Signs and symptoms
In clinical trials and post-marketing experience, accidental or intentional acute overdose of Aripiprazol Sandoz alone was identified in adult patients with reported estimated doses up to 1,260 mg with no fatalities. The potentially medically important signs and symptoms observed included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting and diarrhoea. In addition, reports of accidental overdose with Aripiprazol Sandoz alone (up to 195 mg) in children have been received with no fatalities. The potentially medically serious signs and symptoms reported included somnolence, transient loss of consciousness and extrapyramidal symptoms.
Management of overdose
Management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. The possibility of multiple medicinal product involvement should be considered. Therefore cardiovascular monitoring should be started immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Following any confirmed or suspected overdose with Aripiprazol Sandoz, close medical supervision and monitoring should continue until the patient recovers.
Activated charcoal (50 g), administered one hour after Aripiprazol Sandoz, decreased Aripiprazol Sandoz Cmax by about 41% and AUC by about 51%, suggesting that charcoal may be effective in the treatment of overdose.
Haemodialysis
Although there is no information on the effect of haemodialysis in treating an overdose with Aripiprazol Sandoz, haemodialysis is unlikely to be useful in overdose management since Aripiprazol Sandoz is highly bound to plasma proteins.
Not applicable.
Summary of the safety profile
The most commonly reported adverse reactions in placebo-controlled trials are akathisia and nausea each occurring in more than 3% of patients treated with oral Aripiprazol Sandoz.
Tabulated list of adverse reactions
The following adverse reactions occurred more often (> 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*).
The frequency listed below is defined using the following convention: common (> 1/100 to < 1/10) and uncommon (> 1/1,000 to < 1/100).
| Endocrine disorders | |
Uncommon: | hyperprolactinaemia |
| Psychiatric disorders | |
Common: Uncommon: Not Known: | restlessness, insomnia, anxiety depression* aggression |
| Nervous system disorders | |
Common: | extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache |
| Eye disorders | |
Common: | blurred vision |
| Cardiac disorders | |
Uncommon: | tachycardia* |
| Vascular disorders | |
| Uncommon: | orthostatic hypotension* |
| Gastrointestinal disorders | |
Common: | dyspepsia, vomiting, nausea, constipation, salivary hypersecretion |
| General disorders and administration site conditions | |
Common: | fatigue |
Description of selected adverse reactions
Extrapyramidal symptoms (EPS)
Schizophrenia - in a long term 52-week controlled trial, Aripiprazol Sandoz-treated patients had an overall-lower incidence (25.8%) of EPS including parkinsonism, akathisia, dystonia and dyskinesia compared with those treated with haloperidol (57.3%). In a long term 26-week placebo-controlled trial, the incidence of EPS was 19% for Aripiprazol Sandoz-treated patients and 13.1% for placebo-treated patients. In another long-term 26-week controlled trial, the incidence of EPS was 14.8% for Aripiprazol Sandoz-treated patients and 15.1% for olanzapine-treated patients.
Manic episodes in Bipolar I Disorder - in a 12-week controlled trial, the incidence of EPS was 23.5% for Aripiprazol Sandoz-treated patients and 53.3% for haloperidol-treated patients. In another 12-week trial, the incidence of EPS was 26.6% for patients treated with Aripiprazol Sandoz and 17.6% for those treated with lithium. In the long term 26-week maintenance phase of a placebo-controlled trial, the incidence of EPS was 18.2% for Aripiprazol Sandoz-treated patients and 15.7% for placebo-treated patients.
Akathisia
In placebo-controlled trials, the incidence of akathisia in bipolar patients was 12.1% with Aripiprazol Sandoz and 3.2% with placebo. In schizophrenia patients the incidence of akathisia was 6.2% with Aripiprazol Sandoz and 3.0% with placebo.
Dystonia
Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
Comparisons between Aripiprazol Sandoz and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory and lipid parameters revealed no medically important differences. Elevations of CPK (Creatine Phosphokinase), generally transient and asymptomatic, were observed in 3.5% of Aripiprazol Sandoz treated patients as compared to 2.0% of patients who received placebo.
Other findings
Adverse reactions known to be associated with antipsychotic therapy and also reported during treatment with Aripiprazol Sandoz include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse reactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus.
Paediatric population
Schizophrenia in adolescents aged 15 years and older
In a short-term placebo-controlled clinical trial involving 302 adolescents (13-17 years) with schizophrenia, the frequency and type of undesirable effects were similar to those in adults except for the following reactions that were reported more frequently in adolescents receiving Aripiprazol Sandoz than in adults receiving Aripiprazol Sandoz (and more frequently than placebo):
somnolence/sedation and extrapyramidal disorder were reported very commonly (> 1/10), and dry mouth, increased appetite, and orthostatic hypotension were reported commonly (> 1/100, < 1/10).The safety profile in a 26-week open-label extension trial was similar to that observed in the short term, placebo-controlled trial.
In the pooled adolescent schizophrenia population (13-17 years) with exposure up to 2 years, incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 29.5% and 48.3%, respectively.In the adolescent (13-17 years) schizophrenia population with Aripiprazol Sandoz exposure of 5 to 30 mg up to 72 months, incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 25.6% and 45.0%, respectively.
Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older
The frequency and type of undesirable effects in adolescents with Bipolar I Disorder were similar to those in adults except for the following reactions: very commonly (> 1/10) somnolence (23.0%), extrapyramidal disorder (18.4%), akathisia (16.0%), and fatigue (11.8%); and commonly (> 1/100, < 1/10) abdominal pain upper, heart rate increased, weight increased, increased appetite, muscle twitching, and dyskinesia.
The following undesirable effects had a possible dose response relationship; extrapyramidal disorder (incidences were 10 mg, 9.1%, 30 mg, 28.8%, placebo, 1.7%,); and akathisia (incidences were 10 mg, 12.1%, 30 mg, 20.3%, placebo, 1.7%).
Mean changes in body weight in adolescents with Bipolar I Disorder at 12 and 30 weeks for Aripiprazol Sandoz were 2.4 kg and 5.8 kg, and for placebo 0.2 kg and 2.3 kg, respectively.
In the paediatric population somnolence and fatigue were observed more frequently in patients with bipolar disorder compared to patients with schizophrenia.
In the paediatric bipolar population (10-17 years) with exposure up to 30 weeks, incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 28.0% and 53.3%, respectively.
Hyperprolactinaemia
Post-Marketing
The following adverse reactions have been reported during post-marketing surveillance. The frequency of these reactions is considered not known (cannot be estimated from the available data).
| Blood and lymphatic system disorders: | leukopenia, neutropenia, thrombocytopenia disorders: |
| Immune system disorders: | allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) |
| Endocrine disorders: | hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma |
| Metabolism and nutrition disorders: | weight gain, weight decreased, anorexia, hyponatremia |
| Psychiatric disorders: | agitation, nervousness, pathological gambling; suicide attempt, suicidal ideation, and completed suicide |
| Nervous system disorders: | speech disorder, Neuroleptic Malignant Syndrome (NMS), grand mal convulsion, serotonin syndrome |
| Cardiac disorders: | QT prolongation, ventricular arrhythmias, sudden unexplained death, cardiac arrest, torsades de pointes, bradycardia |
| Vascular disorders: | syncope, hypertension, venous thromboembolism (including pulmonary embolism and deep vein thrombosis) |
| Respiratory, thoracic and mediastinal disorders: | oropharyngeal spasm, laryngospasm, aspiration pneumonia |
| Gastrointestinal disorders: | pancreatitis, dysphagia, abdominal discomfort, stomach discomfort, diarrhoea |
| Hepatobiliary disorders: | hepatic failure, jaundice, hepatitis, increased Alanine Aminotransferase (ALT), increased Aspartate Aminotransferase (AST), increased Gamma Glutamyl Transferase (GGT), increased alkaline phosphatase |
| Skin and subcutaneous tissue disorders: | rash, photosensitivity reaction, alopecia, hyperhidrosis |
| Musculoskeletal and connective tissue disorders: | rhabdomyolysis, myalgia, stiffness |
| Pregnancy, puerperium and perinatal conditions: | drug withdrawal syndrome neonatal |
| Renal and urinary disorders: | urinary incontinence, urinary retention |
| Reproductive system and breast disorders: | priapism |
| General disorders and administration site conditions: | temperature regulation disorder (e.g. hypothermia, pyrexia), chest pain, peripheral oedema |
| Investigations: | increased Creatine Phosphokinase, blood glucose increased, blood glucose fluctuation, glycosylated haemoglobin increased. |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
Summary of the safety profile
The most commonly reported adverse reactions in placebo-controlled trials are akathisia and nausea each occurring in more than 3% of patients treated with oral aripiprazole.
Tabulated list of adverse reactions
The incidences of the Adverse Drug Reactions (ADRs) associated with aripiprazole therapy are tabulated below. The table is based on adverse events reported during clinical trials and/or post-marketing use.
