Denlazyd 50/100 mg XR tablets

Major depressive disorder

DENLAZYD tablets are indicated for the treatment of major depressive disorder (MDD).

Posology:

Major depressive disorder

The recommended dose for DENLAZYD 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.

Discontinuing DENLAZYD

Symptoms associated with discontinuation of DENLAZYD, other serotonin and norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) have been reported. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. 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 medical practitioner may continue decreasing the dose but at a more gradual rate (see sections 4.4 and 4.8).

Switching patients from other antidepressants to DENLAZYD

Discontinuation symptoms have been reported when switching patients from other antidepressants, including venlafaxine, to DENLAZYD. Tapering of the initial antidepressant may be necessary to minimise discontinuation symptoms.

Special populations

Use in patients with renal impairment

The recommended starting dose in patients with severe renal impairment (24-hour creatinine clearance < 30 mL/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 (see section 5.2).

Use in patients with hepatic impairment

No dosage adjustment is necessary for patients with hepatic impairment (see section 5.2).

Use in elderly patients

No dosage adjustment is required solely on the basis of age; however, possible reduced renal clearance of DENLAZYD should be considered when determining the dose (see section 5.2).

Paediatric population

Safety and efficacy in patients less than 18 years of age have not been established.

Method of administration:

For oral use. The film-coated tablet should not be broken because the coating is intended to ensure an extended release.

• Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any of the excipients in DENLAZYD (see section 6).
• DENLAZYD is an inhibitor of both norepinephrine and serotonin reuptake. DENLAZYD 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 DENLAZYD, at least 7 days should be allowed after stopping DENLAZYD before starting an MAOI. Severe adverse reactions have been reported when therapy is initiated with SSRI/SNRI medicines, such as DENLAZYD, 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 (see section 4.5).
• Children less than 18 years of age, as safety and efficacy have not been established (see sections 4.4 and 4.8).
• Pregnancy and lactation (see section 4.6).

SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see sections 4.6 and 4.8).

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 DENLAZYD 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 nonpsychiatric 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 DENLAZYD 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, DENLAZYD should be tapered (see section 4.2).

Short-term trials have not shown 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 aged 65 years and older.

Mania/hypomania

There have been reports of mania in patients treated with desvenlafaxine, as in DENLAZYD. 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. DENLAZYD should be used cautiously 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 DENLAZYD 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) (see section 4.5). The concomitant use of DENLAZYD with serotonin precursors (such as tryptophan supplements) is not recommended.

Narrow-angle glaucoma

Mydriasis has been reported in association with DENLAZYD; therefore, patients with raised intraocular pressure, or those at risk of acute narrow-angle glaucoma (angle-closure glaucoma), should be monitored (see section 4.8).

Ischaemic cardiac adverse events

Ischaemic cardiac adverse events have been reported less frequently including myocardial ischaemia, myocardial infarction, and coronary occlusion requiring revascularisation; these patients had multiple underlying cardiac risk factors. More patients experienced these events during desvenlafaxine treatment as compared to placebo.

Discontinuation symptoms

Adverse reactions reported in association with abrupt discontinuation, dose reduction or tapering of treatment include dizziness, withdrawal syndrome, nausea and headache. In general, discontinuation symptoms occurred more frequently with longer duration of therapy (see section 4.2).

Adverse reactions leading to discontinuation of therapy

The most common adverse reaction leading to discontinuation was nausea.

Adverse reactions reported with other SNRIs

Although gastrointestinal bleeding is not considered an adverse reaction for DENLAZYD, it is an adverse reaction for other SNRIs and may also occur with DENLAZYD.

Abuse and dependence

Physical and psychological dependence

Although DENLAZYD has not been systematically studied for its potential for abuse, no indication of medicine-seeking behaviour has been seen.

Co-administration of medicines containing venlafaxine and/or other medicines containing desvenlafaxine

DENLAZYD is the major active metabolite of venlafaxine, a medicine used to treat major depressive, generalised anxiety, social anxiety and panic disorders. DENLAZYD should not be used concomitantly with medicines containing venlafaxine hydrochloride or other medicines containing DENLAZYD (see section 4.5).

Effects on blood pressure

Increased blood pressure

Increases in blood pressure were observed in some patients, particularly with higher doses. Pre-existing hypertension should be controlled before treatment with DENLAZYD. Patients receiving DENLAZYD should have regular monitoring of blood pressure. Cases of elevated blood pressure requiring immediate treatment have been reported with DENLAZYD. Sustained blood pressure increases could have adverse consequences. For patients who experience a sustained increase in blood pressure while receiving DENLAZYD, either dose reduction or discontinuation should be considered. Caution should be exercised in treating patients with underlying conditions that might be compromised by increases in blood pressure (see section 4.8).

Cardiovascular/cerebrovascular disorders

Caution is advised in administering DENLAZYD to patients with cardiovascular, cerebrovascular or lipid metabolism disorders. Increases in blood pressure and heart rate have been observed in patients using DENLAZYD. DENLAZYD has not been evaluated systematically in patients with a recent history of myocardial infarction, unstable heart disease, uncontrolled hypertension or cerebrovascular disease. Patients with these diagnoses, except for cerebrovascular disease, were excluded from clinical trials (see section 4.8).

