VOXRA Extended-release tablet Ref.[115265] Active ingredients: Bupropion

The recommended dose of VOXRA XL should not be exceeded, since bupropion is associated with a dose-related risk of seizure.

VOXRA XL should be discontinued promptly if patients experience hypersensitivity reactions during treatment (see section 4.8). Clinicians should be aware that symptoms may persist beyond the discontinuation of VOXRA XL and clinical management should be provided accordingly.

The overall incidence of seizure with VOXRA XL in clinical trials was approximately 0,1%. There is an increased risk of seizures occurring with the use of VOXRA XL in the presence of predisposing risk factors, which lower the seizure threshold. Therefore, VOXRA XL should not be administered to patients with one or more conditions predisposing to a lowered seizure threshold, which include:

• history of head trauma
• central nervous system (CNS) tumour
• history of seizures
• concomitant administration of other medications known to lower the seizure threshold excessive use of alcohol or sedatives (see section 4.3), diabetes reated with hypoglycaemics or insulin and use of stimulants or anorectic products.

VOXRA XL should be discontinued and is not recommenced in patients who experience a seizure while on treatment.

Clinical worsening and suicide risk in adults associated with psychiatric disorders

Patients with major depressive disorder may experience worsening of their depression and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications. This risk may persist until significant remission occurs. A causal role, however, for antidepressant medicines in inducing such behaviour has not been established. As improvement may not occur during the first few weeks or more of treatment, patients being treated with VOXRA XL should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of therapy, or at the time of dose changes, either increases or decreases.

Patients with a history of suicidal behaviour or thoughts, young adults and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are at a greater risk of suicidal thoughts or suicide attempts and should receive careful monitoring during treatment.

The following symptoms have been reported in patients being treated with antidepressants for major depressive disorder: anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia, hypomania and mania.

In addition, a meta-analysis of placebo controlled clinical trials of antidepressant medicines in adults with major depressive disorder and other psychiatric disorders showed an increased risk of suicidal thinking and behaviour associated with antidepressant use compared to placebo in patients less than 25 years old. Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. It should be recognised that the onset of neuropsychiatric symptoms could be related either to the underlying disease state or the medicine therapy and an appropriate patient assessment should be undertaken (see Neuropsychiatric symptoms including mania and bipolar disorder below; section 4.8).

Consideration should be given to changing the therapeutic regimen, including discontinuing VOXRA XL, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Although there is no need to taper VOXRA XL upon discontinuation, the patient should be monitored for worsening of depressive symptoms following discontinuation.

Neuropsychiatric symptoms including mania and bipolar disorder

Neuropsychiatric symptoms have been reported (see section 4.8). In particular, psychotic and manic symptomatology has been observed, mainly in patients with a known history of psychiatric illness. Aggression, rage and violent behaviour may occur. Additionally, a major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone can increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Limited clinical data on use of bupropion in combination with mood stabilisers in patients with a history of bipolar disorder suggests a low rate of switch to mania.

Prior to initiating treatment with VOXRA XL, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

Hepatic impairment

Bupropion is extensively metabolised in the liver to active metabolites, which are further metabolised. No statistically significant differences in the pharmacokinetics of bupropion were observed in patients with mild hepatic cirrhosis compared with healthy volunteers, but bupropion plasma levels showed a higher variability between individual patients. Therefore, VOXRA XL should be used with caution in patients with mild hepatic impairment and reduced frequency of dosing should be considered (see sections 5.2 and 4.3).

Renal impairment and elderly patients

Bupropion is extensively metabolised in the liver to active metabolites which are further metabolised and excreted by the kidneys. Therefore, treatment of patients with renal impairment should be initiated at reduced frequency and/or dose as bupropion and its metabolites may accumulate in such patients to a greater extent than usual. The patient should be closely monitored for possible adverse effects (e.g. insomnia, dry mouth, seizures) that could indicate high bupropion or metabolite levels, toxic effects of elevated blood and tissue levels of bupropion and metabolites.

Clinical experience with VOXRA XL has not identified any differences in tolerability between elderly and other adult patients. However, greater sensitivity of some elderly individuals cannot be ruled out, hence a reduced frequency and/or dose may be required (see section 5.2).

Cardiovascular disease

There is insufficient clinical experience of the use of VOXRA XL to treat depression in patients with cardiovascular disease.

Care should be exercised if VOXRA XL is used in these patients. Hypertension has been reported to be severe and may require acute treatment, in patients receiving VOXRA XL. This has been observed in patients with and without pre-existing hypertension.

Cardiac conduction disorders-Bupropion may unmask Brugada syndrome, a rare hereditary disease of the cardiac sodium channel with characteristic ECG changes (ST segment elevation and T wave abnormalities in the right precordial leads), which may lead to cardiac arrest and/or sudden death. Caution is advised in patients with Brugada syndrome or risk factors such as a family history of cardiac arrest or sudden death.

Children and adolescents <18 years

The safety and efficacy with the treatment of VOXRA XL tablets in patients under 18 years of age have not been established. Treatment with antidepressants is associated with an increased risk of suicidal thinking and behaviour in children and adolescents with major depressive disorder and other psychiatric disorders (see section 4.3).

