Pipzol 5
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INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Pipzol 5, Pipzol 10, Pipzol 15, Pipzol 30 (Pipzol 5, Pipzol 10, Pipzol 15, Pipzol 30)
Composition:
Active substance: aripiprazole;
1 tablet contains aripiprazole 5 mg or 10 mg or 15 mg or 30 mg;
Excipients: lactose monohydrate, microcrystalline cellulose, hydroxypropylcellulose, corn starch, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, colorants: indigo carmine (E 132) (for 5 mg); iron oxide yellow (E 172) (for 15 mg); iron oxide red (E 172) (for 10 mg and 30 mg).
Pharmaceutical form. Tablets.
Main physicochemical properties:
- 5 mg tablets: rectangular tablets with rounded edges, blue in color with specks, embossed with "250" on one side and smooth on the other;
- 10 mg tablets: rectangular tablets with rounded edges, pink in color with specks, embossed with "252" on one side and smooth on the other;
- 15 mg tablets: round yellow tablets with specks, beveled edges, embossed with "253" on one side and smooth on the other;
- 30 mg tablets: round pink tablets with specks, beveled edges, embossed with "L 255" on one side and smooth on the other.
Pharmacotherapeutic group. Antipsychotic agents (neuroleptics). Aripiprazole.
ATC code N05A X12.
Pharmacological Properties.
Pharmacodynamics.
The therapeutic effect of aripiprazole in schizophrenia is mediated by a combination of partial agonist activity at D2 dopamine and 5HT1a serotonin receptors and antagonist activity at 5HT2 serotonin receptors.
Aripiprazole has high in vitro affinity for D2 and D3 dopamine receptors, 5HT1a and 5HT2a serotonin receptors, and moderate affinity for D4 dopamine receptors, 5HT2c and 5HT7 serotonin receptors, alpha-1 adrenergic receptors, and H1 histamine receptors. Aripiprazole also exhibits moderate affinity for serotonin reuptake sites and lacks affinity for muscarinic receptors. In animal experiments, aripiprazole demonstrated antagonism toward dopaminergic hyperactivity and agonism toward dopaminergic hypoactivity. The clinical effects of aripiprazole can be explained by its interactions not only with dopamine and serotonin receptors.
Aripiprazole administered to healthy subjects at doses of 0.5 to 30 mg once daily for 2 weeks resulted in a dose-dependent reduction in binding of 11C-raclopride, a D2/D3 receptor ligand, in the caudate nucleus and putamen as measured by positron emission tomography.
Clinical Efficacy
Schizophrenia
It is known that aripiprazole is effective in maintaining clinical improvement during continued treatment in adult patients who initially responded to therapy.
Manic Episodes in Bipolar I Disorder
Aripiprazole has demonstrated superior efficacy compared to placebo in reducing manic symptoms over 3 weeks.
Clinical studies have reported that in patients with manic or mixed episodes of Bipolar I Disorder, with or without psychotic features, aripiprazole showed significant efficacy compared to placebo at 3 weeks and maintained efficacy comparable to lithium or haloperidol at 12 weeks. Aripiprazole also demonstrated a comparable proportion of patients achieving symptomatic remission from mania as lithium or haloperidol at 12 weeks.
Additionally, it has been shown that adding aripiprazole as adjunctive therapy leads to greater efficacy in reducing manic symptoms compared to monotherapy with lithium or valproate.
Aripiprazole has been confirmed to have an advantage over placebo in preventing bipolar relapse, particularly in preventing manic relapses.
Data indicate that aripiprazole demonstrated superiority over placebo, reducing the risk of bipolar relapse by 46% and the risk of manic relapse by 65% compared to adjunctive placebo, although superiority over placebo in preventing depressive relapse was not demonstrated.
Adjunctive aripiprazole showed superiority over placebo on secondary outcome measures of the "Clinical Global Impressions - Bipolar Version (CGI-BP)" Severity of Illness (SOI; mania).
In an open-label study with lithium or valproate to assess partial non-response, Kaplan-Meier estimates of relapse into any mood episode were 16% in the aripiprazole + lithium group and 18% in the aripiprazole + valproate group, compared to 45% in the placebo + lithium group and 19% in the placebo + valproate group.
Pharmacokinetics.