All ADRs are listed by system organ class and frequency; 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse events is qualified as “not knownâ€
| Common | Uncommon | Not known | |
| 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, or urticaria) | ||
| Endocrine disorders | Hyperprolactinaemia | Diabetic hyperosmolar coma Diabetic ketoacidosis | |
| Metabolism and nutrition disorders | Diabetes mellitus | Hyperglycaemia | Hyponatremia Anorexia Weight decreased Weight gain |
| Psychiatric disorders | Insomnia Anxiety Restlessness | Depression, Hypersexuality | Suicide attempt, suicidal ideation and completed suicide Pathological gambling Impulse-control disorders Binge eating Compulsive shopping Poriomania Aggression Agitation Nervousness |
| Nervous system disorders | Akathisia Extrapyramidal disorder Tremor Headache Sedation Somnolence Dizziness | Tardive dyskinesia Dystonia | Neuroleptic Malignant Syndrome (NMS) Grand mal convulsion Serotonin syndrome Speech disorder |
| Eye disorders | Vision blurred | Diplopia | |
| Cardiac disorders | Tachycardia | Sudden unexplained death Torsades de pointes QT prolongation Ventricular arrhythmias Cardiac arrest Bradycardia | |
| Vascular disorders | Orthostatic hypotension | Venous thromboembolism (including pulmonary embolism and deep vein thrombosis) Hypertension Syncope | |
| Respiratory, thoracic and mediastinal disorders | Hiccups | Aspiration pneumonia Laryngospasm Oropharyngeal spasm | |
| Gastrointestinal disorders | Constipation Dyspepsia Nausea Salivary hypersecretion Vomiting | Pancreatitis Dysphagia Diarrhoea Abdominal discomfort Stomach discomfort | |
| Hepatobiliary disorders | Hepatic failure Hepatitis Jaundice Increased Alanine Aminotransferase (ALT) Increased Aspartate Aminotransferase (AST) Increased Gamma Glutamyl Transferase (GGT) Increased alkaline phosphatase | ||
| Skin and subcutaneous tissue disorders | Rash Photosensitivity reaction Alopecia Hyperhidrosis | ||
| Musculoskeletal and connective tissue disorders | Rhabdomyolysis Myalgia Stiffness | ||
| 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 | Fatigue | Temperature regulation disorder (e.g. hypothermia, pyrexia) Chest pain Peripheral oedema | |
| Investigations | Blood glucose increased Glycosylated haemoglobin increased Blood glucose fluctuation Increased creatine phosphokinase |
Description of selected adverse reactions
Adults
Extrapyramidal symptoms (EPS)
Schizophrenia: in a long term 52-week controlled trial, aripiprazole-treated patients had an overall-lower incidence (25.8 %) of EPS including Parkinsonism, akathisia, dystonia and dyskinesia compared with those treated with haloperidol (57.3 %). In a long term 26-week placebo-controlled trial, the incidence of EPS was 19 % for aripiprazole-treated patients and 13.1 % for placebo-treated patients. In another long-term 26-week controlled trial, the incidence of EPS was 14.8 % for aripiprazole-treated patients and 15.1 % for olanzapine-treated patients.
Manic episodes in Bipolar I Disorder: in a 12-week controlled trial, the incidence of EPS was 23.5 % for aripiprazole-treated patients and 53.3 % for haloperidol-treated patients. In another 12-week trial, the incidence of EPS was 26.6 % for patients treated with aripiprazole and 17.6 % for those treated with lithium. In the long term 26-week maintenance phase of a placebo-controlled trial, the incidence of EPS was 18.2 % for aripiprazole-treated patients and 15.7 % for placebo-treated patients.
Akathisia
In placebo-controlled trials, the incidence of akathisia in bipolar patients was 12.1 % with aripiprazole and 3.2 % with placebo. In schizophrenia patients the incidence of akathisia was 6.2 % with aripiprazole and 3.0 % with placebo.
Dystonia
Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic medicinal products. An elevated risk of acute dystonia is observed in males and younger age groups.
Prolactin
In clinical trials for the approved indications and post-marketing, both increase and decrease in serum prolactin as compared to baseline was observed with aripiprazole (section 5.1).
Laboratory parameters
Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory and lipid parameters revealed no medically important differences. Elevations of CPK (Creatine Phosphokinase), generally transient and asymptomatic, were observed in 3.5 % of aripiprazole treated patients as compared to 2.0 % of patients who received placebo.
Paediatric population
Schizophrenia in adolescents aged 15 years and older
In a short-term placebo-controlled clinical trial involving 302 adolescents (13-17 years) with schizophrenia, the frequency and type of adverse reactions were similar to those in adults except for the following reactions that were reported more frequently in adolescents receiving aripiprazole than in adults receiving aripiprazole (and more frequently than placebo):
Somnolence/sedation and extrapyramidal disorder were reported very commonly (> 1/10), and dry mouth, increased appetite, and orthostatic hypotension were reported commonly (> 1/100, < 1/10). The safety profile in a 26-week open-label extension trial was similar to that observed in the short-term, placebo-controlled trial.
The safety profile of a long-term, double-blind placebo controlled trial was also similar except for the following reactions that were reported more frequently than paediatric patients taking placebo: weight decreased, blood insulin increased, arrhythmia, and leukopenia were reported commonly (> 1/100, < 1/10).
In the pooled adolescent schizophrenia population (13-17 years) with exposure up to 2 years, incidence of low serum prolactin levels in females (<3 ng/ml) and males (< 2 ng/ml) was 29.5 % and 48.3 %, respectively. In the adolescent (13-17 years) schizophrenia population with aripiprazole exposure of 5 to 30 mg up to 72 months, incidence of low serum prolactin levels in females (<3 ng/ml) and males (< 2 ng/ml) was 25.6 % and 45.0 %, respectively.
In two long term trials with adolescent (13-17 years) schizophrenia and bipolar patients treated with aripiprazole, incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 37.0 % and 59.4 %, respectively.
Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older
The frequency and type of adverse reactions in adolescents with Bipolar I Disorder were similar to those in adults except for the following reactions: very commonly (> 1/10) somnolence (23.0 %), extrapyramidal disorder (18.4 %), akathisia (16.0 %), and fatigue (11.8 %); and commonly (> 1/100, < 1/10) abdominal pain upper, heart rate increased, weight increased, increased appetite, muscle twitching, and dyskinesia.
The following adverse reactions had a possible dose response relationship; extrapyramidal disorder (incidences were 10 mg, 9.1 %, 30 mg, 28.8 %, placebo, 1.7 %,); and akathisia (incidences were 10 mg, 12.1 %, 30 mg, 20.3 %, placebo, 1.7 %).
Mean changes in body weight in adolescents with Bipolar I Disorder at 12 and 30 weeks for aripiprazole were 2.4 kg and 5.8 kg, and for placebo 0.2 kg and 2.3 kg, respectively.
In the paediatric population somnolence and fatigue were observed more frequently in patients with bipolar disorder compared to patients with schizophrenia.
In the paediatric bipolar population (10-17 years) with exposure up to 30 weeks, incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) was 28.0 % and 53.3 %, respectively.
Pathological gambling and other impulse control disorders
Pathological gambling, hypersexuality, compulsive shopping and binge or compulsive eating can occur in patients treated with aripiprazole.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Non-clinical safety data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.
Toxicologically significant effects were observed only at doses or exposures that were sufficiently in excess of the maximum human dose or exposure, indicating that these effects were limited or of no relevance to clinical use. These included: dose-dependent adrenocortical toxicity (lipofuscin pigment accumulation and/or parenchymal cell loss) in rats after 104 weeks at 20 to 60 mg/kg/day (3 to 10 times the mean steady-state AUC at the maximum recommended human dose) and increased adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas in female rats at 60 mg/kg/day (10 times the mean steady-state AUC at the maximum recommended human dose). The highest nontumorigenic exposure in female rats was 7 times the human exposure at the recommended dose.
An additional finding was cholelithiasis as a consequence of precipitation of sulphate conjugates of hydroxy metabolites of Aripiprazol Sandoz in the bile of monkeys after repeated oral dosing at 25 to 125 mg/kg/day (1 to 3 times the mean steady-state AUC at the maximum recommended clinical dose or 16 to 81 times the maximum recommended human dose based on mg/m2). However, the concentrations of the sulphate conjugates of hydroxy Aripiprazol Sandoz in human bile at the highest dose proposed, 30 mg per day, were no more than 6% of the bile concentrations found in the monkeys in the 39-week study and are well below (6%) their limits of in vitro solubility.
In repeat-dose studies in juvenile rats and dogs, the toxicity profile of Aripiprazol Sandoz was comparable to that observed in adult animals, and there was no evidence of neurotoxicity or adverse effects on development.
