of activated charcoal may also limit medicine absorption. Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for MYLAN VENLAFAXINE XL are known.