Xophanu 10 mg & 15 mg Orodispersible tablets

Schizophrenia: XOPHANU ODT is indicated for the treatment of schizophrenia and for the maintenance of clinical improvement in adults.

Bipolar Mania: XOPHANU ODT is indicated for the treatment of acute manic episodes associated with Bipolar I Disorder and for prevention of recurrence of new manic episodes in patients who experienced predominantly manic episodes and who responded to XOPHANU ODT treatment.

Posology

Schizophrenia: The recommended starting dose for XOPHANU ODT is 10 or 15 mg/day with a maintenance dose of 15 mg/day administered on a once-a-day schedule without regard to meals. XOPHANU ODT is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than the recommended daily dose of 15 mg has not been demonstrated although individual patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.

Bipolar Mania: The recommended starting dose for XOPHANU ODT is 15 mg administered on a once-a-day schedule without regard to meals as monotherapy or combination therapy (see section 4.5). Some patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.

Recurrence prevention of manic episodes in Bipolar I disorder: For preventing recurrence of manic episodes in patients who have been receiving aripiprazole, continue therapy at the same dose. Adjustments of daily dose, including dose reduction should be considered on the basis of clinical status. Prevention of depressive episodes using aripiprazole monotherapy has not been established. Supplementary therapy should be considered for the prevention or treatment of depressive episodes, as clinically appropriate.

Concomitant Medications: Dosage adjustment for patients taking XOPHANU ODT concomitantly with potent CYP3A4 or CYP2D6 inhibitors: When concomitant administration of a potent CYP3A4 or CYP2D6 inhibitor with XOPHANU ODT occurs, the XOPHANU ODT dose should be reduced to one-half of the usual dose. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, the XOPHANU ODT dose should then be increased.

Dosage adjustment for patients taking potent CYP3A4 inducers: When a potent CYP3A4 inducer is added to XOPHANU ODT therapy, the XOPHANU ODT dose should be doubled. Additional dose increases of XOPHANU ODT should be based on clinical evaluation. When the CYP3A4 inducer is withdrawn from the combination therapy, the XOPHANU ODT dose should be reduced.

Method of administration: XOPHANU ODT is for oral use. The orodispersible tablet should be placed in the mouth on the tongue, where it will rapidly disperse in saliva. It can be taken with or without liquid. Removal of the intact orodispersible tablet from the mouth is difficult. Since the orodispersible tablet is fragile, it should be taken immediately on opening the blister. Alternatively, disperse the tablet in water and drink the resulting suspension.

XOPHANU ODT is contra-indicated in patients who are hypersensitive to aripiprazole or any of the excipients.

Paediatric use: The safety and efficacy of XOPHANU ODT in patients under 18 years of age have not been established.

During antipsychotic treatment, improvement in the patientu2019s clinical condition may take several days to some weeks. Patients should be closely monitored during this period.

Suicide: The occurrence of suicidal behaviour is inherent in psychotic illnesses and mood disorders and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should accompany antipsychotic treatment.

Prescriptions for XOPHANU ODT should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Cardiovascular disorders: XOPHANU ODT should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischaemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease, conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medicines) or hypertension, including accelerated or malignant. Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicines. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with aripiprazole and preventive measures undertaken.

Orthostatic hypotension: Potentially due to its u03b11-adrenergic receptor antagonist activity, XOPHANU ODT may be associated with orthostatic hypotension.

QT prolongation: In clinical trials of aripiprazole, the incidence of QT prolongation was comparable to placebo. XOPHANU ODT should be used with caution in patients with a family history of QT prolongation (see section 4.8).

Tardive Dyskinesia: As the risk of tardive dyskinesia increases with long-term exposure to antipsychotic treatment, if signs and symptoms of tardive dyskinesia appear in a patient on XOPHANU ODT, a dose reduction or medicine discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.

Other extrapyramidal symptoms: In paediatric clinical trials of aripiprazole akathisia and Parkinsonism were observed. If signs and symptoms of other EPS appear in a patient taking XOPHANU ODT, dose reduction and close clinical monitoring should be considered.

Neuroleptic Malignant Syndrome: A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic medicines, including XOPHANU ODT must be discontinued.

Seizure: XOPHANU ODT should be used cautiously in patients who have a history of seizure disorder or have conditions associated with seizures.