Based on results of a full range of standard genotoxicity tests, Aripiprazol Sandoz was considered nongenotoxic. Aripiprazol Sandoz did not impair fertility in reproductive toxicity studies. Developmental toxicity, including dose-dependent delayed foetal ossification and possible teratogenic effects, were observed in rats at doses resulting in subtherapeutic exposures (based on AUC) and in rabbits at doses resulting in exposures 3 and 11 times the mean steady-state AUC at the maximum recommended clinical dose. Maternal toxicity occurred at doses similar to those eliciting developmental toxicity.
Aripiprazol Sandoz Milpharm is indicated for the treatment of schizophrenia in adults and in adolescents aged 15 years and older.
Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12
Mechanism of action
It has been proposed that Aripiprazol Sandoz's efficacy in schizophrenia is mediated through a combination of partial agonism at dopamine D2 and serotonin 5HT1a receptors and antagonism of serotonin 5HT2a receptors. Aripiprazol Sandoz exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypoactivity. Aripiprazol Sandoz exhibited high binding affinity in vitro for dopamine D2 and D3, serotonin 5HT1a and 5HT2a receptors and moderate affinity for dopamine D4, serotonin 5HT2c and 5HT7, alpha-1 adrenergic and histamine H1 receptors. Aripiprazol Sandoz also exhibited moderate binding affinity for the serotonin reuptake site and no appreciable affinity for muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of Aripiprazol Sandoz.
Aripiprazol Sandoz doses ranging from 0.5 to 30 mg administered once a day to healthy subjects for 2 weeks produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, to the caudate and putamen detected by positron emission tomography.
Clinical efficacy and safety
Schizophrenia
In three short-term (4 to 6 weeks) placebo-controlled trials involving 1,228 schizophrenic adult patients, presenting with positive or negative symptoms, Aripiprazol Sandoz was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo.
Aripiprazol Sandoz is effective in maintaining the clinical improvement during continuation therapy in adult patients who have shown an initial treatment response. In a haloperidol-controlled trial, the proportion of responder patients maintaining response to medicinal product at 52-weeks was similar in both groups (Aripiprazol Sandoz 77% and haloperidol 73%). The overall completion rate was significantly higher for patients on Aripiprazol Sandoz (43%) than for haloperidol (30%). Actual scores in rating scales used as secondary endpoints, including PANSS and the Montgomery-Asberg Depression Rating Scale showed a significant improvement over haloperidol.
In a 26-week, placebo-controlled trial in adult stabilised patients with chronic schizophrenia, Aripiprazol Sandoz had significantly greater reduction in relapse rate, 34% in Aripiprazol Sandoz group and 57% in placebo.
Weight gain
In clinical trials Aripiprazol Sandoz has not been shown to induce clinically relevant weight gain. In a 26- week, olanzapine-controlled, double-blind, multi-national study of schizophrenia which included 314 adult patients and where the primary end-point was weight gain, significantly less patients had at least 7% weight gain over baseline (i.e. a gain of at least 5.6 kg for a mean baseline weight of ~80.5 kg) on Aripiprazol Sandoz (n= 18, or 13% of evaluable patients), compared to olanzapine (n= 45, or 33% of evaluable patients).
Lipid parameters
In a pooled analysis on lipid parameters from placebo controlled clinical trials in adults, Aripiprazol Sandoz has not been shown to induce clinically relevant alterations in levels of total cholesterol, triglycerides, HDL and LDL.
-Total cholesterol: incidence of changes in levels from normal (<5.18 mmol/l) to high (> 6.22 mmol/l) was 2.5% for Aripiprazol Sandoz and 2.8% for placebo and mean change from baseline was -0.15 mmol/l (95% CI: -0.182, -0.115) for Aripiprazol Sandoz and -0.11 mmol/l (95% CI: -0.148, -0.066) for placebo.
-Fasting triglycerides: incidence of changes in levels from normal (<1.69 mmol/l) to high (> 2.26 mmol/l) was 7.4% for Aripiprazol Sandoz and 7.0% for placebo and mean change from baseline was -0.11 mmol/l (95% CI: -0.182, -0.046) for Aripiprazol Sandoz and -0.07 mmol/l (95% CI: -0.148, 0.007) for placebo.
-HDL: incidence of changes in levels from normal (> 1.04 mmol/l) to low (<1.04 mmol/l) was 11.4% for Aripiprazol Sandoz and 12.5% for placebo and mean change from baseline was -0.03 mmol/l (95% CI: -.046, -0.017) for Aripiprazol Sandoz and -0.04 mmol/l (95% CI: -0.056, -0.022) for placebo.
-Fasting LDL: incidence of changes in levels from normal (<2.59 mmol/l) to high (> 4.14 mmol/l) was 0.6% for Aripiprazol Sandoz and 0.7% for placebo and mean change from baseline was -0.09 mmol/l (95% CI: -0.139, -0.047) for Aripiprazol Sandoz and -0.06 mmol/l (95% CI: -0.116, -0.012) for placebo.
Paediatric population
Schizophrenia in adolescents
In a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients (13-17 years), presenting with positive or negative symptoms, Aripiprazol Sandoz was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo.
In a sub-analysis of the adolescent patients between the ages of 15 to 17 years, representing 74% of the total enrolled population, maintenance of effect was observed over the 26-week open-label extension trial.
The most common treatment-emergent adverse events among patients receiving 30 mg were extrapyramidal disorder (28.3%), somnolence (27.3%), headache (23.2%), and nausea (14.1%). Mean weight gain in the 30 weeks treatment-interval was 2.9 kg as compared to 0.98 kg in patients treated with placebo.
Irritability associated with autistic disorder in paediatric patients
Aripiprazol Sandoz was studied in patients aged 6 to 17 years in two 8-week, placebo-controlled trials [one flexible-dose (2-15 mg/day) and one fixed-dose (5, 10, or 15 mg/day)] and in one 52-week open-label trial. Dosing in these trials was initiated at 2 mg/day, increased to 5 mg/day after one week, and increased by 5 mg/day in weekly increments to the target dose. Over 75% of patients were less than 13 years of age. Aripiprazol Sandoz demonstrated statistically superior efficacy compared to placebo on the Aberrant behaviour Checklist Irritability subscale. However, the clinical relevance of this finding has not been established. The safety profile included weight gain and changes in prolactin levels. The duration of the long-term safety study was limited to 52 weeks. In the pooled trials, the incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) in Aripiprazol Sandoz-treated patients was 27/46 (58.7%) and 258/298 (86.6%), respectively. In the placebo-controlled trials, the mean weight gain was 0.4 kg for placebo and 1.6 kg for Aripiprazol Sandoz.
Aripiprazol Sandoz was also studied in a placebo-controlled, long-term maintenance trial. After a 13-26 week stabilisation on Aripiprazol Sandoz (2-15 mg/day) patients with a stable response were either maintained on Aripiprazol Sandoz or substituted to placebo for further 16 weeks. Kaplan-Meier relapse rates at week 16 were 35% for Aripiprazol Sandoz and 52% for placebo; the hazard ratio for relapse within 16 weeks (Aripiprazol Sandoz/placebo) was 0.57 (non-statistically significant difference). The mean weight gain over the stabilisation phase (up to 26 weeks) on Aripiprazol Sandoz was 3.2 kg, and a further mean increase of 2.2 kg for Aripiprazol Sandoz as compared to 0.6 kg for placebo was observed in the second phase (16 weeks) of the trial. Extrapyramidal symptoms were mainly reported during the stabilisation phase in 17% of patients, with tremor accounting for 6.5%.
Tics associated with Tourette's disorder in paediatric patients
The efficacy of Aripiprazol Sandoz was studied in paediatric subjects with Tourette's disorder (Aripiprazol Sandoz:
n = 99, placebo: n = 44) in a randomised, double-blind, placebo controlled, 8 week study using a fixed dose weight-based treatment group design over the dose range of 5 mg/day to 20 mg/day and a starting dose of 2 mg.).
Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX12
Mechanism of action
It has been proposed that aripiprazole's efficacy in schizophrenia and Bipolar I Disorder is mediated through a combination of partial agonism at dopamine D2 and serotonin 5HT1a receptors and antagonism of serotonin 5HT2a receptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypoactivity. Aripiprazole exhibited high binding affinity in vitro for dopamine D2 and D3, serotonin 5HT1a and 5HT2a receptors and moderate affinity for dopamine D4, serotonin 5HT2c and 5HT7, alpha-1 adrenergic and histamine H1 receptors. Aripiprazole also exhibited moderate binding affinity for the serotonin reuptake site and no appreciable affinity for muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.
Aripiprazole doses ranging from 0.5 to 30 mg administered once a day to healthy subjects for 2 weeks produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, to the caudate and putamen detected by positron emission tomography.
Clinical efficacy and safety
Adults
Schizophrenia
In three short-term (4 to 6 weeks) placebo-controlled trials involving 1,228 schizophrenic adult patients, presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo.