Absorption
Aripiprazole is well absorbed, and peak plasma concentrations occur within 3–5 hours after dosing. Aripiprazole undergoes minimal presystemic metabolism. The absolute bioavailability of the tablet formulation is 87%. A high-fat meal does not affect the pharmacokinetic properties of aripiprazole.
Distribution
Aripiprazole is widely distributed in body tissues. The volume of distribution is 4.9 L/kg, indicating extensive extravascular distribution. At therapeutic concentrations, more than 99% of aripiprazole and dehydro-aripiprazole are protein-bound in plasma, primarily to albumin.
Metabolism
Aripiprazole is extensively metabolized in the liver, primarily via three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. In vitro studies indicate that CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, while N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant active compound in systemic circulation. At steady state, dehydro-aripiprazole, an active metabolite, accounts for approximately 40% of the AUC of aripiprazole in plasma.
Elimination
The mean elimination half-life of aripiprazole is approximately 75 hours in CYP2D6 extensive metabolizers and approximately 146 hours in CYP2D6 poor metabolizers.
The total clearance of aripiprazole is 0.7 mL/min/kg, primarily occurring in the liver. After a single oral dose of aripiprazole, approximately 27% is excreted in urine and approximately 60% in feces. Less than 1% of unchanged aripiprazole is excreted in urine, and about 18% of the administered dose is excreted unchanged in feces.
Elderly Patients
No differences in the pharmacokinetic properties of aripiprazole have been observed between healthy elderly and younger subjects. There is no notable effect of patient age on pharmacokinetic analysis in patients with schizophrenia.
Gender
No differences in the pharmacokinetic properties of aripiprazole have been observed between healthy male and female subjects. There is no notable effect of gender on pharmacokinetic analysis in patients with schizophrenia.
Smoking
Assessment of patient groups revealed no evidence of clinically significant effects of smoking on the pharmacokinetic properties of aripiprazole.
Race
Assessment of patient groups revealed no evidence of clinically significant effects of race on the pharmacokinetic properties of aripiprazole.
Renal Impairment
The pharmacokinetic characteristics of aripiprazole and hydro-aripiprazole were found to be similar in patients with acute renal disease compared to young healthy individuals.
Hepatic Impairment
A single-dose clinical study in patients with varying degrees of hepatic cirrhosis (Child-Pugh classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetic properties of aripiprazole and hydro-aripiprazole. However, the study included only three patients with Child-Pugh class C cirrhosis, which is insufficient to draw conclusions about their metabolic capacity.
Clinical characteristics.
Indications.
Treatment of schizophrenia in adults.
Treatment of moderate to severe manic episodes in bipolar I disorder, and prevention of recurrent manic episodes in adults who have previously experienced manic episodes and responded to treatment with aripiprazole.
Contraindications.
Hypersensitivity to aripiprazole or to any other component of the medicinal product.
Interaction with other medicinal products and other forms of interaction.
Due to antagonism at α1-adrenergic receptors, aripiprazole may enhance the effect of certain antihypertensive agents.
Since aripiprazole affects the central nervous system (CNS), caution should be exercised when co-administering alcohol or other CNS-acting drugs due to possible additive adverse reactions, such as sedative effects (see section "Adverse reactions").
Aripiprazole should be used with caution in combination with other medicinal products that prolong the QT interval or disrupt electrolyte balance.
Potential influence of other medicinal products on the effect of aripiprazole.
The H2-histamine receptor antagonist and gastric acid secretion inhibitor famotidine reduces the absorption rate of aripiprazole, but this effect is not considered clinically significant.
Aripiprazole is metabolized via multiple pathways involving CYP2D6 and CYP3A4 enzymes, but not CYP1A enzymes. Therefore, dose adjustment is not required in smokers.
Quinidine and other CYP2D6 inhibitors.
In studies conducted in healthy volunteers, potent inhibitors of the CYP2D6 isoenzyme (quinidine) increased the AUC of aripiprazole by 107%, while Cmax remained unchanged. AUC and Cmax of dehydroaripiprazole, the active metabolite, decreased by 32% and 47%, respectively. Therefore, the dose of aripiprazole should be reduced by approximately half when co-administered with quinidine. Other potent CYP2D6 inhibitors, such as fluoxetine and paroxetine, are likely to have a similar effect; hence, a comparable dose reduction is necessary.
Ketoconazole and other CYP3A4 inhibitors.