Serum lipids

Dose-related elevations in fasting serum total cholesterol, LDL (low density lipoprotein) cholesterol and triglycerides have been observed. Measurement of serum lipids should be considered during treatment with DENLAZYD (see section 4.8).

Seizures

Cases of seizures were reported in premarketing clinical trials with desvenlafaxine. DENLAZYD has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from premarketing clinical trials. DENLAZYD should be prescribed with caution in patients with a seizure disorder (see section 4.8).

Discontinuation effects

During marketing of SNRIs and SSRIs, such as DENLAZYD, there have been spontaneous reports of adverse events occurring upon discontinuation of these medicines, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paraesthesia such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored when discontinuing treatment with DENLAZYD. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered (see sections 4.2 and 4.8).

Abnormal bleeding

Medicines that inhibit serotonin uptake in platelets may lead to abnormalities of platelet aggregation. As with other medicines that inhibit serotonin reuptake, DENLAZYD should be used cautiously in patients predisposed to bleeding.

Hyponatraemia

Cases of hyponatraemia and/or the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have been described with SNRIs and SSRIs, including DENLAZYD, usually in volume-depleted or dehydrated patients, including elderly patients and patients taking diuretics (see section 4.8).

Interstitial lung disease and eosinophilic pneumonia

Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent medicine of DENLAZYD) therapy have been reported. The possibility of these adverse events should be considered in patients treated with DENLAZYD who present with progressive dyspnoea, cough or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of DENLAZYD should be considered.

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 DENLAZYD (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 DENLAZYD in patients taking MAOIs, including selegiline and linezolid (an antibiotic which is a reversible non-selective MAOI), is contraindicated (see sections 4.3 and 4.4).

Central nervous system (CNS)-active medicines

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

Serotonin syndrome

Serotonin syndrome, a potentially life-threatening condition, may occur with DENLAZYD treatment, particularly with concomitant use of other medicines 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 [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 section 4.4).

Ethanol

Patients should be advised to avoid alcohol consumption while taking DENLAZYD.

Potential for other medicines to affect DENLAZYD

Inhibitors of CYP3A4

CYP3A4 is involved in DENLAZYD elimination. Concomitant use of DENLAZYD with potent inhibitors of CYP3A4 may result in higher exposure to DENLAZYD.

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 DENLAZYD.

Potential for DENLAZYD to affect other medicines

Medicines metabolised by CYP2D6

Clinical trials have shown that desvenlafaxine is a weak inhibitor of CYP2D6 at a dose of 100 mg daily. Concomitant use of DENLAZYD 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, desvenlafaxine does not inhibit or induce the CYP3A4 isozymes. Concomitant use of DENLAZYD 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 desvenlafaxine (100 mg daily) does not have a clinically relevant effect on medicines metabolised by a combination of both CYP2D6 and CYP3A4 enzymes.

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

In vitro, desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9 and 2C19 isozymes and would not be expected to affect the pharmacokinetics of medicines that are metabolised by these CYP isozymes.

P-glycoprotein transporter

In vitro, desvenlafaxine is not a substrate or an inhibitor of the P-glycoprotein transporter.

Laboratory test interactions

False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking desvenlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of DENLAZYD therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish DENLAZYD from PCP and amphetamine.

Electroconvulsive therapy

There are no clinical data establishing the risks and/or benefits of electroconvulsive therapy combined with DENLAZYD treatment for MDD.

Pregnancy

DENLAZYD must not be administered to pregnant women. Safety during pregnancy has not been established (see section 4.3). If DENLAZYD 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. Observational data indicate an increased risk (less than 2-fold) of postpartum haemorrhage following SSRI/SNRI exposure within the month prior to birth (see sections 4.4 and 4.8).

Breastfeeding

DENLAZYD must not be administered to lactating women. Safety during lactation has not been established (see section 4.3). DENLAZYD (O-desmethylvenlafaxine) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from DENLAZYD, a decision should be made whether or not to discontinue nursing or to discontinue DENLAZYD, taking into account the importance of DENLAZYD to the mother.

Fertility

No data on male or female fertility is available.

DENLAZYD may impair judgement, thinking and motor skills. Therefore, patients should be cautioned about their ability to drive a vehicle or operate hazardous machinery (see section 4.4).

Tabulated summary of adverse reactions

* Frequency is calculated based on men only. ** Adverse reaction identified during post-approval use. *** This event has been reported for the therapeutic class of SSRIs/SNRIs (see sections 4.4 and 4.6).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of DENLAZYD is important. It allows continued monitoring of the benefit/risk balance of DENLAZYD. Health care providers are requested to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

There is limited clinical experience with desvenlafaxine overdosage in humans. No specific antidotes for DENLAZYD are known. Induction of emesis is not recommended. Because of the moderate volume of distribution of DENLAZYD, forced diuresis, dialysis, haemoperfusion and exchange transfusion is 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. Activated charcoal should be administered.