Summary of medicine characteristics - ARIPIPRAZOLE TORRENT 5 MG TABLETS
1 NAME OF THE MEDICINAL PRODUCT
Aripiprazole Torrent 5 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5 mg of aripiprazole.
For the full list of excipients, see section 6.1.
Tablet
Aripiprazole 5 mg tablets are white to off white, round uncoated tablets debossed with “5” on one side and plain on other side with an approx. diameter of 4.8 mm.
4.1 Therapeutic indications
4.1 Therapeutic indicationsAripiprazole is indicated for the treatment of schizophrenia in adults and in adolescents aged 15 years and older.
4.2 Posology and method of administration
Posology
Adults
Schizophrenia: the recommended starting dose for aripiprazole is 10 or 15 mg/day with a maintenance dose of 15 mg/day administered on a once-a-day schedule without regard to meals.
Aripiprazole 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
Schizophrenia in adolescents aged 15 years and older: the recommended dose for aripiprazole 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 (see section 5.1).
Aripiprazole 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.
Aripiprazole is not recommended for use in patients with schizophrenia below 15 years of age due to insufficient data on safety and efficacy (see sections 4.8 and 5.1).
Irritability associated with autistic disorder: the safety and efficacy of aripiprazole in children and adolescents aged below 18 years have not yet been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made.
Tics associated with Tourette’s disorder: the safety and efficacy of aripiprazole in children and adolescents 6 to 18 years of age have not yet been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made.
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 (see section 5.2). Renal impairment
No dosage adjustment is required in patients with renal impairment.
Elderly
The safety and efficacy of aripiprazole 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 (see section 4.4).
Gender
No dosage adjustment is required for female patients as compared to male patients (see section 5.2).
Smoking status
According to the metabolic pathway of aripiprazole no dosage adjustment is required for smokers (see section 4.5).
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 (see section 4.5).
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 (see section 4.5).
Method of administration
Aripiprazole tablets are for oral use.
Since the tablet is fragile, it should be swallowed immediately with water on removing from the blister.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
4 CLINICAL PARTICULARS
4.5 Interaction with other medicinal products and other forms of interaction
Due to its a1-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive medicinal products.
Given the primary CNS effects of aripiprazole, caution should be used when aripiprazole is administered in combination with alcohol or other CNS medicinal products with overlapping adverse reactions such as sedation (see section 4.8).
If aripiprazole is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used.
A gastric acid blocker, the H2 antagonist famotidine, reduces aripiprazole rate of absorption but this effect is deemed not clinically relevant.
Aripiprazole is metabolised by multiple pathways involving the CYP2D6 and CYP3A4 enzymes but not CYP1A enzymes. Thus, no dosage adjustment is required for smokers.
Quinidine and other CYP2D6 inhibitors
In a clinical trial in healthy subjects, a potent inhibitor of CYP2D6 (quinidine) increased aripiprazole AUC by 107%, while Cmax was unchanged. The AUC and Cmax of dehydro-aripiprazole, the active metabolite, decreased by 32% and 47%, respectively. Aripiprazole dose should be reduced to approximately one-half of its prescribed dose when concomitant administration of aripiprazole with quinidine occurs. Other potent inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose reductions should therefore be applied.
Ketoconazole and other CYP3A4 inhibitors
In a clinical trial in healthy subjects, a strong inhibitor of CYP3A4 (ketoconazole) increased aripiprazole AUC and Cmax by 63% and 37%, respectively. The AUC and Cmax of dehydro-aripiprazole increased by 77% and 43%, respectively. In CYP2D6 poor metabolisers, concomitant use of strong inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazole compared to that in CYP2D6 extensive metabolizers. When considering concomitant administration of ketoconazole or other strong CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the potential risks to the patient. When concomitant administration of ketoconozole with aripiprazole occurs, aripiprazole dose should be reduced to approximately one-half of its prescribed dose. Other strong inhibitors of CYP3A4, such as itraconazole and HIV protease inhibitors, may be expected to have similar effects and similar dose reductions should therefore be applied (see section 4.2).
Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dosage of aripiprazole should be increased to the level prior to the initiation of the concomitant therapy.
When weak inhibitors of CYP3A4 (e.g., diltiazem) or CYP2D6 (e.g. escitalopram) are used concomitantly with aripiprazole, modest increases in plasma aripiprazole concentrations may be expected.
Carbamazepine and other CYP3A4 inducers
Following concomitant administration of carbamazepine, a strong inducer of CYP3A4 and oral aripiprazole to patients with schizophrenia or schizoaffective disorder, the geometric means of Cmax and AUC for aripiprazole were 68% and 73% lower, respectively, compared to when aripiprazole (30 mg) was administered alone. Similarly, for dehydro-aripiprazole the geometric means of Cmax and AUC after carbamazepine coadministration were 69% and 71% lower, respectively, than those following treatment with aripiprazole alone.
Aripiprazole dose should be doubled when concomitant administration of aripiprazole occurs with carbamazepine. Concomitant administration of aripiprazole and other potent inducers of CYP3A4 (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St. John's Wort) may be expected to have similar effects and similar dose increases should therefore be applied. Upon discontinuation of strong CYP3A4 inducers, the dosage of aripiprazole should be reduced to the recommended dose.
Valproate and lithium
When either valproate or lithium was administered concomitantly with aripiprazole, there was no clinically significant change in aripiprazole concentrations and therefore no dose adjustment is necessary when either valproate or lithium is administered with aripiprazole.
4.6 Fertility, pregnancy and lactation
4 CLINICAL PARTICULARS
4.7 Effects on ability to drive and use machines
Aripiprazole has minor to moderate influence on the ability to drive and use machines due to potential nervous system and visual effects, such as sedation, somnolence, syncope, vision blurred, diplopia (see section 4.8).
4.8 Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions in placebo-controlled trials were 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 known“.
| 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 (see section 4.4) Pathological gambling Impulse-control disorders Binge eating Compulsive shopping Poriomania Aggression Agitation Nervousness |
| Nervous system disorders | Akathisia Extrapyramidal disorder Tremor Headache | Tardive dyskinesia Dystonia | Neuroleptic Malignant Syndrome (NMS) Grand mal convulsion Serotonin syndrome |
| Sedation Somnolence Dizziness | Speech disorder | ||
| Eye disorders | Vision blurred | Diplopia Photophobia | Oculogyric crisis |
| 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 (see section 4.6) | ||
| 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 longterm 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 (see section 5.1) 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 undesirable effects 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 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 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 (see section 4.4).
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: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
5 PHARMACOLOGICAL PROPERTIES
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6.1 List of excipients
Mannitol
Crospovidone (Type B)
Silica, colloidal anhydrous
Hydroxypropyl cellulose
Microcrystalline cellulose
Magnesium Stearate
Tartaric acid
Acesulfame potassium
Vanilla flavor including
Nature identical flavourings, natural flavor, maize maltodextrin, modified corn starch, triacetin.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 years
6.4 Special precautions for storage
This medicinal product does not require any special storage condition.
6.5 Nature and contents of container
OPA/Al/PVC/Al-blisters containing 10, 14, 28, 30, 49, 56, 60, 98 or 100 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
6.6 Special precautions for disposalAny unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Torrent Pharma (UK) Ltd.
Unit 4, Charlwood Court
County Oak Way
Crawley
West Sussex
RH11 7XA
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 36687/0073
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
13/07/2020