In studies conducted in healthy volunteers, the potent CYP3A4 inhibitor ketoconazole increased the AUC and Cmax of aripiprazole by 63% and 37%, respectively. AUC and Cmax of dehydroaripiprazole increased by 77% and 43%, respectively. In individuals with reduced CYP2D6 metabolism, concomitant use of potent CYP3A4 inhibitors may result in higher plasma concentrations of aripiprazole compared to those in patients with normal CYP2D6 metabolism. When co-administration of ketoconazole or other potent CYP3A4 inhibitors with aripiprazole is necessary, the potential benefits should outweigh the possible risks to the patient. When aripiprazole is co-administered with ketoconazole, the dose of aripiprazole should be reduced by approximately half. Other potent CYP3A4 inhibitors, such as itraconazole and HIV protease inhibitors, may theoretically produce similar effects; therefore, dose adjustments are required (see section "Dosage and administration").
After discontinuation of a CYP2D6 or CYP3A4 inhibitor, the aripiprazole dose should be increased to the level used prior to initiation of concomitant therapy.
A slight increase in plasma concentrations of aripiprazole may occur when co-administered with weak CYP3A4 inhibitors (e.g., diltiazem) or weak CYP2D6 inhibitors (e.g., escitalopram).
Carbamazepine and other CYP3A4 inducers.
When co-administered with carbamazepine, a potent CYP3A4 inducer, geometric mean Cmax and AUC of oral aripiprazole in patients with schizophrenia and schizoaffective disorder were 68% and 73% lower, respectively, compared to monotherapy with aripiprazole 30 mg. Geometric mean Cmax and AUC of dehydroaripiprazole decreased by 69% and 71%, respectively, during co-administration with carbamazepine compared to aripiprazole monotherapy.
The dose of aripiprazole should be doubled when co-administered with carbamazepine. Concomitant use of aripiprazole with other potent CYP3A4 inducers (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine, and St. John’s wort) is theoretically expected to have a similar effect; therefore, appropriate dose increases are required. After discontinuation of potent CYP3A4 inducers, the aripiprazole dose should be reduced to the recommended level.
Valproate and lithium.
No clinically significant changes in aripiprazole concentrations were observed when valproate or lithium were co-administered with aripiprazole; therefore, dose adjustment is not required.
Potential effect of aripiprazole on the action of other medicinal products.
In clinical studies, aripiprazole at doses of 10–30 mg/day did not cause clinically relevant drug interactions mediated by CYP2D6 (dextromethorphan/3-methoxymorphine ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), or CYP3A4 (dextromethorphan). Additionally, aripiprazole and dehydroaripiprazole have not been shown to affect CYP1A2-mediated metabolism in vitro. Therefore, it is unlikely that aripiprazole exerts a clinically significant effect on substances metabolized by this enzyme.
No clinically significant changes in plasma concentrations of valproate, lithium, or lamotrigine were observed when co-administered with aripiprazole.
Serotonin syndrome.
Cases of serotonin syndrome have been reported in patients receiving aripiprazole, particularly when used concomitantly with other serotonergic agents such as SSRIs (selective serotonin reuptake inhibitors) or SNRIs (serotonin-norepinephrine reuptake inhibitors), or with drugs that increase aripiprazole concentrations (see section "Adverse reactions").
Special precautions for use.
Improvement of the patient's clinical condition during antipsychotic treatment may take from several days to several weeks. During this period, careful monitoring of patients is required.
Suicidal tendencies.
Suicidal behavior is characteristic of patients with psychotic disorders and mood disturbances, and has been observed shortly after initiation of antipsychotic therapy or switching from one antipsychotic to another, including treatment with aripiprazole (see section "Adverse reactions"). Antipsychotic treatment should be accompanied by careful monitoring of patients belonging to high-risk groups.
Cardiovascular disorders.
Aripiprazole should be used with caution in patients with a history of cardiovascular diseases (myocardial infarction or ischemic heart disease, heart failure, or conduction disorders), cerebrovascular disorders, conditions predisposing patients to hypotension (dehydration, hypovolemia, use of antihypertensive medicinal products) or hypertension, including progressive or malignant hypertension.
Cases of venous thromboembolism (VTE) have been observed during antipsychotic treatment.