Elderly patients with Dementia-related psychosis: Increased mortality In clinical trials (mean age: 82.4 years; range: 56 to 99 years) of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease, patients treated with aripiprazole were at increased risk of death compared to placebo. The rate of death in aripiprazole-treated patients was 3,5 % compared to 1,7 % in the placebo group. Although the causes of deaths were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature (see section 4.8).

Cerebrovascular adverse reactions: In the same trials, cerebrovascular adverse reactions (e.g., stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78 to 88 years). Overall, 1,3 % of aripiprazole-treated patients reported cerebrovascular adverse reactions compared with 0.6 % of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse reactions in patients treated with aripiprazole (see section 4.8). Aripiprazole is not indicated for the treatment of patients with dementia-related psychosis.

Hyperglycaemia and diabetes mellitus: Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including aripiprazole, as contained in XOPHANU ODT. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse reactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse reactions in patients treated with aripiprazole and with other atypical antipsychotics are not available to allow direct comparisons. Patients treated with XOPHANU ODT, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control (see section 4.8). Patients who develop symptoms of hyperglycaemia during treatment with XOPHANU ODT should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when XOPHANU ODT was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect medicine.

Hypersensitivity: Hypersensitivity reactions, characterised by allergic symptoms, may occur with XOPHANU ODT (see section 4.8).

Weight Gain: Weight gain is commonly seen in schizophrenic and bipolar mania patients due to co-morbidities, use of antipsychotics known to cause weight gain and poorly managed life-style might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed aripiprazole. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain in adults. In clinical trials of adolescent patients with bipolar mania, aripiprazole has been shown to be associated with weight gain after 4 weeks of treatment. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should be considered (see section 4.8).

Dysphagia: Oesophageal dysmotility and aspiration have been associated with antipsychotic medicine use, including aripiprazole. XOPHANU ODT and other antipsychotic medicines should be used cautiously in patients at risk of aspiration pneumonia.

Pathological gambling and other impulse control disorders: Patients can experience increased urges, particularly for gambling, and the inability to control these urges while taking XOPHANU ODT. Other urges, reported include: increased sexual urges, compulsive spending, binge or compulsive eating, and other impulsive and compulsive behaviours. It is important for medical practitioners to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, compulsive spending, binge or compulsive eating, or other urges while being treated with XOPHANU ODT. It should be noted that impulse-control symptoms can be associated with the underlying disorder; however, in some cases, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Impulse control disorders may result in harm to the patient and others if not recognised. Consider dose reduction or stopping the medication if a patient develops such urges while taking aripiprazole (see section 4.8).

Patients with attention deficit hyperactivity (ADHD) comorbidity: Despite the high comorbidity frequency of Bipolar I Disorder and ADHD, very limited safety data are available on concomitant use of aripiprazole and stimulants; therefore, extreme caution should be taken when these medicines are co-administered.

Falls: XOPHANU ODT may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls. Caution should be taken when treating patients at higher risk, and a lower starting dose should be considered (e.g., elderly or debilitated patients; see section 4.2).

Body temperature regulation: Disruption of the bodyu2019s ability to reduce core body temperature has been attributed to antipsychotic medicines. Appropriate care is advised when prescribing XOPHANU ODT for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

Laboratory Findings: Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory parameters revealed no medically important differences.

Aspartame: XOPHANU ODT orodispersible tablets contain aspartame. Aspartame is a source of phenylalanine. It may be harmful for people with phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly.

Lactose: XOPHANU ODT orodispersible tablets contain lactose. Patients with rare hereditary problems of galactose intolerance e.g., galactosaemia, total lactase deficiency, glucose-galactose malabsorption should not take XOPHANU ODT.

Sodium: XOPHANU ODT orodispersible tablets contain sodium. This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

Due to its u03b11-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive medicines. Given the primary CNS effects of aripiprazole, caution should be used when XOPHANU ODT is administered in combination with other CNS medicines with overlapping adverse reactions such as sedation (see section 4.8). Combination use of XOPHANU ODT with alcohol should be avoided. If XOPHANU ODT is administered concomitantly with medicines known to cause QT prolongation or electrolyte imbalance, caution should be used.

Potential for other medicines to affect XOPHANU ODT: A gastric acid blocker, the H2 antagonist famotidine, reduces aripiprazole rate of absorption but this effect is deemed not clinically relevant. Aripiprazole is metabolised by multiple pathways involving the CYP2D6 and CYP3A4 enzymes but not CYP1A enzymes. Thus, no dosage adjustment is required for smokers.

