Aripiprazole Tablets

Schizophrenia: Aripiprazole Alkem is indicated for the treatment of schizophrenia and for the maintenance of clinical improvements in adults.

Bipolar Mania: Aripiprazole Alkem is indicated for the treatment of acute manic episodes associated with Bipolar I disorder and for the prevention of recurrence of new manic episode in patients who experienced predominantly manic episodes and who responded to Aripiprazole Alkem treatment.

Posology: Schizophrenia: The recommended starting dose for Aripiprazole Alkem 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. Aripiprazole Alkem 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 Aripiprazole Alkem 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 Alkem, 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 Alkem monotherapy has not been established. Supplementary therapy should be considered for the prevention or treatment of depressive episodes, as clinically appropriate.

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 When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, the Aripiprazole Alkem dose should then be increased.

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 When the CYP3A4 inducer is withdrawn from the combination therapy, the Aripiprazole Alkem dose should be reduced.

Method of administration: Aripiprazole Alkem is for oral use.

Aripiprazole Alkem is contra-indicated in:

• patients with hypersensitivity to aripiprazole or any other component of Aripiprazole Alkem as listed in section 6.1.
• The safety and efficacy of Aripiprazole Alkem in children under 18 years of age has not been established.

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

Suicide: The possibility of suicide attempt is inherent in psychotic illnesses and mood disorders and close supervision of high-risk patients should accompany medicine therapy. Prescriptions for Aripiprazole Alkem should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Cardiovascular disorders: Aripiprazole as in Aripiprazole Alkem 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 Alkem and preventive measures undertaken.

QT prolongation: Aripiprazole as in Aripiprazole Alkem 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 Aripiprazole Alkem, dose reduction or discontinuation should be considered (see section 4.8). These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.

Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex associated with antipsychotics. Clinical symptoms 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. If a patient develops signs and symptoms indicative of NMS, or present with unexplained high fever without additional clinical manifestation of NMS, all antipsychotic medicine, including Aripiprazole Alkem must be discontinued.

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

Elderly Patients with Dementia - Related Psychosis: Elderly patients with dementia-related psychosis treated with Aripiprazole Alkem are at an increased risk of death. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Cerebrovascular adverse events (e.g. stroke, transient ischaemic attack) including fatalities were reported in elderly patients with psychosis associated with Alzheimeru2019s disease. Aripiprazole Alkem is not indicated for the treatment of patients with dementia-related psychosis.

Orthostatic hypotension: Aripiprazole Alkem may be associated with orthostatic hypotension, perhaps due to its u03b1-1 adrenergic receptor antagonism. Aripiprazole Alkem must be used with caution in patients with hypotension predisposition.

Hypersensitivity: Hypersensitivity reactions, characterised by allergic symptoms, may occur with Aripiprazole Alkem.

Dysphagia: Oesophageal dysmotility and aspiration have been associated with the use of antipsychotics, including Aripiprazole Alkem. Aripiprazole Alkem should be used cautiously in patients at risk for aspiration pneumonia.

Hyperglycaemia/ Diabetes Mellitus: Hyperglycaemia, in some cases extreme and associated with diabetic ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with aripiprazole as in Aripiprazole Alkem. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. Patients treated with any antipsychotics, including Aripiprazole Alkem 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. Patients who develop symptoms of hyperglycaemia during treatment with Aripiprazole Alkem should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when aripiprazole as in Aripiprazole Alkem was discontinued, however some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect medicine.

Weight Gain: Antipsychotic medicines have been associated with metabolic changes, including weight gain. Weight gain has been reported post-marketing experience among patients prescribed oral aripiprazole as in Aripiprazole Alkem. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. Aripiprazole as in Aripiprazole Alkem has not been shown to induce clinically relevant weight gain.

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 Aripiprazole Alkem 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 medicine with anticholinergic activity, or being subject to dehydration.

Pathological gambling and other impulse control disorders: Patients can experience increased urges, particularly for gambling, and the inability to control these urges while taking Aripiprazole Alkem. Other urges, reported, include increased sexual urges, compulsive shopping, binge or compulsive eating, and other impulsive and compulsive behaviours. It is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with Aripiprazole Alkem. 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 medicine was discontinued. Impulse control disorders may result in harm to the patient and others if not recognised. Consider dose reduction or stopping the medicine if a patient develops such urges while taking Aripiprazole Alkem (see section 4.8).

Patients with ADHD comorbidity: Despite the high comorbidity frequency of Bipolar I disorder and ADHD, very limited safety data are available on concomitant use of aripiprazole as in Aripiprazole Alkem and stimulants; therefore, extreme caution should be taken when these medicines are co-administered.

Falls: Aripiprazole as in Aripiprazole Alkem 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).

Excipients: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take Aripiprazole Alkem.

General: Due to its u03b11-adrenergic receptor antagonism, Aripiprazole Alkem has the potential to enhance the effect of certain antihypertensive medicines. There was no effect of a high fat meal on pharmacokinetic of Aripiprazole Alkem. Given the primary central nervous system (CNS) effects of Aripiprazole Alkem, caution should be used when Aripiprazole Alkem is administered in combination with CNS medicines with overlapping adverse reactions such as sedation (see section 4.8). Combination use of Aripiprazole Alkem with alcohol should be avoided. If Aripiprazole Alkem is administered concomitantly with medicines known to cause QT prolongation or electrolyte imbalance, caution should be used.

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

Potential for other medicines to affect Aripiprazole Alkem: A gastric acid blocker, the H2 antagonist famotidine, reduces Aripiprazole Alkem rate of absorption but this effect is deemed not clinically relevant. Aripiprazole Alkem is metabolised by multiple pathways involving the CYP 2D6 and CYP 3A4 enzymes but not CYP 1A enzymes. Thus, no dosage adjustment is required for smokers.