Since patients taking antipsychotics often have acquired risk factors for VTE, all possible VTE risk factors should be identified before and during aripiprazole treatment, and all preventive measures should be taken.
Prolongation of QT interval.
Caution should be exercised when administering aripiprazole to patients with a family history of QT interval prolongation (see section "Adverse reactions").
Tardive dyskinesia.
Tardive dyskinesia symptoms have been rarely reported in patients treated with aripiprazole for periods up to one year. If symptoms of tardive dyskinesia occur in a patient receiving aripiprazole, dose reduction or discontinuation of treatment should be considered (see section "Adverse reactions"). These symptoms may transiently worsen or even emerge after discontinuation of treatment.
Other extrapyramidal symptoms.
Akathisia and parkinsonism have been observed during aripiprazole use in children. If signs of other extrapyramidal symptoms occur, dose reduction should be considered and careful clinical monitoring of the patient should be maintained.
Malignant neuroleptic syndrome (MNS).
MNS is a syndrome complex associated with the use of antipsychotic medicinal products, which may potentially be fatal. Cases of MNS development were rare in clinical studies of aripiprazole. Clinical manifestations of MNS include hyperpyrexia (extremely high body temperature), muscular rigidity, altered mental status, and signs of autonomic nervous system dysfunction (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmia). Additional signs may include elevated creatine kinase levels, myoglobinuria (rhabdomyolysis), and acute renal failure. However, isolated cases of increased creatine kinase levels and rhabdomyolysis, not necessarily associated with MNS, have also been observed. If a patient develops symptoms of MNS or unexplained extremely high body temperature without additional clinical signs of MNS, all antipsychotic medicinal products, including aripiprazole, should be discontinued.
Seizures.
Seizures have been observed infrequently during aripiprazole treatment. Therefore, aripiprazole should be used with caution in patients with a history of seizures or conditions associated with seizure occurrence.
Elderly patients with psychosis associated with dementia.
Increased mortality.
When aripiprazole was used in elderly patients (mean age 82 years) with psychosis associated with Alzheimer's disease, the risk of mortality was increased. Although the causes of death varied, most were of cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) origin (see section "Adverse reactions").
Cerebrovascular adverse reactions.
Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatal cases, were observed in elderly patients (mean age − 84 years; range 78−88 years). A strong dose-dependent relationship between aripiprazole use and the occurrence of cerebrovascular adverse reactions was noted in patients receiving the drug.
The medicinal product is not indicated for the treatment of psychosis associated with dementia.
Hyperglycemia and diabetes mellitus.
Hyperglycemia, in some cases extremely severe and associated with ketoacidosis or hyperosmolar coma, including fatal outcomes, has been reported in patients treated with atypical antipsychotics, including aripiprazole. Risk factors for severe complications include obesity and a family history of diabetes. There is no precise comparative assessment of the risks of adverse reactions related to hyperglycemia in patients using aripiprazole versus other atypical antipsychotics. Careful monitoring of patients taking any antipsychotics, including aripiprazole, is necessary, with attention to symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). The condition of patients with diabetes or risk factors for diabetes development should be regularly monitored for increased glucose levels.
Hypersensitivity.
Hypersensitivity reactions characterized by allergic symptoms may develop during aripiprazole use (see section "Adverse reactions").
Weight gain.
Weight gain is frequently observed in patients with schizophrenia and bipolar mania due to comorbid conditions, use of antipsychotics known to cause weight gain, and lack of a healthy lifestyle; this phenomenon may lead to serious complications. During aripiprazole treatment, weight gain has generally been observed in patients with significant risk factors, such as diabetes, thyroid disorders, or pituitary adenoma in their medical history.
Aripiprazole does not cause clinically significant weight gain in adults.
Dysphagia.
Antipsychotics, including aripiprazole, may cause esophageal motility disorders and gastric content aspiration. Aripiprazole and other antipsychotics should be used with caution in patients at increased risk of aspiration pneumonia.
Pathological gambling and other impulse control disorders.
Patients may experience increased episodes of pathological gambling and inability to control these urges during aripiprazole treatment. Cases of hypersexuality, compulsive shopping, binge eating, or uncontrolled eating urges, and other impulse control disorders have also been reported. It is important for physicians to inform patients about the development of new or aforementioned disorders during aripiprazole treatment. It should be noted that impulse control symptoms may be related to the underlying disorder; however, cessation of urges has sometimes been reported upon dose reduction or discontinuation of treatment. Impulse control disorders may harm the patient and others if not recognized. If such tendencies develop during aripiprazole treatment, consideration should be given to dose reduction or discontinuation of treatment (see section "Adverse reactions").
