DEPVEN XL Extended release tablet Ref.[50494] Active ingredients:

Clinical worsening of depressive symptoms, unusual changes in behaviour and suicidality

Patients with major depressive disorder may experience worsening of their depression and/or suicidal ideation and behaviour, whether or not they are taking antidepressant medicines. This risk may persist until significant remission occurs. Although a causal role for antidepressant medicines in inducing such behaviour has not been established, patients being treated with DEPVEN XL should be observed closely for clinical worsening and suicidality, especially at the beginning of a course of therapy or when changes in dosage are made.

Due to the possibility of co-morbidity, the same precautions should be taken when treating patients with other psychiatric and non-psychiatric disorders.

Symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania and mania may occur in patients treated with antidepressants for major depressive disorder as well as other indications, both psychiatric and non-psychiatric. Although a causal link between the emergence of suicidal impulses has not been established, changing the therapeutic regimen, including possibly discontinuing DEPVEN XL may be considered in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patients presenting symptoms.

If a decision is made to discontinue treatment, DEPVEN XL should be tapered. (see section 4.2).

Screening patients for bipolar disorder

Major depressive disorder may be the initial presentation of bipolar disorder. Treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Patients should therefore be adequately screened for the risk of bipolar disorder. Such screening should include a detailed psychiatric history, including family history of suicide, bipolar disorder and depression. DEPVEN XL is not approved for treating bipolar disorder.

Mania / hypomania

Mania/hypomania may occur in patients treated with DEPVEN XL therefore caution should be exercised in patients with a history or family history of mania or hypomania (see section 4.8).

Serotonin syndrome

The development of a potentially life-threatening serotonin syndrome may occur with DEPVEN XL treatment, particularly with concomitant use of other serotonergic medicines (such as SSRI’s, SNRI’s and triptans) and medicines that impair metabolism of serotonin (including (MAOI’s). Serotonin syndrome symptoms may include mental state changes (such as agitation, hallucinations and coma), autonomic instability (e.g. tachycardia, labile blood pressure and hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination) and/or gastrointestinal symptoms (such as nausea, vomiting and diarrhoea) (see section 4.8).

The concomitant use of DEPVEN XL with serotonin precursors such as tryptophan supplements is not recommended.

All patients taking DEPVEN XL should be monitored for serotonin syndrome and it should be discontinued if symptoms occur.

Switching patients from a monoamine oxidase inhibitor (MAOI) intended to treat psychiatric disorders

At least 14 days should lapse between discontinuation of a MAOI and initiation of therapy with DEPVEN XL. At least 7 days should be allowed after stopping DEPVEN XL treatment before starting a MAOI.

Use of DEPVEN with other MAOI’s such as linezolid or methylene blue

Patients being treated with linezolid or intravenous methylene blue should not be started on DEPVEN XL as there is an increased risk of serotonin syndrome. In patients already being treated with DEPVEN XL, alternatives to linezolid or methylene blue should be considered.

Narrow-angle glaucoma

Mydriasis may occur with DEPVEN XL treatment therefore patients with raised intraocular pressure or those at risk of developing acute narrow-angle glaucoma should be monitored (see section 4.8).

Ischemic cardiac adverse events

Cardiac adverse events such as myocardial ischemia, myocardial infarction, and coronary occlusion requiring revascularisation may occur in patients with underlying cardiac risk factors taking DEPVEN XL.

Discontinuation symptoms

Adverse reactions that may occur with discontinuation of DEPVEN XL include dizziness, withdrawal syndrome, nausea and headache. Discontinuation symptoms occur more frequently with longer duration treatment.

Abrupt discontinuation of DEPVEN XL may also have adverse effects such as dysphoric mood, irritability, agitation, sensory disturbances (e.g. paraesthiasis such as electric shock sensations), anxiety, confusion, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. These events are generally selflimiting; however, serious discontinuation symptoms may occur.

Patients should be monitored when discontinuing DEPVEN XL. A gradual dose reduction is recommended whenever possible. If intolerable symptoms occur after dose reduction or discontinuation of treatment, resuming the previously prescribed dose may be considered.

Adverse reactions leading to discontinuation of therapy

Adverse effects such as nausea, dizziness, headache and vomiting may lead to discontinuation of treatment with DEPVEN XL.