Aripiprazole is effective in maintaining the clinical improvement during continuation therapy in adult patients who have shown an initial treatment response. In a haloperidol-controlled trial, the proportion of responder patients maintaining response to medicinal product at 52-weeks was similar in both groups (aripiprazole 77 % and haloperidol 73 %). The overall completion rate was significantly higher for patients on aripiprazole (43 %) than for haloperidol (30 %). Actual scores in rating scales used as secondary endpoints, including PANSS and the Montgomery-Asberg Depression Rating Scale showed a significant improvement over haloperidol.
In a 26-week, placebo-controlled trial in adult stabilised patients with chronic schizophrenia, aripiprazole had significantly greater reduction in relapse rate, 34 % in aripiprazole group and 57 % in placebo.
Weight gain
In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain. In a 26-week, olanzapine-controlled, double-blind, multi-national study of schizophrenia which included 314 adult patients and where the primary end-point was weight gain, significantly less patients had at least 7 % weight gain over baseline (i.e. a gain of at least 5.6 kg for a mean baseline weight of ~80.5 kg) on aripiprazole (n = 18, or 13 % of evaluable patients), compared to olanzapine (n = 45, or 33 % of evaluable patients).
Lipid parameters
In a pooled analysis on lipid parameters from placebo controlled clinical trials in adults, aripiprazole has not been shown to induce clinically relevant alterations in levels of total cholesterol, triglycerides, HDL and LDL.
Prolactin
Prolactin levels were evaluated in all trials of all doses of aripiprazole (n = 28,242). The incidence of hyperprolactinaemia or increased serum prolactin in patients treated with aripiprazole (0.3 %) was similar to that of placebo (0.2 %). For patients receiving aripiprazole, the median time to onset was 42 days and median duration was 34 days.
The incidence of hypoprolactinaemia or decreased serum prolactin in patients treated with aripiprazole was 0.4 %, compared with 0.02 % for patients treated with placebo. For patients receiving aripiprazole, the median time to onset was 30 days and median duration was 194 days.
Manic episodes in Bipolar I Disorder
In two 3-week, flexible-dose, placebo-controlled monotherapy trials involving patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole demonstrated superior efficacy to placebo in reduction of manic symptoms over 3 weeks. These trials included patients with or without psychotic features and with or without a rapid-cycling course.
In one 3-week, fixed-dose, placebo-controlled monotherapy trial involving patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole failed to demonstrate superior efficacy to placebo.
In two 12-week, placebo- and active-controlled monotherapy trials in patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, aripiprazole demonstrated superior efficacy to placebo at week 3 and a maintenance of effect comparable to lithium or haloperidol at week 12. Aripiprazole also demonstrated a comparable proportion of patients in symptomatic remission from mania as lithium or haloperidol at week 12.
In a 6-week, placebo-controlled trial involving patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, who were partially non-responsive to lithium or valproate monotherapy for 2 weeks at therapeutic serum levels, the addition of aripiprazole as adjunctive therapy resulted in superior efficacy in reduction of manic symptoms than lithium or valproate monotherapy.
In a 26-week, placebo-controlled trial, followed by a 74-week extension, in manic patients who achieved remission on aripiprazole during a stabilization phase prior to randomisation, aripiprazole demonstrated superiority over placebo in preventing bipolar recurrence, primarily in preventing recurrence into mania but failed to demonstrate superiority over placebo in preventing recurrence into depression.
In a 52-week, placebo-controlled trial, in patients with a current manic or mixed episode of Bipolar I Disorder who achieved sustained remission (Y-MRS and MADRS total scores ≤ 12) on aripiprazole (10 mg/day to 30 mg/day) adjunctive to lithium or valproate for 12 consecutive weeks, adjunctive aripiprazole demonstrated superiority over placebo with a 46 % decreased risk (hazard ratio of 0.54) in preventing bipolar recurrence and a 65 % decreased risk (hazard ratio of 0.35) in preventing recurrence into mania over adjunctive placebo but failed to demonstrate superiority over placebo in preventing recurrence into depression. Adjunctive aripiprazole demonstrated superiority over placebo on the secondary outcome measure, CGI-BP Severity of Illness score (mania). In this trial, patients were assigned by investigators with either open-label lithium or valproate monotherapy to determine partial non-response. Patients were stabilised for at least 12 consecutive weeks with the combination of aripiprazole and the same mood stabilizer. Stabilized patients were then randomised to continue the same mood stabilizer with double-blind aripiprazole or placebo. Four mood stabilizer subgroups were assessed in the randomised phase: aripiprazole + lithium; aripiprazole + valproate; placebo + lithium; placebo + valproate. The Kaplan-Meier rates for recurrence to any mood episode for the adjunctive treatment arm were 16 % in aripiprazole + lithium and 18 % in aripiprazole + valproate compared to 45 % in placebo + lithium and 19 % in placebo + valproate.
Paediatric population
Schizophrenia in adolescents
In a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients (13-17 years), presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo. In a sub-analysis of the adolescent patients between the ages of 15 to 17 years, representing 74 % of the total enrolled population, maintenance of effect was observed over the 26-week open-label extension trial.
In a 60- to 89-week, randomised, double-blind, placebo-controlled trial in adolescent subjects (n = 146; ages 13-17 years) with schizophrenia, there was a statistically significant difference in the rate of relapse of psychotic symptoms between the aripiprazole (19.39%) and placebo (37.50%) groups. The point estimate of the hazard ratio (HR) was 0.461 (95% confidence interval, 0.242-0.879) in the full population. In subgroup analyses the point estimate of the HR was 0.495 for subjects 13 to 14 years of age compared to 0.454 for subjects 15 to 17 years of age. However, the estimation of the HR for the younger (13-14 years) group was not precise, reflecting the smaller number of subjects in that group (aripiprazole, n = 29; placebo, n = 12), and the confidence interval for this estimation (ranging from 0.151 to 1.628) did not allow conclusions to be drawn on the presence of a treatment effect. In contrast the 95% confidence interval for the HR in the older subgroup (aripiprazole, n = 69; placebo, n = 36) was 0.242 to 0.879 and hence a treatment effect could be concluded in the older patients.
Manic episodes in Bipolar I Disorder in children and adolescents
Aripiprazole was studied in a 30-week placebo-controlled trial involving 296 children and adolescents (10-17 years), who met DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes with or without psychotic features and had a Y-MRS score > 20 at baseline. Among the patients included in the primary efficacy analysis, 139 patients had a current co-morbid diagnosis of ADHD.
Aripiprazole was superior to placebo in change from baseline at week 4 and at week 12 on the Y-MRS total score. In a post-hoc analysis, the improvement over placebo was more pronounced in the patients with associated co-morbidity of ADHD compared to the group without ADHD, where there was no difference from placebo. Recurrence prevention was not established.
The most common treatment-emergent adverse events among patients receiving 30 mg were extrapyramidal disorder (28.3 %), somnolence (27.3 %), headache (23.2 %), and nausea (14.1 %). Mean weight gain in the 30 weeks treatment-interval was 2.9 kg as compared to 0.98 kg in patients treated with placebo.
Irritability associated with autistic disorder in paediatric patients
Aripiprazole was studied in patients aged 6 to 17 years in two 8-week, placebo-controlled trials [one flexible-dose (2-15 mg/day) and one fixed-dose (5, 10, or 15 mg/day)] and in one 52-week open-label trial. Dosing in these trials was initiated at 2 mg/day, increased to 5 mg/day after one week, and increased by 5 mg/day in weekly increments to the target dose. Over 75 % of patients were less than 13 years of age. Aripiprazole demonstrated statistically superior efficacy compared to placebo on the Aberrant Behaviour Checklist Irritability subscale. However, the clinical relevance of this finding has not been established. The safety profile included weight gain and changes in prolactin levels. The duration of the long-term safety study was limited to 52 weeks. In the pooled trials, the incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) in aripiprazole-treated patients was 27/46 (58.7 %) and 258/298 (86.6 %), respectively. In the placebo-controlled trials, the mean weight gain was 0.4 kg for placebo and 1.6 kg for aripiprazole.
Aripiprazole was also studied in a placebo-controlled, long-term maintenance trial. After a 13-26 week stabilisation on aripiprazole (2-15 mg/day) patients with a stable response were either maintained on aripiprazole or substituted to placebo for further 16 weeks. Kaplan-Meier relapse rates at week 16 were 35 % for aripiprazole and 52 % for placebo; the hazard ratio for relapse within 16 weeks (aripiprazole/placebo) was 0.57 (non-statistically significant difference). The mean weight gain over the stabilisation phase (up to 26 weeks) on aripiprazole was 3.2 kg, and a further mean increase of 2.2 kg for aripiprazole as compared to 0.6 kg for placebo was observed in the second phase (16 weeks) of the trial. Extrapyramidal symptoms were mainly reported during the stabilisation phase in 17 % of patients, with tremor accounting for 6.5 %.