Lactose.
The medicinal product contains lactose. Patients with rare hereditary problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Patients with comorbid ADHD (attention deficit hyperactivity disorder). Despite the high prevalence of comorbid bipolar I disorder and ADHD, safety data on the concomitant use of aripiprazole and stimulants are very limited; therefore, extreme caution is required when prescribing these agents together.
General disorders.
Aripiprazole may cause somnolence, postural hypotension, and motor or sensory instability, which may lead to falls. Caution is advised when treating patients at higher risk, and a lower initial dose should be considered (e.g., elderly or debilitated patients; see section "Dosage and administration").
Use during pregnancy or breastfeeding.
Pregnancy.
There are no adequate and well-controlled studies of aripiprazole use in pregnant women. Congenital anomalies have been reported; however, a causal relationship with aripiprazole could not be established. Animal studies did not exclude a potential adverse effect on fetal development. Patients should be advised to inform their physician if they become pregnant or plan to become pregnant during aripiprazole treatment. Due to insufficient safety data in humans and problems identified in reproductive animal studies, this medicinal product should not be used during pregnancy unless the expected benefit clearly outweighs the potential risk to the fetus.
Newborns whose mothers have taken antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk of developing adverse reactions, including extrapyramidal symptoms and/or withdrawal syndrome, which may vary in severity and duration after birth. Cases of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorders have been reported. Therefore, newborns should be closely monitored.
Breastfeeding.
Aripiprazole passes into breast milk. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from aripiprazole therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.
Fertility.
According to reproductive toxicity studies, aripiprazole does not affect fertility.
Ability to influence reaction speed when driving or operating machinery.
Aripiprazole has a negligible or moderate influence on the ability to drive or operate machinery due to its potential effects on the nervous system and visual organs and the occurrence of adverse reactions such as sedation, somnolence, syncope, blurred vision, and diplopia (see section "Adverse reactions").
Method of Administration and Dosage
Adults
Schizophrenia: The recommended initial dose is 10 or 15 mg/day, with a maintenance dose of 15 mg/day. This dose should be taken once daily, regardless of food intake. The drug is effective within a dosage range of 10 to 30 mg/day. Increased efficacy with daily doses exceeding 15 mg has not been demonstrated, although higher doses may be beneficial for some individual patients.
The maximum daily dose should not exceed 30 mg.
Manic episodes in bipolar I disorder: The recommended initial dose is 15 mg. This dose should be taken once daily, regardless of food intake, either as monotherapy or as part of combination therapy (see section "Pharmacological Properties"). Higher doses may be beneficial for some individual patients. The maximum daily dose should not exceed 30 mg.
Prevention of new manic episodes in bipolar I disorder: To prevent recurrence of manic episodes in patients receiving aripiprazole as monotherapy or combination therapy, treatment should be continued at the same dose. Adjustment of the daily dose, including dose reduction, should be considered based on clinical status.
Special Patient Groups
Hepatic impairment
Dose adjustment is not required in patients with mild or moderate hepatic impairment. There is insufficient data available to make dosage recommendations for patients with severe hepatic impairment. Dosing in these patients should be performed with caution. The maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment (see section "Pharmacological Properties").
Renal impairment
Dose adjustment is not required in patients with renal impairment.
Elderly patients
The safety and efficacy of the drug in treating schizophrenia or manic episodes in bipolar I disorder in patients aged 65 years and older have not been established. Due to increased sensitivity in this patient group, a lower initial dose should be considered when clinical factors are present (see section "Special Warnings and Precautions for Use").
Gender
Female patients do not require dose adjustment compared to male patients (see section "Pharmacokinetics").
Smoking
Due to the metabolic pathway of aripiprazole, dose adjustment for smokers is not required (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").
Dose adjustment due to interactions
When co-administering strong CYP3A4 or CYP2D6 inhibitors with aripiprazole, the dose of aripiprazole should be reduced. If a CYP3A4 or CYP2D6 inhibitor is discontinued from the combination regimen, the aripiprazole dose should be increased (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").