Adverse reactions reported with other SNRI’s

While gastrointestinal bleeding is not considered an adverse effect for DEPVEN XL, it is an adverse event for other SNRI’s and therefore may occur with DEPVEN XL.

Physical and psychological dependence

DEPVEN XL has not been studied for its potential for abuse. However, similar medicines have shown no indication of dependence.

Co-administration with medicines containing venlafaxine

DEPVEN XL (o-desmethylvenlafaxine) is the major active metabolite of venlafaxine, a medicine used to treat major depressive disorder, generalised anxiety, social anxiety and panic disorders. DEPVEN XL should not be used with medicines containing venlafaxine hydrochloride or other medicines containing the active ingredient of DEPVEN XL.

Increased blood pressure

Increases of blood pressure may occur with DEPVEN XL treatment, especially in patients receiving higher doses. Pre-existing hypertension should be controlled before treatment with DEPVEN XL.

Patients receiving DEPVEN XL should have regular monitoring of blood pressure as increases requiring immediate treatment may occur. Sustained blood pressure increases could have adverse consequences therefore a dose reduction or discontinuation of DEPVEN XL should be considered in patients who experience a sustained increase in blood pressure.

Caution should be exercised when treating patients with underlying conditions which might be compromised by increased blood pressure (see section 4.8).

Cardiovascular / Cerebrovascular

Caution should be exercised when administering DEPVEN XL to patients with cardiovascular, cerebrovascular or lipid metabolism disorders due to potential to increases in blood pressure and heart rate.

Serum lipids

Dose-related elevations in fasting serum total cholesterol, low density lipoprotein (LDL) cholesterol, and triglycerides may occur with DEPVEN XL treatment. Measurement of serum lipids should be considered during treatment with DEPVEN XL.

Seizures

Seizures may occur in patients taking DEPVEN XL. Caution should therefore be taken when prescribing DEPVEN XL to patients with seizure disorder.

Abnormal bleeding

Medicines that inhibit serotonin reuptake may lead to abnormalities of platelet aggregation. Concomitant use of aspirin, nonsteroidal anti-inflammatory medicines, warfarin and other anticoagulants with DEPVEN XL may add to the risk of bleeding. Bleeding related adverse events related to SSRI’s and SNRI’s may range from ecchymosis, hematoma, epistaxis, and petechiae to life threatening haemorrhages. DEPVEN XL should be used cautiously in patients predisposed to bleeding.

Hyponatraemia

Hyponatraemia and/or the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion may occur with SSRI’s and SSRI’s, including DEPVEN XL, usually in volume depleted or dehydrated patients (including elderly patients taking diuretics) (see section 4.8).

Interstitial lung disease and eosinophilic pneumonia

Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (which desvenlafaxine is an active metabolite of) may occur with DEPVEN XL use. The possibility of these adverse events should be considered in patients being treated with DEPVEN XL who present with dyspnoea, cough or chest discomfort. Discontinuation of DEPVEN XL may be considered.

Use in elderly

No dosage adjustment is required solely on the basis of age; however, possible reduced clearance of DEPVEN XL should be considered when determining dose. There may be an increased incidence of orthostatic hypotension in patients ≥65 years of age treated with DEPVEN XL.

Increases in systolic blood pressure may be more prevalent in patients ≥65 years of age treated with DEPVEN XL.

Paediatric population

Safety and efficacy in children under 18 years of age has not been established (see section 4.4).

List of medicines that interact with DEPVEN XL

Monoamine oxidase inhibitors (MAOI)

Serious adverse effects may occur in patients who have been recently discontinued from a monoamine oxidase inhibitor (MAOI) and started on antidepressants with pharmacological properties such as DEPVEN XL (SSRI’s and SNRI’s), or patients who have recently had SSRI or SNRI therapy discontinued prior to initiation of a MAOI. These adverse effects include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures and death. Concomitant use of DEPVEN XL with MAOI’s is contraindicated (see section 4.3 and 4.4).

Central nervous system (CNS)-active medicines

Caution should be exercised when combining DEPVEN XL with other CNS-active medicine as safety has not been evaluated.