Tics associated with Tourette's disorder in paediatric patients
The efficacy of aripiprazole was studied in paediatric subjects with Tourette's disorder (aripiprazole: n = 99, placebo: n = 44) in a randomised, double-blind, placebo controlled, 8 week study using a fixed dose weight-based treatment group design over the dose range of 5 mg/day to 20 mg/day and a starting dose of 2 mg. Patients were 7 - 17 years of age and presented an average score of 30 on Total Tic Score on the Yale Global Tic Severity Scale (TTS-YGTSS) at baseline. Aripiprazole showed an improvement on TTS-YGTSS change from baseline to week 8 of 13.35,for the low dose group (5 mg or 10 mg) and 16.94 for the high dose group (10 mg or 20 mg) as compared with an improvement of 7.09 in the placebo group.
The efficacy of aripiprazole in paediatric subjects with Tourette's syndrome (aripiprazole: n = 32, placebo: n = 29) was also evaluated over a flexible dose range of 2 mg/day to 20 mg/day and a starting dose of 2 mg, in a 10 week, randomised, double blind, placebo-controlled study conducted in South-Korea. Patients were 6 - 18 years and presented an average score of 29 on TTS-YGTSS at baseline. Aripiprazole group showed an improvement of 14.97 on TTS-YGTSS change from baseline to week 10 as compared with an improvement of 9.62 in the placebo group.
In both of these short term trials, the clinical relevance of the efficacy findings has not been established, considering the magnitude of treatment effect compared to the large placebo effect and the unclear effects regarding psycho-social functioning. No long term data are available with regard to the efficacy and the safety of aripiprazole in this fluctuating disorder.
).
Absorption
Aripiprazol Sandoz is well absorbed, with peak plasma concentrations occurring within 3-5 hours after dosing. Aripiprazol Sandoz undergoes minimal pre-systemic metabolism. The absolute oral bioavailability of the tablet formulation is 87%. There is no effect of a high fat meal on the pharmacokinetics of Aripiprazol Sandoz.
Distribution
Aripiprazol Sandoz is widely distributed throughout the body with an apparent volume of distribution of 4.9 l/kg, indicating extensive extravascular distribution. At therapeutic concentrations, Aripiprazol Sandoz and dehydro-Aripiprazol Sandoz are greater than 99% bound to serum proteins, binding primarily to albumin.
Biotransformation
Aripiprazol Sandoz is extensively metabolised by the liver primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of Aripiprazol Sandoz, and N- dealkylation is catalysed by CYP3A4. Aripiprazol Sandoz is the predominant medicinal product moiety in systemic circulation. At steady state, dehydro-Aripiprazol Sandoz, the active metabolite, represents about 40% of Aripiprazol Sandoz AUC in plasma.
Elimination
The mean elimination half-lives for Aripiprazol Sandoz are approximately 75 hours in extensive metabolisers of CYP2D6 and approximately 146 hours in poor metabolisers of CYP2D6.
The total body clearance of Aripiprazol Sandoz is 0.7 ml/min/kg, which is primarily hepatic.
Following a single oral dose of [14C]-labelled Aripiprazol Sandoz, approximately 27% of the administered radioactivity was recovered in the urine and approximately 60% in the faeces. Less than 1% of unchanged Aripiprazol Sandoz was excreted in the urine and approximately 18% was recovered unchanged in the faeces.
Pharmacokinetics in special patient groups
Paediatric population
The pharmacokinetics of Aripiprazol Sandoz and dehydro-Aripiprazol Sandoz in paediatric patients 10 to 17 years of age were similar to those in adults after correcting for the differences in body weights.
Older people
There are no differences in the pharmacokinetics of Aripiprazol Sandoz between healthy elderly and younger adult subjects, nor is there any detectable effect of age in a population pharmacokinetic analysis in schizophrenic patients.
Gender
There are no differences in the pharmacokinetics of Aripiprazol Sandoz between healthy male and female subjects nor is there any detectable effect of gender in a population pharmacokinetic analysis in schizophrenic patients.
Smoking and Race
Population pharmacokinetic evaluation has revealed no evidence of clinically significant race-related differences or effects from smoking upon the pharmacokinetics of Aripiprazol Sandoz.
Renal impairment
The pharmacokinetic characteristics of Aripiprazol Sandoz and dehydro-Aripiprazol Sandoz were found to be similar in patients with severe renal disease compared to young healthy subjects.
Hepatic impairment
A single-dose study in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetics of Aripiprazol Sandoz and dehydro-Aripiprazol Sandoz, but the study included only 3 patients with Class C liver cirrhosis, which is insufficient to draw conclusions on their metabolic capacity.
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.
Suicidality
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. Close supervision of high-risk patients should accompany antipsychotic treatment.
Cardiovascular disorders
Aripiprazole 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 medicinal products) or hypertension, including accelerated or malignant. Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. 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.
QT prolongation
In clinical trials of aripiprazole, the incidence of QT prolongation was comparable to placebo. Aripiprazole should be used with caution in patients with a family history of QT prolongation.
Tardive dyskinesia
In clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can 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 aripiprazole, dose reduction and close clinical monitoring should be considered.
Neuroleptic Malignant Syndrome (NMS)
NMS is a potentially fatal symptom complex associated with antipsychotics. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. 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 antipsychotics, including aripiprazole, must be discontinued.
Seizure
In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures.
Elderly patients with dementia-related psychosis
Increased mortality
In three placebo-controlled trials (n = 938; mean age: 82.4 years; range: 56-99 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.
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: 78-88 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.
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. 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 any antipsychotics, including aripiprazole, 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.
Hypersensitivity
Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole.
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, poorly managed life-style, and 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.
Dysphagia
Oesophageal dysmotility and aspiration have been associated with the use of antipsychotics, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for 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 aripiprazole. 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. 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.
Phenylketonurics
Aripiprazol Sandoz orodispersible tablets contain aspartame, a source of phenylalanine which may be harmful for people with phenylketonuria.
Lactose
Aripiprazol Sandoz orodispersible tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
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 and stimulants; therefore, extreme caution should be taken when these medicinal products are co-administered.
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.
Use in patients who are in an acutely agitated or severely psychotic state
Aripiprazol Sandoz should not be used to manage acutely agitated or severely psychotic states when immediate symptom control is warranted.
Suicidality
The occurrence of suicidal behaviour is inherent in psychotic illnesses, and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole. Close supervision of high risk patients should accompany antipsychotic treatment.
Cardiovascular disorders
Aripiprazole 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 medicinal products) or hypertension, including accelerated or malignant. Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. 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.
QT prolongation
In clinical trials of treatment with oral aripiprazole, the incidence of QT prolongation was comparable to placebo. Aripiprazole should be used with caution in patients with a family history of QT prolongation.
Tardive dyskinesia
In clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, dose reduction or discontinuation should be considered. 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. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. 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 antipsychotics, including aripiprazole, must be discontinued.
Seizure
In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures.
Elderly patients with dementia-related psychosis
Increased mortality
In three placebo-controlled trials of oral aripiprazole in elderly patients with psychosis associated with Alzheimer's disease (n = 938; mean age: 82.4 years; range: 56-99 years), patients treated with aripiprazole were at an increased risk of death compared to placebo. The rate of death in oral aripiprazole-treated patients was 3.5 % compared to 1.7 % in placebo. 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.
Cerebrovascular adverse reactions
In the same trials with oral aripiprazole, cerebrovascular adverse reactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78-88 years). Overall, 1.3 % of oral 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.
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. 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 any antipsychotics, including aripiprazole, 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.
Hypersensitivity
Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole.
Weight gain
Weight gain is commonly seen in schizophrenic patients due to use of antipsychotics known to cause weight gain, co-morbidities, poorly managed life-style and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed oral 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.
Dysphagia
Oesophageal dysmotility and aspiration have been associated with the use of antipsychotics, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for 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 aripiprazole. 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. 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.
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.
Use in patients who are in an acutely agitated or severely psychotic state
Abilify Maintena should not be used to manage acutely agitated or severely psychotic states when immediate symptom control is warranted.
Suicidality
The occurrence of suicidal behaviour is inherent in psychotic illnesses, and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole. Close supervision of high risk patients should accompany antipsychotic treatment.
Cardiovascular disorders
Aripiprazole 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 medicinal products) or hypertension, including accelerated or malignant. Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. 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.
QT prolongation
In clinical trials of treatment with oral aripiprazole, the incidence of QT prolongation was comparable to placebo. Aripiprazole should be used with caution in patients with a family history of QT prolongation.
Tardive dyskinesia
In clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, dose reduction or discontinuation should be considered. 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. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. 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 antipsychotics, including aripiprazole, must be discontinued.
Seizure
In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures.
Elderly patients with dementia-related psychosis
Increased mortality
In three placebo-controlled trials of oral aripiprazole in elderly patients with psychosis associated with Alzheimer's disease (n = 938; mean age: 82.4 years; range: 56-99 years), patients treated with aripiprazole were at an increased risk of death compared to placebo. The rate of death in oral aripiprazole-treated patients was 3.5 % compared to 1.7 % in placebo. 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.