Inappropriate routes of administration

VOXRA XL is intended for oral use only. The inhalation of crushed tablets or injection of dissolved bupropion has been reported, and may lead to a rapid release, faster absorption and a potential overdose. Seizures and/or cases of death have been reported when VOXRA XL has been administered intra-nasally or by parenteral injection.

Serotonin syndrome

There have been post-marketing reports of serotonin syndrome, a potentially life-threatening condition, when VOXRA XR is co-administered with a serotonergic agent, such as Selective Serotonin Reuptake Inhibitors (SSRI) or Serotonin Norepinephrine Re- uptake Inhibitors (SNRIs) (see section 4.5). If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea). If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

Serotonin syndrome has also been reported with bupropion-only overdose (see section 4.9).

Bupropion is metabolised to its major active metabolite hydroxybupropion primarily by the cytochrome P450 IIB6 (CYP2B6) (see section 5.2).

Care should therefore be exercised when VOXRA XL is co-administered with medicines known to affect the CYP2B6 isoenzyme (e.g., orphenadrine, cyclophosphamide, ifosfamide, ticlopidine, clopidogrel).

Although bupropion is not metabolised by the CYP2D6 isoenzyme, in vitro human P450 studies have shown that bupropion and hydroxybupropion are inhibitors of the CYP2D6 pathway. In a human pharmacokinetic study, administration of bupropion increased plasma levels of desipramine. This effect was present for at least 7 days after the last dose of bupropion.

Concomitant therapy with medicines predominantly metabolised by this isoenzyme (such as certain beta-blockers, anti-dysrrhythmics, selective serotonin re-uptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), antipsychotics) should be initiated at the lower end of the dose range of the concomitant medication. If VOXRA XL is added to the treatment regimen of a patient already receiving a medication metabolised by CYP2D6, the need to decrease the dose of the original medication should be considered, particularly for those concomitant medications with a narrow therapeutic index (see section 5.2).

Medicines which require metabolic activation by CYP2D6 in order to be effective (e.g., tamoxifen), may have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion.

Although citalopram is not primarily metabolised by CYP2D6, in one study, bupropion increased the C_max and AUC of citalopram by 30% and 40%, respectively. Since bupropion is extensively metabolised, the co-administration of medicines known to induce metabolism (e.g., carbamazepine, phenobarbitone, phenytoin, ritonavir, efavirenz) or inhibit metabolism may affect its clinical activity.

In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir 100 mg plus lopinavir 400 mg twice daily reduced the exposure of bupropion and its major metabolites in a dose dependent manner by approximately 20% up to 80% (See section 4.3.). Similarly, efavirenz 600 mg once daily for two weeks reduced the exposure of bupropion by approximately 55%. This effect of Ritonavir and Efavirenz is thought to be due to the induction of bupropion metabolism. Patients receiving Efavirenz with VOXRA XL may need increased doses of VOXRA XL but the maximum recommended dose of VOXRA XL should not be exceeded.

There have been reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients drinking alcohol during VOXRA XL treatment. The consumption of alcohol during VOXRA XL treatment should be avoided.

There have been post-marketing reports of serotonin syndrome, a potentially life-threatening condition, when WELLBUTRIN XR is co-administered with a serotonergic agent, such as Selective Serotonin Reuptake Inhibitors (SSRI) or Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs) (see section 4.4).

Clinical data suggest a higher incidence of adverse events in patients receiving concurrent administration of bupropion and levodopa. Administration of VOXRA XL to patients receiving either levodopa or amantadine concurrently should be undertaken with caution. Concomitant use of VOXRA XL and a nicotine transdermal system (NTS) may result in elevations of blood pressure.

Co-administration of digoxin with VOXRA XL may decrease digoxin levels. Clinicians should be aware that digoxin levels may rise on discontinuation of VOXRA XL, and the patient should be monitored for possible digoxin toxicity.

Interactions involving laboratory tests

VOXRA XL interferes with the assay used in some rapid urine drug screens, which can result in false positive readings, particularly for amphetamines. A more specific alternative chemical method should be considered to confirm a positive result.

Pregnancy

Safety in pregnancy and lactation has not been established.

VOXRA XL should not be used during pregnancy unless the clinical condition of the woman requires treatment with bupropion and alternative treatments are not an option. Women of childbearing potential must use reliable contraception. Studies of pregnancy outcomes following maternal exposure to bupropion in pregnancy have reported an increased risk of congenital cardiovascular malformations including ventricular septal defects and left outflow tract defects.

Breastfeeding

Safety in lactation has not been established. As bupropion and its metabolites are excreted in human breast milk, mothers should be advised not to breastfeed while taking VOXRA XL.

Fertility

There are no data on the effect of bupropion on human fertility. A reproductive study in rats revealed no evidence of impaired fertility.

Patients should exercise caution before driving or use of machinery until they are reasonably certain VOXRA XL tablets do not adversely affect their performance.

The list below provides information on the undesirable effects identified from clinical experience, categorised 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), very rare (≥1/10, 000).

Reporting of suspected adverse events

Reporting suspected adverse events after authorisation of VOXRA XL 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 publications, https://www.sahpra.org.za/Publications/index/8

Not applicable.