Ketoconazole and other CYP 3A4 inhibitors: A strong inhibitor of CYP 3A4 (such as ketoconazole) increased Aripiprazole Alkem AUC and Cmax by 63 % and 37 %, respectively. The AUC and Cmax of dehydro-aripiprazole increased by 77 % and 43 %, respectively. In CYP 2D6 poor metabolisers, concomitant use of strong inhibitors of CYP 3A4 may result in higher plasma concentrations of Aripiprazole Alkem compared to that in CYP 2D6 extensive metabolisers. When considering concomitant administration of ketoconazole or other strong CYP 3A4 inhibitors with Aripiprazole Alkem, potential benefits should outweigh the potential risks to the patient. When concomitant administration of ketoconazole with Aripiprazole Alkem occurs, Aripiprazole Alkem dose should be reduced to approximately one-half of its prescribed dose. Other strong inhibitors of CYP 3A4, such as itraconazole and HIV protease inhibitors may be expected to have similar effects and similar dose reductions should therefore be applied (see SECTION 4.8). Upon discontinuation of the CYP 2D6 or CYP 3A4 inhibitor, the dosage of Aripiprazole Alkem should be increased to the level prior to the initiation of the concomitant therapy.

When weak inhibitors of CYP 3A4 (e.g. diltiazem) or CYP 2D6 (e.g. escitalopram) are used concomitantly with Aripiprazole Alkem, modest increases in plasma Aripiprazole Alkem concentrations may be expected.

Quinidine and other CYP2D6 inhibitors: A strong inhibitor of CYP2D6 (quinidine) increased aripiprazole as in Aripiprazole Alkem AUC by 107 %, while Cmax was unchanged. The AUC and Cmax of dehydro-aripiprazole, the active metabolite, decreased by 32 % and 47 %, respectively. Aripiprazole Alkem dose should be reduced to approximately one-half of its prescribed dose when concomitant administration of Aripiprazole Alkem 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.

Carbamazepine and other CYP 3A4 inducers: After concomitant administration of carbamazepine, a potent inducer of CYP 3A4, the geometric means of Cmax and AUC for aripiprazole as in Aripiprazole Alkem were 68 % and 73 % lower, respectively, compared to when Aripiprazole Alkem (30 mg) was administered alone. Similarly, for dehydro-aripiprazole the geometric means of Cmax and AUC after carbamazepine co-administration were 69 % and 71 % lower, respectively, than those following treatment with aripiprazole as in Aripiprazole Alkem alone. Aripiprazole Alkem dose should be doubled when concomitant administration of Aripiprazole Alkem occurs with carbamazepine. Other potent inducers of CYP 3A4 (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 potent CYP 3A4 inducers, the dosage of Aripiprazole Alkem should be reduced to the recommended dose.

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

Potential for Aripiprazole Alkem to affect other medicines: 10 u2013 30 mg/day doses of Aripiprazole Alkem had no significant effect on the metabolism of substrates of CYP 2D6 (dextromethorphan/3-methoxymorphinan ratio), CYP 2C9 (warfarin), CYP 2C19 (omeprazole), and CYP 3A4 (dextromethorphan). Additionally, aripiprazole as in Aripiprazole Alkem and dehydro-aripiprazole did not show potential for altering CYP 1A2-mediated metabolism in vitro. Thus, Aripiprazole Alkem is unlikely to cause clinically important medicine interactions mediated by these enzymes. When Aripiprazole Alkem was administered concomitantly with lamotrigine, there was no clinically important change in lamotrigine concentrations.

Pregnancy: Safety of use of Aripiprazole Alkem in pregnancy 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 Aripiprazole Alkem. Neonates exposed to antipsychotics (including Aripiprazole Alkem) 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: Safety of use of aripiprazole as in Aripiprazole Alkem during lactation has not been established. Aripiprazole as in Aripiprazole Alkem is excreted in human breast milk.

Aripiprazole Alkem 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, syncope, vision blurred and diplopia (see section 4.8). Patients should be cautioned about operating hazardous machinery, including motor vehicles until they are reasonably certain that Aripiprazole Alkem does not adversely affect them.

A. Summary of the safety profile: The frequent adverse reactions are akathisia and nausea each occurring in more than 3 % of patients treated with oral aripiprazole.

B. Tabulated list of the adverse reactions: Adverse reactions reported are shown below. Frequencies were defined using the following convention: frequent, less frequent, frequency unknown:

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 u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8. Alternatively all adverse events can be reported to Ascend Laboratories via the e-mail: [email protected].

Accidental or intentional acute overdose of Aripiprazole Alkem alone was identified in adult patients after ingestion of doses up to 1,260 mg with no fatalities. The signs and symptoms are lethargy, increased blood pressure, somnolence, tachycardia and vomiting. Accidental overdose with aripiprazole alone (up to 195 mg) in children had no fatalities. The serious signs and symptoms include somnolence and transient loss of consciousness.

Management of overdose concentrates 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 be started immediately and should include continuous electrocardiographic monitoring to detect possible dysrhythmias. Following any confirmed or suspected overdose with Aripiprazole Alkem, close medical supervision and monitoring should continue until the patient recovers. Activated charcoal (50 g), administered one hour after Aripiprazole Alkem, decreases aripiprazole Cmax by about 41 % and AUC by about 51 %, suggesting that charcoal may be effective in the treatment of overdose management. Although there is no information on the effect of haemodialysis in treating an overdose with aripiprazole, haemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.