When co-administering strong CYP3A4 inducers with aripiprazole, the dose of aripiprazole should be increased. If a CYP3A4 inducer is discontinued from the combination regimen, the aripiprazole dose should be reduced to the recommended dose (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").
Children
Not recommended for children (under 18 years of age).
Overdose.
Symptoms.
Cases of intentional or accidental acute overdose with aripiprazole at doses up to 1260 mg without fatal outcome have been reported in adult patients. Medically significant observed symptoms included lethargy, elevated blood pressure, somnolence, tachycardia, nausea, vomiting, and diarrhea.
Additionally, cases of accidental overdose with aripiprazole alone (at doses up to 195 mg) in children, without fatal outcome, have been reported. Medically significant observed symptoms included somnolence, transient loss of consciousness, and extrapyramidal symptoms.
Treatment.
Management of overdose should include supportive care, ensuring airway patency, oxygenation, mechanical ventilation if necessary, and control of symptoms. The possibility of overdose with multiple medicinal products should be considered. Therefore, immediate cardiovascular monitoring is required, including continuous ECG monitoring to detect possible arrhythmias.
After confirmed or suspected aripiprazole overdose, careful medical supervision and monitoring of the patient's condition are necessary until full recovery.
Activated charcoal (50 g), administered one hour after aripiprazole intake, reduced the Cmax of aripiprazole by approximately 41% and the AUC by approximately 51%, indicating potential effectiveness of activated charcoal in overdose management.
Hemodialysis.
Although there is no information on the effect of hemodialysis in the treatment of aripiprazole overdose, hemodialysis is unlikely to be beneficial because aripiprazole is highly protein-bound in plasma.
Adverse reactions.
Short summary of safety profile.
The most commonly observed adverse reactions were akathisia and nausea. Each of these symptoms occurred in more than 3% of patients treated with oral aripiprazole.
List of adverse reactions.
All adverse reactions are listed by system organ classes and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency 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 identified during the post-marketing period cannot be estimated because they are derived from spontaneous reports; therefore, the frequency of these adverse reactions is classified as not known.
| System organ class |
Common |
Uncommon |
Frequency not known |
| Blood and lymphatic system disorders |
Leukopenia, neutropenia, thrombocytopenia |
||
| Immune system disorders |
Allergic reactions (e.g. anaphylactic reactions; angioneurotic oedema, including tongue swelling; tongue oedema, facial swelling, pruritus or urticaria) |
||
| Endocrine system disorders |
Hyperprolactinaemia |
Diabetic hyperosmolar coma, diabetic ketoacidosis |
|
| Metabolism and nutrition disorders |
Diabetes mellitus |
Hypoglycaemia |
Hyponatraemia, anorexia, weight decreased, weight increased |
| Psychiatric disorders |
Insomnia, restlessness, agitation |
Depression, hypersexuality |
Suicide attempts, |
| Nervous system disorders |
Akathisia, |
Tardive dyskinesia, |
Neuroleptic malignant syndrome (NMS), grand mal seizure, serotonin syndrome, speech disorder |
| Eye disorders |
Blurred vision |
Diplopia |
Oculogyric crisis |
| Cardiac disorders |
Tachycardia, |
Sudden death, torsades de pointes, QT interval prolongation, ventricular arrhythmia, cardiac arrest, bradycardia |
|
| Vascular disorders |
Orthostatic hypotension |
Venous thromboembolism (including pulmonary embolism and deep vein thrombosis), hypertension, |
|
| Respiratory, thoracic and mediastinal disorders |
Hiccough |
Aspiration pneumonia, laryngospasm, |
|
| Gastrointestinal disorders |
Constipation, dyspepsia, nausea, hypersalivation, vomiting |
Pancreatitis, dysphagia, diarrhoea, gastrointestinal discomfort |
|
| Hepatobiliary disorders |
Hepatic failure, hepatitis, jaundice, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased gamma-glutamyltransferase (GGT), increased alkaline phosphatase |
||
| Skin and subcutaneous tissue disorders |
Rash, photosensitivity reactions, alopecia, increased sweating |
||
| Musculoskeletal and connective tissue disorders |
Rhabdomyolysis, myalgia, |
||
| Renal and urinary disorders |
Urinary incontinence, urinary retention |
||
| Pregnancy, puerperium and perinatal conditions |
Drug withdrawal syndrome in newborns (see section "Use during pregnancy or breastfeeding") |
||
| Reproductive system and breast disorders |
Priapism |
||
| General disorders and administration site conditions |
Fatigue |
Thermoregulatory disorders (e.g. hypothermia, pyrexia), chest pain, peripheral oedema |
|
| Investigations |
Increased blood glucose, increased glycated haemoglobin, fluctuation of blood glucose, increased creatine phosphokinase |
Description of individual adverse reactions
Extrapyramidal symptoms (EPS)
Schizophrenia: In a 52-week long-term controlled study, patients treated with aripiprazole had a lower overall incidence (25.8%) of EPS, including parkinsonism, akathisia, dystonia, and dyskinesia, compared to patients receiving haloperidol (57.3%). In a long-term 26-week placebo-controlled study, the incidence of EPS was 19% for patients treated with aripiprazole and 13.1% for patients receiving placebo. In another long-term 26-week controlled study, the incidence of EPS was 14.8% for patients receiving aripiprazole and 15.1% for patients receiving olanzapine.