Medicines that affect the serotonergic neurotransmitter system

Serotonin syndrome, a potentially life-threatening condition may occur with DEPVEN XL treatment, particularly when combined with other medicines that affect the serotonergic neurotransmitter system (including triptans, SSRI’s, other SNRI’s, lithium, sibutramine, tramadol, St. Johns' wort (hypericum perforatum), pethidine), with medicines that impair metabolism of serotonin (such as MAOI’s, including linezolid, an antibiotic which is a reversible non-selective MAOI), or with serotonin precursors (such as tryptophan supplements). Serotonin syndrome may manifest as mental changes, autonomic instability, neuromuscular aberrations and/or gastrointestinal symptoms.

Ethanol

Patients taking DEPVEN XL should be advised to avoid alcohol consumption.

Medicines that interfere with haemostasis

The concomitant use of DEPVEN XL with antiplatelet or anticoagulant medicines such as nonsteroidal anti-inflammatory medicines and warfarin may increase the risk of bleeding.

CYP3A4 inhibitors

CYP3A4 is involved in the elimination of DEPVEN XL. Concomitant use of DEPVEN XL with medicines which are potent inhibitors of CYP3A4 may result in increased exposure to DEPVEN XL.

Inhibitors of other CYP enzymes

Medicines which inhibit CYP isozymes 1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19 and 2E1 are not expected to have a significant impact on the pharmacokinetic profile of DEPVEN XL.

Medicines metabolised by CYP2D6

DEPVEN XL is a weak inhibitor of CYP2D6 at a dose of 100 mg daily. Concomitant use of DEPVEN XL with medicines metabolised by CYP2D6 such as desipramine, atomoxetine, dextromethorphan, metoprolol, nebivolol perphenazine and tolterodine may result in increased concentrations of that medicine and decreased concentrations of its CYP2D6 metabolites.

Medicines metabolised by CYP3A4

Concomitant use of DEPVEN XL with a medicine metabolised by CYP3A4, such as midazolam may result in decreased exposure to that medicine.

Medicines metabolised by a combination of both CYP2D6 and CYP3A4

DEPVEN XL does not have a clinically relevant effect on medicines such as tamoxifen and aripiprazole which are metabolised by a combination of both CYP2D6 and CYP3A4 enzymes.

Medicines metabolised by CYP1A2, 2A6, 2C8, 2C9, and 2C19

DEPVEN XL does not inhibit CYP1A2, 2A6, 2C8, 2C9, and 2C19 isozymes and would not be expected to affect the pharmacokinetic profile of medicines metabolised by them.

P-glycoprotein transporter

DEPVEN XL is not a substrate nor inhibitor of P-glycoprotein transporter.

Laboratory test interactions

False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine may occur in patients taking DEPVEN XL. This is due to the lack of specificity of the screening tests. These false positive results may occur for several days after discontinuation of DEPVEN XL. Confirmatory tests such as gas chromatography or mass spectrometry will distinguish DEPVEN XL from PCP and amphetamine.

Electroconvulsive therapy

There are no data on the risks or benefits of electroconvulsive therapy combined with DEPVEN treatment for MDD.

Pregnancy

The safety of DEPVEN XL in pregnancy has not been established. If DEPVEN XL is used until, or shortly before birth, discontinuation symptoms may occur in the newborn.

Complications such as the need for respiratory support, tube feeding, or prolonged hospitalisation may occur in neonates exposed to SNRI’s or SSRI’s late in the third trimester. Such complications can arise immediately upon delivery. Patients should therefore be advised to notify their doctor if they become pregnant or intend to become pregnant during therapy.

Lactation

DEPVEN XL (o-desmethylvenlafaxine) is secreted in human milk. Due to the potential of serious adverse effects in breastfed infants from DEPVEN XL, a decision should be made whether to discontinue breastfeeding or discontinue DEPVEN XL taking into account the importance of the medicine to the mother.

Fertility

The effect on fertility has not been established.

Since DEPVEN XL is a CNS-active medicine, it may impair judgement, thinking and motor skills. Patients should therefore be cautioned about their ability to drive or operate machinery while taking DEPVEN XL.

Summary of side effect profile

The most common adverse events associated with DEPVEN XL include nausea, dry mouth, constipation, dizziness, headache, insomnia and hyperhidrosis.

Tabulated list of adverse reactions

The following adverse reactions have been classified in the following way: “Frequent, less frequent and frequency not known”.

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. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the 6.04 Adverse Drug Reaction Reporting Form, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8 or to Cipla Medpro (Pty) Ltd (by email: drugsafetysa@cipla.com).

Not applicable.