Cerebrovascular adverse reactions
In the same trials with oral aripiprazole, cerebrovascular adverse reactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78-88 years). Overall, 1.3 % of oral 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.
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. 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 any antipsychotics, including aripiprazole, 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.
Hypersensitivity
Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole.
Weight gain
Weight gain is commonly seen in schizophrenic patients due to use of antipsychotics known to cause weight gain, co-morbidities, poorly managed life-style and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed oral 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.
Dysphagia
Oesophageal dysmotility and aspiration have been associated with the use of antipsychotics, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for 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 aripiprazole. 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. 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.
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.
Suicidality
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. Close supervision of high-risk patients should accompany antipsychotic treatment.
Cardiovascular disorders
Aripiprazole 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 medicinal products) or hypertension, including accelerated or malignant. Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. 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.
QT prolongation
In clinical trials of aripiprazole, the incidence of QT prolongation was comparable to placebo. Aripiprazole should be used with caution in patients with a family history of QT prolongation.
Tardive dyskinesia
In clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can 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 aripiprazole, dose reduction and close clinical monitoring should be considered.
Neuroleptic Malignant Syndrome (NMS)
NMS is a potentially fatal symptom complex associated with antipsychotics. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. 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 antipsychotics, including aripiprazole, must be discontinued.
Seizure
In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures.
Elderly patients with dementia-related psychosis
Increased mortality
In three placebo-controlled trials (n = 938; mean age: 82.4 years; range: 56-99 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.
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: 78-88 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.
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. 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 any antipsychotics, including aripiprazole, 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.
Hypersensitivity
Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole.
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, poorly managed life-style, and 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.
Dysphagia
Oesophageal dysmotility and aspiration have been associated with the use of antipsychotics, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for 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 aripiprazole. 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. 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.
Phenylketonurics
ABILIFY orodispersible tablets contain aspartame, a source of phenylalanine which may be harmful for people with phenylketonuria.
Lactose
ABILIFY orodispersible tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
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 and stimulants; therefore, extreme caution should be taken when these medicinal products are co-administered.
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.
Suicidality:
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 therapy, including treatment with Aripiprazol Sandoz. Close supervision of high-risk patients should accompany antipsychotic therapy. Results of an epidemiological study suggested that there was no increased risk of suicidality with Aripiprazol Sandoz compared to other antipsychotics among adult patients with schizophrenia or bipolar disorder. There are insufficient paediatric data to evaluate this risk in younger patients (below 18 years of age), but there is evidence that the risk of suicide persists beyond the first 4 weeks of treatment for atypical antipsychotics, including Aripiprazol Sandoz.
Cardiovascular disorders:
Aripiprazol Sandoz 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 medicinal products) or hypertension, including accelerated or malignant.
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. 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 Aripiprazol Sandoz and preventive measures undertaken.
Conduction abnormalities:
In clinical trials of Aripiprazol Sandoz, the incidence of QT prolongation was comparable to placebo. As with other antipsychotics, Aripiprazol Sandoz should be used with caution in patients with a family history of QT prolongation.
Tardive dyskinesia:
In clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with Aripiprazol Sandoz. If signs and symptoms of tardive dyskinesia appear in a patient on Aripiprazol Sandoz, dose reduction or discontinuation should be considered.These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.
Other extrapyramidal symptoms:
In paediatric clinical trials of Aripiprazol Sandoz akathisia and parkinsonism were observed. If signs and symptoms of other EPS appear in a patient taking Aripiprazol Sandoz, dose reduction and close clinical monitoring should be considered.
Neuroleptic Malignant Syndrome (NMS):
NMS is a potentially fatal symptom complex associated with antipsychotic medicinal products. In clinical trials, rare cases of NMS were reported during treatment with Aripiprazol Sandoz. 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 medicinal products, including Aripiprazol Sandoz, must be discontinued.
Seizure:
In clinical trials, uncommon cases of seizure were reported during treatment with Aripiprazol Sandoz.
Therefore, Aripiprazol Sandoz should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures.
Elderly patients with dementia-related psychosis:
Increased mortality:
In three placebo-controlled trials (n= 938; mean age: 82.4 years; range: 56-99 years) of Aripiprazol Sandoz in elderly patients with psychosis associated with Alzheimer's disease, patients treated with Aripiprazol Sandoz were at increased risk of death compared to placebo. The rate of death in Aripiprazol Sandoz-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.
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: 78-88 years). Overall, 1.3% of Aripiprazol Sandoz-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 Aripiprazol Sandoz.
Aripiprazol Sandoz Milpharm is not indicated for the treatment of 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 antipsychotic agents, including Aripiprazol Sandoz. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with Aripiprazol Sandoz, 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 Aripiprazol Sandoz and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including Aripiprazol Sandoz, 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.
Hypersensitivity:
As with other medicinal products, hypersensitivity reactions, characterised by allergic symptoms, may occur with Aripiprazol Sandoz.
Weight gain:
Weight gain is commonly seen in schizophrenic and bipolar mania patients due to comorbidities, use of antipsychotics known to cause weight gain, poorly managed life-style, and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed Aripiprazol Sandoz. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials Aripiprazol Sandoz has not been shown to induce clinically relevant weight gain in adults. In clinical trials of adolescent patients with bipolar mania, Aripiprazol Sandoz 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.
Dysphagia:
Oesophageal dysmotility and aspiration have been associated with antipsychotic treatment, including Aripiprazol Sandoz. Aripiprazol Sandoz and other antipsychotic active substances should be used cautiously in patients at risk for aspiration pneumonia.
Pathological gambling:
Post-marketing reports of pathological gambling have been reported among patients prescribed Aripiprazol Sandoz, regardless of whether these patients had a prior history of gambling. Patients with a prior history of pathological gambling may be at increased risk and should be monitored carefully.
Lactose:
Aripiprazol Sandoz Milpharm tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
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 Aripiprazol Sandoz and stimulants; therefore, extreme caution should be taken when these drugs are co-administered.
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.
Suicidality
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. Close supervision of high-risk patients should accompany antipsychotic treatment.
Cardiovascular disorders
Aripiprazole 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 medicinal products) or hypertension, including accelerated or malignant.
Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. 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.
QT prolongation
In clinical trials of aripiprazole, the incidence of QT prolongation was comparable to placebo. A, aripiprazole should be used with caution in patients with a family history of QT prolongation.
Tardive dyskinesia
In clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can 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 aripiprazole, dose reduction and close clinical monitoring should be considered.
Neuroleptic Malignant Syndrome (NMS)
NMS is a potentially fatal symptom complex associated with antipsychotics. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. 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 antipsychotics, including aripiprazole, must be discontinued.
Seizure
In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures.
Elderly patients with dementia-related psychosis
Increased mortality
In three placebo-controlled trials (n = 938; mean age: 82.4 years; range: 56-99 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.
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: 78-88 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.
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. 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 any antipsychotics, including aripiprazole, 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.
Hypersensitivity
Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole.
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, poorly managed life-style, and 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.
Dysphagia
Oesophageal dysmotility and aspiration have been associated with the use of antipsychotics, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for 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 aripiprazole. 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. 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.
Lactose
Aripiprazol Sandoz contains lactose. Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
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 and stimulants; therefore, extreme caution should be taken when these medicinal products are co-administered.
As with other antipsychotics, patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that Aripiprazol Sandoz does not affect them adversely. Some paediatric patients with Bipolar I Disorder have an increased incidence of somnolence and fatigue.
Posology
Adults
Schizophrenia: the recommended starting dose for Aripiprazol Sandoz 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. Aripiprazol Sandoz is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a 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.
Manic episodes in Bipolar I Disorder: the recommended starting dose for Aripiprazol Sandoz is 15 mg administered on a once-a-day schedule without regard to meals as monotherapy or combination therapy. 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 as monotherapy or combination therapy, continue therapy at the same dose. Adjustments of daily dosage, including dose reduction should be considered on the basis of clinical status.
Paediatric population
Schizophrenia in adolescents aged 15 years and older: the recommended dose for Aripiprazol Sandoz is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using Aripiprazol Sandoz oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg. Aripiprazol Sandoz is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated although individual patients may benefit from a higher dose.
Aripiprazol Sandoz is not recommended for use in patients with schizophrenia below 15 years of age due to insufficient data on safety and efficacy.
Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older: the recommended dose for Aripiprazol Sandoz is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using Aripiprazol Sandoz oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. The treatment duration should be the minimum necessary for symptom control and must not exceed 12 weeks. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated, and a daily dose of 30 mg is associated with a substantially higher incidence of significant adverse reactions including EPS related events, somnolence, fatigue and weight gain. Doses higher than 10 mg/day should therefore only be used in exceptional cases and with close clinical monitoring. Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, Aripiprazol Sandoz is not recommended for use in patients below 13 years of age.
Irritability associated with autistic disorder: the safety and efficacy of Aripiprazol Sandoz in children and adolescents aged below 18 years have not yet been established.