Manic episodes in bipolar I disorder: In a controlled 12-week study, the incidence of EPS was 23.5% for patients treated with aripiprazole and 53.3% for patients receiving haloperidol. In another 12-week study, the incidence of EPS was 26.6% for patients receiving aripiprazole and 17.6% for patients receiving lithium. In the long-term 26-week placebo-controlled maintenance phase of the study, the incidence of EPS was 18.2% for patients treated with aripiprazole and 15.7% for patients receiving placebo.
Akathisia
In placebo-controlled studies, the incidence of akathisia in bipolar patients was 12.1% with aripiprazole and 3.2% with placebo. In patients with schizophrenia, the incidence of akathisia was 6.2% with aripiprazole and 3.0% with placebo.
Dystonia
Symptoms of dystonia, characterized by prolonged pathological contraction of muscle groups, may occur in susceptible patients during the first few days of treatment. Dystonic symptoms include neck muscle spasms, sometimes progressing to throat constriction; difficulty in swallowing; breathing difficulties; and/or tongue protrusion. Although these symptoms may occur at low doses, they are more frequent and severe with higher doses of first-generation antipsychotics. The risk of acute dystonia is higher in males and younger age groups.
Prolactin
In clinical trials for approved indications and in post-marketing observations, both increases and decreases in serum prolactin levels compared to baseline have been reported.
Serum prolactin levels were assessed in all trials across all doses of aripiprazole (n = 28,242). The incidence of hyperprolactinemia or elevated serum prolactin levels in patients receiving aripiprazole (0.3%) was similar to that with placebo (0.2%). For patients receiving aripiprazole, the median time to onset was 42 days and the mean duration was 34 days.
The incidence of hypoprolactinemia or decreased serum prolactin levels in patients receiving aripiprazole was 0.4%, compared to 0.02% in patients receiving placebo. For patients receiving aripiprazole, the median time to onset was 30 days and the mean duration was 194 days.
Laboratory findings
Elevated creatine phosphokinase levels, usually transient and asymptomatic, were observed in 3.5% of patients receiving aripiprazole.
Pathological gambling and other impulse control disorders
Pathological gambling, hypersexuality, compulsive shopping, binge eating, or uncontrolled eating urges may occur in patients taking aripiprazole.
Other.
Adverse reactions associated with antipsychotic therapy and reported during treatment with aripiprazole include: neuroleptic malignant syndrome, tardive dyskinesia, seizures, cerebrovascular adverse reactions, increased mortality in elderly patients with dementia; hyperglycemia and diabetes mellitus (see section "Special precautions").
Reporting of suspected adverse reactions
It is important to report suspected adverse reactions during the post-marketing surveillance period. This enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report suspected adverse reactions.
Shelf life. 3 years.
Storage conditions.
Store in the original packaging, protected from light, in a place inaccessible to children, at a temperature not exceeding 25 °C.
Packaging.
10 tablets in a blister. One blister in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
Alembic Pharmaceuticals Limited.
Manufacturer's address.
Panelav, P.O. Tajpura, Taluka Halol, Panchmahal, Gujarat – 389 350, India
Formulation Division, Panelav, P.O. Tajpura, Taluka Halol, Panchmahal, Gujarat, IN - 389350, India.