Quinidine and other CYP2D6 inhibitors: In a clinical trial in healthy subjects, a strong inhibitor of CYP2D6 (quinidine) increased plasma exposure (AUC) of aripiprazole, while Cmax was unchanged. The AUC and Cmax of dehydro-aripiprazole, the active metabolite, decreased. XOPHANU ODT dose should be reduced to approximately one-half of its prescribed dose when concomitant administration of XOPHANU ODT with quinidine occurs. Other strong inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose reductions should therefore be applied.

Ketoconazole and other CYP3A4 inhibitors: In a clinical trial in healthy subjects, a strong inhibitor of CYP3A4 (ketoconazole) increased aripiprazole and dehydro-aripiprazole AUC and Cmax substantially. In CYP2D6 poor metabolisers, concomitant use of strong inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazole compared to that in CYP2D6 extensive metabolizers. When considering concomitant administration of ketoconazole or other strong CYP3A4 inhibitors with XOPHANU ODT, potential benefits should outweigh the potential risks to the patient. When concomitant administration of ketoconazole with XOPHANU ODT occurs, XOPHANU ODT dose should be reduced to approximately one-half of its prescribed dose. Other strong inhibitors of CYP3A4, such as itraconazole and HIV protease inhibitors may be expected to have similar effects and similar dose reductions should therefore be applied (see section 4.2). Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dosage of XOPHANU ODT should be increased to the level prior to the initiation of the concomitant therapy. When weak inhibitors of CYP3A4 (e.g., diltiazem) or CYP2D6 (e.g., escitalopram) are used concomitantly with XOPHANU ODT, modest increases in plasma aripiprazole concentrations may be expected.

Carbamazepine and other CYP3A4 inducers: Concomitant administration of carbamazepine, a strong inducer of CYP3A4, and oral aripiprazole to patients with schizophrenia or schizoaffective disorder, resulted in decreased plasma exposure of aripiprazole and metabolite dehydro-aripiprazole compared to when aripiprazole (30 mg) was administered alone. XOPHANU ODT dose should be doubled when concomitant administration of XOPHANU ODT occurs with carbamazepine. Concomitant administration of XOPHANU ODT and other inducers of CYP3A4 (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St. John's Wort) may be expected to have similar effects and similar dose increases should therefore be applied. Upon discontinuation of strong CYP3A4 inducers, the dosage of XOPHANU ODT should be reduced to the recommended dose.

Valproate and lithium: When either valproate or lithium was administered concomitantly with aripiprazole, there was no clinically significant change in aripiprazole concentrations and therefore no dose adjustment is necessary when either valproate or lithium is administered with XOPHANU ODT.

Potential for XOPHANU ODT to affect other medicines: In clinical studies, 10 to 30 mg/day doses of aripiprazole had no significant effect on the metabolism of substrates of CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP3A4 (dextromethorphan). Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro. Thus, XOPHANU ODT is unlikely to cause clinically important medicine interactions mediated by these enzymes. When aripiprazole was administered concomitantly with either valproate, lithium or lamotrigine, there was no clinically important change in valproate, lithium or lamotrigine concentrations.

Serotonin syndrome: Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and symptoms for this condition can occur especially in cases of concomitant use with other serotonergic medicines, such as selective serotonin reuptake inhibitor/selective serotonin noradrenaline reuptake inhibitor (SSRI/SNRI), or with medicines that are known to increase aripiprazole concentrations (see section 4.8).

Pregnancy: Safety of use of XOPHANU ODT during pregnancy and lactation has not been established. Patients should be advised to notify their medical practitioner if they become pregnant or intend to become pregnant during treatment with XOPHANU ODT. Neonates exposed to antipsychotics (including XOPHANU ODT) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.

Breastfeeding: Aripiprazole is excreted in human breast milk.

Fertility: Aripiprazole did not impair fertility based on data from reproductive toxicity studies.

Patients should be cautioned about operating hazardous machinery, including motor vehicles until they are reasonably certain that XOPHANU ODT does not adversely affect them. XOPHANU ODT has minor to moderate influence on the ability to drive and use machines due to potential nervous system and visual effects, such as sedation, somnolence, dizziness, syncope, vision blurred, diplopia (see section 4.8).