Tics associated with Tourette's disorder: the safety and efficacy of Aripiprazol Sandoz in children and adolescents 6 to 18 years of age have not yet been established.
Special populations
Hepatic impairment
No dosage adjustment is required for patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients dosing should be managed cautiously. However, the maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment.
Renal impairment
No dosage adjustment is required in patients with renal impairment.
Elderly
The safety and efficacy of Aripiprazol Sandoz in the treatment of schizophrenia or manic episodes in Bipolar I Disorder in patients aged 65 years and older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant.
Gender
No dosage adjustment is required for female patients as compared to male patients.
Smoking status
According to the metabolic pathway of aripiprazole no dosage adjustment is required for smokers.
Dose adjustments due to interactions
When concomitant administration of strong CYP3A4 or CYP2D6 inhibitors with aripiprazole occurs, the aripiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased.
When concomitant administration of strong CYP3A4 inducers with aripiprazole occurs, the aripiprazole dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should then be reduced to the recommended dose.
Method of administration
Aripiprazol Sandoz 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.
Orodispersible tablets or oral solution may be used as an alternative to Aripiprazol Sandoz tablets for patients who have difficulty swallowing Aripiprazol Sandoz tablets.
Posology
For patients who have never taken aripiprazole, tolerability with oral aripiprazole must occur prior to initiating treatment with Aripiprazol Sandoz.
The recommended starting and maintenance dose of Aripiprazol Sandoz is 400 mg.
Titration of the dose of this medicinal product is not required. It should be administered once monthly as a single injection (no sooner than 26 days after the previous injection).
After the first injection, treatment with 10 mg to 20 mg oral aripiprazole should be continued for 14 consecutive days to maintain therapeutic aripiprazole concentrations during initiation of therapy.
If there are adverse reactions with the 400 mg dosage, reduction of the dose to 300 mg once monthly should be considered.
Missed doses
| Missed doses | |
| If 2nd or 3rd dose is missed and time since last injection is: | Action |
| > 4 weeks and < 5 weeks | The injection should be administered as soon as possible and then resume monthly injection schedule. |
| > 5 weeks | Concomitant oral aripiprazole should be restarted for 14 days with next administered injection and then resume monthly injection schedule. |
| If 4th or subsequent doses are missed (i.e., after attainment of steady state) and time since last injection is: | Action |
| > 4 weeks and < 6 weeks | The injection should be administered as soon as possible and then resume monthly injection schedule. |
| > 6 weeks | Concomitant oral aripiprazole should be restarted for 14 days with next administered injection and then resume monthly injection schedule. |
Special populations
Elderly
The safety and efficacy of Aripiprazol Sandoz in the treatment of schizophrenia in patients 65 years of age or older has not been established.
Renal impairment
No dosage adjustment is required for patients with renal impairment.
Hepatic impairment
No dosage adjustment is required for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients dosing should be managed cautiously. Oral formulation should be preferred.
Known CYP2D6 poor metabolisers
In patients who are known to be CYP2D6 poor metabolisers, the starting and maintenance dose should be 300 mg. When used concomitantly with strong CYP3A4 inhibitors the dose should be reduced to 200 mg.
Dose adjustments due to interactions
Dosage adjustments should be made in patients taking concomitant strong CYP3A4 inhibitors or strong CYP2D6 inhibitors for more than 14 days. If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the dosage may need to be increased to the previous dose. In case of adverse reactions despite dose adjustments of Aripiprazol Sandoz, the necessity of concomitant use of CYP2D6 or CYP3A4 inhibitor should be reassessed.
Concomitant use of CYP3A4 inducers with Aripiprazol Sandoz should be avoided for more than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels.
Dose adjustments of Aripiprazol Sandoz in patients who are taking concomitant strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, and/or CYP3A4 inducers for more than 14 days
| Adjusted dose | |
| Patients taking 400 mg of Aripiprazol Sandoz | |
| Strong CYP2D6 or strong CYP3A4 inhibitors | 300 mg |
| Strong CYP2D6 and strong CYP3A4 inhibitors | 200 mg* |
| CYP3A4 inducers | Avoid use |
| Patients taking 300 mg of Aripiprazol Sandoz | |
| Strong CYP2D6 or strong CYP3A4 inhibitors | 200 mg* |
| Strong CYP2D6 and strong CYP3A4 inhibitors | 160 mg* |
| CYP3A4 inducers | Avoid use |
* 200 mg and 160 mg can be achieved via adjustment of the injection volume only by using Aripiprazol Sandoz powder and solvent for prolonged-release suspension for injection.
Paediatric population
The safety and efficacy of Aripiprazol Sandoz in children and adolescents aged 0-17 years have not been established. No data are available.
Method of administration
Aripiprazol Sandoz is only intended for intramuscular use and should not be administered intravenously or subcutaneously. It should only be administered by a healthcare professional.
Aripiprazol Sandoz powder and solvent for prolonged-release suspension for injection
The suspension should be injected immediately after reconstitution but can be stored below 25 °C for up to 4 hours in the vial.
Aripiprazol Sandoz powder and solvent for prolonged-release suspension for injection in pre-filled syringe
The suspension should be injected immediately after reconstitution but can be stored below 25 °C for up to 2 hours in the syringe.
The suspension should be injected slowly as a single injection (doses must not be divided) into the gluteal or deltoid muscle. Care should be taken to avoid inadvertent injection into a blood vessel.
Gluteal muscle administration
The recommended needle for gluteal administration is a 38 mm (1.5 inch), 22 gauge hypodermic safety needle; for obese patients (Body mass index > 28 kg/m2), a 51 mm (2 inch), 21 gauge hypodermic safety needle should be used. Gluteal injections should be alternated between the two gluteal muscles.
Deltoid muscle administration
The recommended needle for deltoid administration is a 25 mm (1 inch), 23 gauge hypodermic safety needle; for obese patients, a 38 mm (1.5 inch), 22 gauge hypodermic safety needle should be used.
Deltoid injections should be alternated between the two deltoid muscles.
The powder and solvent vials and the pre-filled syringe are for single-use only.
Full instructions for use and handling of Aripiprazol Sandoz are provided in the package leaflet (information intended for healthcare professionals).
Posology
For patients who have never taken aripiprazole, tolerability with oral aripiprazole must occur prior to initiating treatment with Abilify Maintena.
The recommended starting and maintenance dose of Abilify Maintena is 400 mg.
Titration of the dose of this medicinal product is not required. It should be administered once monthly as a single injection (no sooner than 26 days after the previous injection).
After the first injection, treatment with 10 mg to 20 mg oral aripiprazole should be continued for 14 consecutive days to maintain therapeutic aripiprazole concentrations during initiation of therapy.
If there are adverse reactions with the 400 mg dosage, reduction of the dose to 300 mg once monthly should be considered.
Missed doses
| Missed doses | |
| If 2nd or 3rd dose is missed and time since last injection is: | Action |
| > 4 weeks and < 5 weeks | The injection should be administered as soon as possible and then resume monthly injection schedule. |
| > 5 weeks | Concomitant oral aripiprazole should be restarted for 14 days with next administered injection and then resume monthly injection schedule. |
| If 4th or subsequent doses are missed (i.e., after attainment of steady state) and time since last injection is: | Action |
| > 4 weeks and < 6 weeks | The injection should be administered as soon as possible and then resume monthly injection schedule. |
| > 6 weeks | Concomitant oral aripiprazole should be restarted for 14 days with next administered injection and then resume monthly injection schedule. |
Special populations
Elderly
The safety and efficacy of Abilify Maintena in the treatment of schizophrenia in patients 65 years of age or older has not been established.
Renal impairment
No dosage adjustment is required for patients with renal impairment.
Hepatic impairment
No dosage adjustment is required for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients dosing should be managed cautiously. Oral formulation should be preferred.
Known CYP2D6 poor metabolisers
In patients who are known to be CYP2D6 poor metabolisers, the starting and maintenance dose should be 300 mg. When used concomitantly with strong CYP3A4 inhibitors the dose should be reduced to 200 mg.
Dose adjustments due to interactions
Dosage adjustments should be made in patients taking concomitant strong CYP3A4 inhibitors or strong CYP2D6 inhibitors for more than 14 days. If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the dosage may need to be increased to the previous dose. In case of adverse reactions despite dose adjustments of Abilify Maintena, the necessity of concomitant use of CYP2D6 or CYP3A4 inhibitor should be reassessed.
Concomitant use of CYP3A4 inducers with Abilify Maintena should be avoided for more than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels.
Dose adjustments of Abilify Maintena in patients who are taking concomitant strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, and/or CYP3A4 inducers for more than 14 days
| Adjusted dose | |
| Patients taking 400 mg of Abilify Maintena | |
| Strong CYP2D6 or strong CYP3A4 inhibitors | 300 mg |
| Strong CYP2D6 and strong CYP3A4 inhibitors | 200 mg* |
| CYP3A4 inducers | Avoid use |
| Patients taking 300 mg of Abilify Maintena | |
| Strong CYP2D6 or strong CYP3A4 inhibitors | 200 mg* |
| Strong CYP2D6 and strong CYP3A4 inhibitors | 160 mg* |
| CYP3A4 inducers | Avoid use |
* 200 mg and 160 mg can be achieved via adjustment of the injection volume only by using Abilify Maintena powder and solvent for prolonged-release suspension for injection.
Paediatric population
The safety and efficacy of Abilify Maintena in children and adolescents aged 0-17 years have not been established. No data are available.
Method of administration
Abilify Maintena is only intended for intramuscular use and should not be administered intravenously or subcutaneously. It should only be administered by a healthcare professional.
Abilify Maintena powder and solvent for prolonged-release suspension for injection
The suspension should be injected immediately after reconstitution but can be stored below 25 °C for up to 4 hours in the vial.
Abilify Maintena powder and solvent for prolonged-release suspension for injection in pre-filled syringe
The suspension should be injected immediately after reconstitution but can be stored below 25 °C for up to 2 hours in the syringe.
The suspension should be injected slowly as a single injection (doses must not be divided) into the gluteal or deltoid muscle. Care should be taken to avoid inadvertent injection into a blood vessel.
Gluteal muscle administration
The recommended needle for gluteal administration is a 38 mm (1.5 inch), 22 gauge hypodermic safety needle; for obese patients (Body mass index > 28 kg/m2), a 51 mm (2 inch), 21 gauge hypodermic safety needle should be used. Gluteal injections should be alternated between the two gluteal muscles.
Deltoid muscle administration
The recommended needle for deltoid administration is a 25 mm (1 inch), 23 gauge hypodermic safety needle; for obese patients, a 38 mm (1.5 inch), 22 gauge hypodermic safety needle should be used.
Deltoid injections should be alternated between the two deltoid muscles.
The powder and solvent vials and the pre-filled syringe are for single-use only.
Full instructions for use and handling of Abilify Maintena are provided in the package leaflet (information intended for healthcare professionals).
Posology
Adults
Schizophrenia: the recommended starting dose for ABILIFY 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. ABILIFY is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a 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.
Manic episodes in Bipolar I Disorder: the recommended starting dose for ABILIFY is 15 mg administered on a once-a-day schedule without regard to meals as monotherapy or combination therapy. 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 as monotherapy or combination therapy, continue therapy at the same dose. Adjustments of daily dosage, including dose reduction should be considered on the basis of clinical status.
Paediatric population
Schizophrenia in adolescents aged 15 years and older: the recommended dose for ABILIFY is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using ABILIFY oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg. ABILIFY is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated although individual patients may benefit from a higher dose.
ABILIFY is not recommended for use in patients with schizophrenia below 15 years of age due to insufficient data on safety and efficacy.
Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older: the recommended dose for ABILIFY is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using ABILIFY oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. The treatment duration should be the minimum necessary for symptom control and must not exceed 12 weeks. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated, and a daily dose of 30 mg is associated with a substantially higher incidence of significant adverse reactions including EPS related events, somnolence, fatigue and weight gain. Doses higher than 10 mg/day should therefore only be used in exceptional cases and with close clinical monitoring. Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, ABILIFY is not recommended for use in patients below 13 years of age.
Irritability associated with autistic disorder: the safety and efficacy of ABILIFY in children and adolescents aged below 18 years have not yet been established.
Tics associated with Tourette's disorder: the safety and efficacy of ABILIFY in children and adolescents 6 to 18 years of age have not yet been established.
Special populations
Hepatic impairment
No dosage adjustment is required for patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients dosing should be managed cautiously. However, the maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment.
Renal impairment
No dosage adjustment is required in patients with renal impairment.
Elderly
The safety and efficacy of ABILIFY in the treatment of schizophrenia or manic episodes in Bipolar I Disorder in patients aged 65 years and older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant.
Gender
No dosage adjustment is required for female patients as compared to male patients.
Smoking status
According to the metabolic pathway of aripiprazole no dosage adjustment is required for smokers.
Dose adjustments due to interactions
When concomitant administration of strong CYP3A4 or CYP2D6 inhibitors with aripiprazole occurs, the aripiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased.
When concomitant administration of strong CYP3A4 inducers with aripiprazole occurs, the aripiprazole dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should then be reduced to the recommended dose.
Method of administration
ABILIFY 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.
Orodispersible tablets or oral solution may be used as an alternative to ABILIFY tablets for patients who have difficulty swallowing ABILIFY tablets.
Posology
Adults
Schizophrenia: the recommended starting dose for Aripiprazol Sandoz Milpharm 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.
Aripiprazol Sandoz Milpharm is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a 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.
Paediatric population
Other pharmaceutical formulations containing Aripiprazol Sandoz are available and may be more suitable to perform any initial titration in paediatric population.
Schizophrenia in adolescents aged 15 years and older: the recommended dose for Aripiprazol Sandoz is 10 mg/day administered on a once-a-day schedule without regard to meals.
Tics associated with Tourette's disorder: the safety and efficacy of Aripiprazol Sandoz in children and adolescents 6 to 18 years of age have not yet been established.
Patients with hepatic impairment:
No dosage adjustment is required for patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients dosing should be managed cautiously. However, the maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment.
Patients with renal impairment:
No dosage adjustment is required in patients with renal impairment.
Older people:
The effectiveness of Aripiprazol Sandoz in the treatment of schizophrenia in patients aged 65 years and older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant.
Gender:
No dosage adjustment is required for female patients as compared to male patients.
Smoking status:
According to the metabolic pathway of Aripiprazol Sandoz Milpharm no dosage adjustment is required for smokers.
Dose adjustments due to interactions:
When concomitant administration of potent CYP3A4 or CYP2D6 inhibitors with Aripiprazol Sandoz occurs, the Aripiprazol Sandoz dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, Aripiprazol Sandoz dose should then be increased.
When concomitant administration of potent CYP3A4 inducers with Aripiprazol Sandoz occurs, the Aripiprazol Sandoz dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the Aripiprazol Sandoz dose should then be reduced to the recommended dose.
Method of administration
Aripiprazol Sandoz Milpharm tablets are for oral use.
Posology
Adults
Schizophrenia: the recommended starting dose for Aripiprazol Sandoz 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.
Aripiprazol Sandoz is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a 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.
Manic episodes in Bipolar I Disorder: the recommended starting dose for Aripiprazol Sandoz is 15 mg administered on a once-a-day schedule without regard to meals as monotherapy or combination therapy. 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 as monotherapy or combination therapy, continue therapy at the same dose. Adjustments of daily dosage, including dose reduction should be considered on the basis of clinical status.
Paediatric population
Schizophrenia in adolescents aged 15 years and older: the recommended dose for Aripiprazol Sandoz is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using aripiprazole oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg.
Aripiprazol Sandoz is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated although individual patients may benefit from a higher dose.
Aripiprazol Sandoz is not recommended for use in patients with schizophrenia below 15 years of age due to insufficient data on safety and efficacy.
Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older: the recommended dose for Aripiprazol Sandoz is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using aripiprazole oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg.
The treatment duration should be the minimum necessary for symptom control and must not exceed 12 weeks. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated, and a daily dose of 30 mg is associated with a substantially higher incidence of significant adverse reactions including EPS related events, somnolence, fatigue and weight gain. Doses higher than 10 mg/day should therefore only be used in exceptional cases and with close clinical monitoring.
Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, Aripiprazol Sandoz is not recommended for use in patients below 13 years of age.
Irritability associated with autistic disorder: the safety and efficacy of Aripiprazol Sandoz in children and adolescents aged below 18 years have not yet been established.
Tics associated with Tourette's disorder: the safety and efficacy of Aripiprazol Sandoz in children and adolescents 6 to 18 years of age have not yet been established.
Special population
Hepatic impairment
No dosage adjustment is required for patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients dosing should be managed cautiously. However, the maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment.
Renal impairment
No dosage adjustment is required in patients with renal impairment.
Elderly
The safety and efficacy of Aripiprazol Sandoz in the treatment of schizophrenia or manic episodes inBipolar I Disorder in patients aged 65 years and older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant.
Gender
No dosage adjustment is required for female patients as compared to male patients.
Smoking status
According to the metabolic pathway of aripiprazole no dosage adjustment is required for smokers.
Dose adjustments due to interactions
When concomitant administration of strong CYP3A4 or CYP2D6 inhibitors with aripiprazole occurs, the aripiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased.
When concomitant administration of strong CYP3A4 inducers with aripiprazole occurs, the aripiprazole dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should then be reduced to the recommended dose.
Method of administration
Aripiprazol Sandoz is for oral use.
Any unused product or waste material should be disposed of in accordance with local requirements.
Any unused medicinal product or waste material must be disposed of in accordance with local requirements.