Tabulated list of adverse reactions

Frequent

• Blood and lymphatic system disorders: Leukopenia, neutropenia, thrombocytopenia.
• Immune system disorders: Allergic reaction (e.g., anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus allergic, or urticaria).
• Endocrine disorders: Hyperprolactinaemia, Blood prolactin decreased. Diabetic hyperosmolar coma, Diabetic ketoacidosis.
• Metabolism and nutrition disorders: Hyponatremia, Anorexia, Hyperglycaemia, Diabetes mellitus.
• Psychiatric disorders: Insomnia, Anxiety, Restlessness. Depression. Suicide attempt, suicidal ideation and completed suicide, Pathological gambling, Hypersexuality, Impulse-control disorders, Binge eating, Compulsive shopping Poriomania, Aggression, Agitation, Nervousness.
• Nervous system disorders: Akathisia, Extrapyramidal disorder, Tremor, Headache, Sedation, Somnolence, Dizziness. Dystonia. Neuroleptic Malignant Syndrome (NMS), Seizures, Grand mal convulsion, Serotonin syndrome, Speech disorder, Tardive dyskinesia, Restless leg syndrome.
• Eye disorders: Vision blurred. Photophobia. Diplopia, Oculogyric crisis.
• Cardiac disorders: Tachycardia (Bipolar condition). Sudden unexplained death, Torsades de pointes, Ventricular-dysrhythmia, Cardiac arrest, Bradycardia.
• Vascular disorders: Orthostatic hypotension (Schizophrenia condition). Orthostatic hypotension (Bipolar Mania condition). Venous thromboembolism (including pulmonary embolism and deep vein thrombosis), Hypertension, Syncope.
• Respiratory, thoracic and mediastinal disorders: Aspiration pneumonia, Laryngospasm, Oropharyngeal spasm, Hiccups.
• Gastrointestinal disorders: Constipation, Dyspepsia, Nausea, Salivary hypersecretion, Vomiting, Abdominal discomfort. Pancreatitis, Dysphagia, Diarrhoea, Stomach discomfort.
• Hepatobiliary disorders: Hepatic failure, Hepatitis, Jaundice.
• Skin and subcutaneous tissue disorders: Rash, Photosensitivity reaction, Alopecia, Hyperhidrosis, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
• Musculoskeletal and connective tissue disorders: Musculoskeletal stiffness (Bipolar Mania condition). Rhabdomyolysis, Myalgia, Stiffness, Prolonged abnormal contractions of muscle groups.
• Renal and urinary disorders: Urinary incontinence, Urinary retention.
• Pregnancy, puerperium and perinatal conditions: Drug withdrawal syndrome neonatal.
• Reproductive system and breast disorders: Priapism.
• General disorders and administration site conditions: Asthenia/ fatigue. Peripheral oedema (Bipolar Mania condition). Temperature regulation disorder (e.g., hypothermia, pyrexia), Chest pain, Peripheral oedema.
• Investigations: Weight decreased, Weight gain, Alanine Aminotransferase increased, Aspartate Aminotransferase increased, Gamma-glutamyltransferase increased, Alkaline phosphatase increased, QT prolonged, Blood glucose increased, Glycosylated haemoglobin increased, Blood glucose fluctuation, Creatine phosphokinase increased.

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 Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on the SAHPRA website.

In clinical studies and post-marketing experience, accidental or intentional acute overdosage of aripiprazole alone was identified in patients with estimated doses up to 1260 mg with no fatalities. The potentially medically important signs and symptoms observed included lethargy, blood pressure increased, somnolence, tachycardia and vomiting. In addition, reports of accidental overdose with aripiprazole alone (up to 195 mg) in children have been received with no fatalities. The potentially medically serious signs and symptoms reported include somnolence and transient loss of consciousness. Management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. The possibility of multiple medicine involvement should be considered. Therefore, cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible dysrhythmias. Following any confirmed or suspected overdose of XOPHANU ODT, close medical supervision and monitoring should continue until the patient recovers. Activated charcoal (50 g), administered one hour after aripiprazole, decreased aripiprazole AUC and Cmax by 51 and 41 %, respectively, suggesting that charcoal may be effective for overdose management. Although there is no information on the effect of haemodialysis in treating an overdose with XOPHANU ODT, haemodialysis is unlikely to be useful in overdose management since XOPHANU ODT is not eliminated unchanged by the kidneys and is highly bound to plasma proteins.